What you’re saying about Padian et al. just clicked for me. I’d got it into my head that they were allocating each recruited couple to either a retrospective track or a prospective track, with couples switching from the retrospective track to the prospective track after 1990, but without their data being carried over. But you’re saying the couples already enrolled in the study pre-1990 were automatically entered into the prospective part with their earlier questionnaires & lab work retained, right? That’d make more sense than how I first interpreted the paper. (Serves me right for skipping the abstract and diving straight into the methods section. Twice.)
Alright, let’s crunch some numbers.
Abstenence was between 0 and 14.5%, consistent condom use betwen 32% and 74%, and anal between 37 and 8%. We should probably also factor in that condoms are not 100% effective. Lets ignore that for a second and assume midpoints of the above numbers, with around 100 sex acts per year, or 10 per month.
Using the midpoints of the ranges is a good first guess in the absence of other information. However, I think there’s a good reason to use estimates much closer to the follow-up percentages (14.5%, 74% & 8%) than the baseline percentages (0%, 32% & 37%). The prospective results section says that “approximately 97 percent of behavior change was reported between baseline and the first follow-up visit”. That is, when couples started/stopped using condoms consistently (or abstaining, or having anal sex), they almost always did so before their first follow-up visit, suggesting the couples changed their behaviour shortly after counselling, not gradually. If so, then the baseline percentages only represent the couples’ behaviour distribution for a few weeks; after that, the distribution would be much better represented by the rates at final follow-up.
This could have a big impact on the surprisingness of the zero seroconversions result. Switching from the midpoint rates to the final follow-up rates boosts the abstinence rate to 14.5% and the consistent condom use rate to 74%, while cutting the “[a]ny anal intercourse” rate from 22.5% to 8%. So the neither-abstinent-nor-consistently-condom-using rate sinks from 39.7% to 11.5%. Carrying that forward, I get an unsafe act count ≈1600 instead of ≈5600 (assuming 50% condom use in that 11.5% of couples).
That of course makes a big difference: with a 0.1% risk per act (and I’d peg the risk as being far closer to 0.1% than 0.5%, given the low rate of couples admitting to any anal sex, let alone repeated anal sex), 1600 sex acts have a 20% chance of not causing any transmissions, but 5000 sex acts have only a 0.03% chance. Evidently the unlikeliness of getting no seroconversions under a hypothesis of low-but-nonzero transmission rates hinges on the numerical assumptions made about sexual behaviours. (And there are yet more tweaks one could make to the numbers: whether to adjust for the couples that were female HIV+ instead of male HIV+, how much to adjust for condom unreliability, how much to adjust for the time lag between HIV infection and showing up as HIV+ on a blood test, and so on.) A claim that HIV isn’t an STI is a hefty claim to hang on this single result.
Sure it would have been better with 10,000 couples over many years, but how much specific negative evidence for sexual transmission does one require?
If I’m remembering correctly, the only pieces of specific negative evidence I’ve seen cited here were the transmission rates’ small sizes (which I don’t see as evidence that HIV isn’t an STI, because the fact that a number is small doesn’t mean I can safely assume it’s nil), and the zero seroconversions result from Padian et al., the strength of which is arguable.
Is there any specific positive evidence?
I think the other studies of heterosexual transmission are at least suggestive. Explaining away the hundreds of female HIV seroconversions detected in those studies by assuming that each case of male-to-female transmission “involves iv drug use” does not seem credible to me. IV drug use is more common that it once was, but surely it’s not that common!
My scepticism is stronger still because a few of the studies have methodological features that would make transmission via needle sharing even less likely. I mentioned this Madrid study before. There’s also this ingenious study, which used sequence analysis on the subjects’ HIV samples to confirm that transmission was within pairs, making it less likely that non-index partners who seroconverted caught HIV from sharing needles with strangers.
Not at all—the data just shows that seropositivity is not sexually transmittable. A great deal of other evidence, combined with this clear lack of sexual transmission shows that seropositivity is clearly linked to risk groups with immunosuppression in general.
Immunosuppressed or not, a person won’t get infected by a virus unless that virus makes it into their body. Even with immunosuppression as a cofactor for HIV transmission, it can’t substitute for HIV transmission.
I almost forgot to ask for a reference for this:
There is a larger set of data Deusberg points to for lack of sexual transmission, which is the hemophiliac population, around 75% of which tested positive for HIV in the 80′s.
I’m unwilling to take Duesberg’s synopsis of these data on trust, and would want to see where he got his numbers from, and which methodological issues he might’ve glossed over. I can think of a few issues already, without even looking. The fact that the couples were having sex for years before getting tested in the 1980s wouldn’t mean much if HIV hadn’t been circulating in the blood supply for long. Different AIDS risk groups often have different constellations of AIDS-defining illness: Haitians often present with diarrhoea & TB, whereas US gay men often present with KS, for example, so I would guess haemophiliacs & their wives might have their own distinct AIDS-associated illnesses. Counting AIDS cases would underestimate HIV transmissions, because only some HIV+ wives would have progressed to AIDS. And so forth.
Also note this ‘ingenious’ study has an important point of evidence that does agree with the Padian study and points to a non-sexually transmitted etiology:
There was no significant difference in the rate of HIV transmission per coital act with inconsistent condom use, compared with no reported use, at any stage of infection.
The circumcision studies from Africa don’t tell us much either, as circumcision is associated with ethnic/cultural groups and thus drug use and other factors.
Immunosuppressed or not, a person won’t get infected by a virus unless that virus makes it into their body. Even with immunosuppression as a cofactor for HIV transmission, it can’t substitute for HIV transmission.
There are other more parsimonious explanations that don’t rely on a ‘virus’ at all, and HIV—as far as it exists as a rather arbitrary collection of DNA/RNA sequences, may not be a virus at all. It could just as easily be trash RNA being secreted in exosomes tagged for immune system garbage collection. It could be regulatory RNA exosome messages intended for other cells. It could be a mutant form of an endogenous regulatory RNA exosome. It could be an endogenous ‘virus’ that forms as a cancer-like mutation of normal endogenous regulatory RNA exosome communication. And yes, it could actually be a true exogenous RNA virus that just happens to be remarkably similar to sequences embedded in the human genome (such as the so called “HERV” sequences) - and just happens to look like typical RNA exosomes in the microscope.
But even if it is a true exogenous virus that can jump between cells and that is a huge if, there is astonishingly little evidence it causes much harm.
There is a mountain of evidence that drug use causes harm, and specifically that particular drugs linked especially to the gay community cause specific types of chronic accumulated immune damage.
Methanphetamine (speed) and its derivatives for example is tightly correlated with HIV/AIDS, it is endemic in the “party and play” gay community, and we have a large amount of evidence that Meth does significant long term harm.
Firstly, Meth is a hyper-stimulant of the “flight or fight” stress response. This stress response essentially temporarily shuts down the immune system and digestion to focus the body on a temporary threat. A lion may kill you in a matter of minutes, while your body’s normal symbiotes/parasites such as fungal candida are not going to do much in this time frame—so stress is bad for the immune system, but this is ok because stress normally is temporary.
What happens when go on a multi-day meth binge and hyper-stimulate your stress response? Well, we don’t entirely know, but it appears to be pretty bad for your immune system. And finally, the drug itself has potential DNA damaging effects through oxidative free radicals. This is a particular problem for any drugs that are often heated up and burnt in either the consumption or production phases, resulting in oxidative byproducts. The typical crack-cocaine ‘cooking’ procedure is especially bad in this respect.
The ‘immune system’ - which really should be called the ‘regulatory system’, is second only to the brain in complexity. It is responsible for not only protecting the body from foreign invaders, but also for general regulation of symbiotes/parasites in the gut, identification and control of rebellions (cancer), as well as normal tissue generation and regeneration (healing).
The CD4 cell pathway in particular is especially complex, and these cells are responsible for identification and long-term memory of particular antigens. They go through an extensive selection process to eliminate possible identification errors (auto-immune disorders). This system is especially sensitive to DNA damage, which is happening all the time—and these cells are expected to stick around for many years to hold antigen memory. They also use a random DNA shuffling process early on to generate their antigen recognition system, and these cells are bouncing around constantly in the blood in such a way that makes essential complex DNA repairs—double strand break repairs—much more difficult.
Consider the insults that AIDS patients are inflecting on this system: known potent stress inducing immuno-suppressants such as Meth and Cocaine type drugs, and oxidized byproducts of cooked drugs directly injected or smoked. Also consider that the rectum is second only to injection as a route into the bloodstream, and associated with anal sex are lubricants which can be absorbed. Has anybody seriously evaluated the long-term health effects of anal lubricants? I haven’t seen such a study. Consider that earlier in the AIDS era more toxic oil based lubricants, possibly containing benzoprene deriatives, were more common. Fortunately presumably safer water based lubricants are more common today, as the oil-lubricants can destroy condoms. All of this stuff goes—right up into the bloodstream.
And finally we should look at gay related intestinal disorders—as most of the CD4 cells are actually in the gut, and gut problems are endemic in gay men. Whether it’s semen absorption, lubricants, or anal douching is unclear, but it appears to cause some chronic gut problem—and possibly leaky gut syndrome, allowing more foreign antigens to pass directly into the blood. Exposure to all these strange antigens may simply confuse the immune system. Now combine that with chronic meth use and you have a clear recipe for AIDS which doesn’t require a virus. Overall, the gut/immune system is designed for forward entry.
The hetero groups that get AIDS in the west tend to be hardcore drug users. The other known group is hemophiliacs. The “AIDS” each of these groups gets are quite different and really only have the low CD4 count and blood reaction test in common—which really are just general markers of a dysfunctional immune system. Hemophilliacs have a genetic disorder of the blood and never lived long until the AIDS era anyway, and injecting foreign protein for the clotting agent is immuno-suppressive in itself.
AIDS, like cancer, is something that anybody can get—but most will not progress to AIDS or cancer until they are already quite old, and will usually die of something else well before that. AIDS is really just a common immune disorder—the elderly often have it to some degree—lower CD4 counts and opportunistic infections. You can accelerate the aging of your immune system and progress to AIDS faster by chronic use of immune supressing hyper-stressors such as Meth/coke drugs and or direct toxic DNA damage through injecting or absorbing (anally) foreign matter into the blood.
None of this causes much immediate damage, but like smoking it ages particular vulnerable systems, probably through accumulated DNA damage, and this is why many people who quit eventually will progress to AIDS anyway a decade later or so—the damage has already been done, just as many smokers who quit will still progress to lung cancer at an accelerated rate.
But the insults that these risk groups are doing to their blood and lymph are considerably worse than smoking. Although notice there is a huge amount of overlap—someone who chronically smokes crack cocaine is much more likely to die of some lung infection than say karposi’s sarcoma.
Also note this ‘ingenious’ study has an important point of evidence that does agree with the Padian study and points to a non-sexually transmitted etiology:
There was no significant difference in the rate of HIV transmission per coital act with inconsistent condom use, compared with no reported use, at any stage of infection.
Flicking to page 354 of Padian et al. I see this: “the practice of anal sex and lack of condom use have remained strong predictors of transmission since the beginning of the study”. And table 2 of the paper suggests that not using condoms is a statistically significant transmission risk factor, after adjusting for number of contacts (as I previously mentioned). I would not interpret that as agreement with a finding of “no significant difference”.
The circumcision studies from Africa don’t tell us much either, as circumcision is associated with ethnic/cultural groups and thus drug use and other factors.
This argument might go through for observational studies, although even there I’d want a quantitative argument for why I should expect those confounders to have as strong (or stronger) an effect as circumcision’s apparent effect. But I also referred to three large randomized trials, and randomization reduces the association between confounders and treatment effects to statistical noise — that’s why people conduct randomized trials. So I still regard the trials as strong evidence for circumcision having an effect on HIV transmission; confounders don’t have a substantial effect on the results of randomized trials unless the randomization process was faulty.
(Incidentally, my original links to the 2nd & 3rd trials are now broken. Hereare alternative links, although they may be paywalled.)
I’m skipping over the paragraphs on whether or not HIV is a virus since what HIV is specifically doesn’t bear on the point I was trying to make, which is that cofactors can’t subtitute for exposure to HIV (whatever one thinks HIV is).
There is a mountain of evidence that drug use causes harm,
Agreed.
and specifically that particular drugs linked especially to the gay community cause specific types of chronic accumulated immune damage.
Even if I grant you that, it doesn’t mean much to me unless one of those “specific types” of immune damage is the massive reduction in CD4 cell counts characteristic of AIDS. There are different kinds of immunosuppression, and it won’t do to presume that because something causes one kind of immunosuppression, it causes the kind of immunosuppression associated with AIDS.
At any rate, I suspect properly accounting for HIV+ status eliminates the link between whichever drugs you have in mind and AIDS. (Note that I am not denying any association between drug use and some form of immunosuppression — just non-spurious associations between drug use and substantial depletion of CD4 counts.) This 1993 Nature report describes results from the Multicenter AIDS Cohort Study. Check out the graph: there is a clear difference in CD4 count between seronegatives & seropositives, and only the seropositives suffer a downward slide in CD4 counts over the years, whereas differing levels of drug use show only meagre effects on CD4 count trajectories.
Methanphetamine (speed) and its derivatives for example is tightly correlated with HIV/AIDS, it is endemic in the “party and play” gay community, and we have a large amount of evidence that Meth does significant long term harm.
But how much does it affect CD4 counts?
What happens when go on a multi-day meth binge and hyper-stimulate your stress response? Well, we don’t entirely know, but it appears to be pretty bad for your immune system. And finally, the drug itself has potential DNA damaging effects through oxidative free radicals. This is a particular problem for any drugs that are often heated up and burnt in either the consumption or production phases, resulting in oxidative byproducts.
But how much do they affect CD4 counts?
Skipping the background commentary on the immune system and the speculation about lubricants & intestinal disorders.
The hetero groups that get AIDS in the west tend to be hardcore drug users. The other known group is hemophiliacs. The “AIDS” each of these groups gets are quite different and really only have the low CD4 count and blood reaction test in common -
CD4 counts below 200-400 are AIDS’ key feature. The Nature paper I linked refers to “CD4+ T-lymphocyte depletion” as “the primary pathognomonic feature of AIDS”. Opportunistic infections of course vary in prevalence across subpopulations, but that doesn’t somehow negate the common symptom that allows them to get a foothold: low CD4 counts.
which really are just general markers of a dysfunctional immune system.
Do you have references for this?
Hemophilliacs have a genetic disorder of the blood and never lived long until the AIDS era anyway, and injecting foreign protein for the clotting agent is immuno-suppressive in itself.
But how much does it affect CD4 counts?
AIDS, like cancer, is something that anybody can get -
If they have HIV. Or idiopathic CD4+ T-lymphoctyopenia, come to think of it. Other than that...?
but most will not progress to AIDS or cancer until they are already quite old, and will usually die of something else well before that. AIDS is really just a common immune disorder—the elderly often have it to some degree—lower CD4 counts and opportunistic infections.
Hedging with the phrase “to some degree” makes that statement too vague for me to get a handle on, and it’d help to put a number on it. At any rate, CD4 counts don’t appear to be much lower among the elderly than among younger adults. A quick poke around for CD4 reference counts brings up this Mayo Medical Laboratories page, which gives a range of 424-1509 for people aged 18-55, and a range of 430-1513 for people aged 55+.
You can probably anticipate what I’d say/ask for the rest of the parent post, so I’ll save you the repetition.
This thread is now at 4.5*10^4 words (counted by copying into a text editor, and find/replacing to delete words that’re actually headers or vote/navigation links). I believe it should have been taken off-line at approximately the 5*10^3 word mark, if not sooner.
I admit I’m obsessively addicted. The more I look into it, the more I have found that HIV science has gone horribly, horribly wrong, and ‘HIV’ - whatever it is—if it even exists—is neither necessary nor sufficient to cause AIDS.
Considering that we have spent hundreds of billions of dollars on this hypothesis, this has larger implications for rationality and the scientific establishment in general.
Even if I grant you that, it doesn’t mean much to me unless one of those “specific types” of immune damage is the massive reduction in CD4 cell counts characteristic of AIDS. There are different kinds of immunosuppression, and it won’t do to presume that because something causes one kind of immunosuppression, it causes the kind of immunosuppression associated with AIDS.
This is absolutely true, and is a very good point. However, keep in mind that seropositivity is not a direct measure of HIV, and isn’t even especially correlated with HIV (see my reply in the other thread). Seropositivity is a rather good measure of CD4 cell decline—simply glance at that graph in the Nature paper and you can see that. Although I should point out I’m not sure if it’s actual cell loss that is measured or simply more CD8 expressing T-cells vs CD4.
Also note that there was no body of non-users of nitrates in the homo risk group in this study—they were split simply into ‘light’ and ‘heavy’, and the heavy users were twice as likely to get KS—I’d say that is a rather significant correlation.
This study has some flaws for looking at toxological causes though, as it was only looking at rather recent drug use (24 months), which is not quite the same as use history overall.
But how much does it affect CD4 counts?
I’m not sure about Meth’s effects on CD4 counts in particular, but heavy cocaine use has a strong depleting effect on CD4 counts. First google result
But there are other factors in the homosexual risk group, the most important of which is simply semen. Semen is loaded with immunosuppressants that are designed to temporarily and locally deactivate the female immune system in the vaginal tract. One of those components are the prostglandins. It appears that evolution has struck a balance between semen’s need to disable immunity and the female’s need to regulate opportunistic microbes in the vagina (namely candida) - this balance sometimes fails and yeast infections result.
AIDS is in general associated with candidiasis—yeast infections—which overgrows in the rectal tract and eventually in the blood, and some of the seminal components absorb into the blood. Large-scale overuse of antibiotics to combat STD’s in the gay community is another significant cofactor, but semen itself may be a major part of the problem.
Many papers about semen’s immune suppression effects are a simple google search away—here is one typical example.
They found that just seven daily rectal semen insertions had a marked immune suppression effect, but only in male rats, female rats didn’t seem to be particularly effected.
You seem to think that the CD4 count decline is somehow completely explained by HIV theory. It is not. The CD4 count decline is the defining feature of AIDS, but HIV’s role, if any, is theoretical and not well understood. So it makes sense to look at all the factors involved—for there are many independent immune suppressing factors in the primary AIDs risk groups—homosexuals and injection drug users.
In the original AIDS defining population of homosexuals, AIDS is associated with a tightly bundled set of cofactors:
passive anal sex
drug use
a history of a large number of past sexual partners and STD’s
a history of heavy antibiotic treatment
More on all the known immune suppressing factors in the gay cohort here. All of this needs to be taken into consideration before one starts chasing some new ‘virus’.
The drugs have changed over time (meth and MDMA being more popular now), but the correlation has remained.
The second significant risk group of AIDS patients appears to be injection drug users—really crack cocaine injectors in particular, and cocaine is known to deplete CD4 cells and cause AIDS all by itself.
Hemophilliacs have a genetic disorder of the blood and never lived long until the AIDS era anyway, and injecting foreign protein for the clotting agent is immuno-suppressive in itself.
But how much does it affect CD4 counts?
I don’t know. Do you know? Do you want to investigate this? How? Keep in mind that before the AIDS era, hemophiliacs didn’t live all that long. We simply didn’t have much data on their longer term health problems. Then in 1985 the HIV panic mania spread, and the hemophiliac population was tested with Gallo’s “HIV’ test—which really is just a CD4 decline surrogate test. And we found that a big % of this population had declining CD4 counts and somewhat AIDS-like blood. What does this really mean?
And their wives don’t get it, btw. Neither do non-drug using prostitutes. Porn actresses in general do not appear to be at an elevated risk of developing AIDS either. None of this makes any sense for a sexually transmittable viral theory, but it makes perfect sense if AIDS is caused by primarily toxological chronic immune suppression.
At any rate, CD4 counts don’t appear to be much lower among the elderly than among younger adults.
I’m not so sure about that. I’m not sure that low CD4 counts in particular is common in the elderly, but compromised immune function is a typical problem of the elderly:
“Opportunistic infections occur with greater frequency or severity in patients with impaired host defenses. Growing numbers of HIV-infected persons, transplant recipients, and elderly persons are at increased risk.”
“Elderly persons have defects in T-cell immunity that result in increased incidence and death from TB”
You can probably anticipate what I’d say/ask for the rest of the parent post, so I’ll save you the repetition.
I won’t reply to this comment in full, but there’s a little loose end of my own making here, and I should tie it up:
You can probably anticipate what I’d say/ask for the rest of the parent post, so I’ll save you the repetition.
?
“But how much does it affect CD4 counts?” (In response to the references to meth, cocaine, direct DNA damage due to injection and rectal absorption of foreign matter, and smoking.)
Evidently the unlikeliness of getting no seroconversions under a hypothesis of low-but-nonzero transmission rates hinges on the numerical assumptions made about sexual behaviors.
A claim that HIV isn’t an STI is a hefty claim to hang on this single result.
Strong claims shouldn’t hinge on a single study, but this study can be used to update probabilities for certain theories. You can think of it as eliminating possibilities.
Namely it eliminates or vastly reduces any hypotheses involving a typical STD transmission route. It allows for a very small possible horizontal transmission rate, but the most likely cluster is centered around zero. That doesn’t prove it is zero, it is just that this evidence strongly favors zero transmission rate theories over all others.
Is there any specific positive evidence?
I think the other studies of heterosexual transmission are at least suggestive. Explaining away the hundreds of female HIV seroconversions detected in those studies
The what? I don’t think there is a single “female HIV seroconversion” to be “explained away” in any of those studies. From what I understand, and what Padian et al claim, the Padian study is the only properly controlled prospective study of heterosexual transmission. The other studies are just observational guesswork that are all circularly dependent on the notion that seropositivity is transmissible—they see a couple where both test positive and they just assume it was sexually transmissible—hardly anything resembling evidence for the theory—just circular logic.
by assuming that each case of male-to-female transmission “involves iv drug use” does not seem credible to me. IV drug use is more common that it once was, but surely it’s not that common!
First of all, in the other theories, there is no transmission to explain—and it certainly doesn’t have to involve iv drug use.
You have to understand what exactly seropositivity actually means. It is a blood test that was specifically designed to classify “aids-like” blood. Gallo developed it by comparing and testing a large amount of antibody combinations (biological IDs essentially), until he found a combination which successfully partitioned the AIDS-like and pre-AIDS-like blood from the normal blood. There are a host of other conditions that can cause full or partial seropositivity—think of it as a semi-general measure of CD4 immune malfunction. And actually, ‘malfunction’ is not even the right term, as one can test positive under some normal circumstances as well—such as pregnancy or during the course of some illnesses.
Testing positive multiple times, for no other apparent reasons, is a clear sign of some persistent CD4 immune malfunction which is highly correlated with full-blown AIDS in the future.
I glanced at the Madrid study and find it largely worthless compared to the Padin study. It is small, not properly controlled, and not prospective. They found higher “viral load” in couples that were both positive vs couples where only one partner was positive? That makes sense simply because as viral load loosely correlates with degree of sickness, we expect that to be correlated in couples. More sick people are more likely to not have partners at all or have sick partners.
You would see the exact same effect in smokers, and keep that analogy in mind when looking at any of this data.
Your “ingenious study” is not well controlled for drug use, and in fact barely even mentions it. As HIV/AIDS is highly correlated with drug use in all the epidemological data I have seen in the west, I don’t think this study allows us to differentiate much of anything.
For example, if you want to determine if lung cancer is predominantly caused by a sexually transmittable virus or toxicological effects of smoking, you need to design studies that carefully differentiate between the two. If you don’t screen for drug use (or smoking) you won’t learn much. Smoking (and drug use) are both highly correlated in long-term couples. If you just simply assume from the get go that the sexually transmitted viral theory is correct, you would naturally see an apparent low rate of transmission proportional to the length of time the couple is together (because this correlates with the smoking behavior ‘catching’.)
So to show that lung cancer is caused by a sexually transmitted vector, you would need to focus on non-smokers. That is why the Padian study is useful, and this African study you point to is not useful.
The part that you seem to think is ingenious—the so called “sequence analysis”, I do not find necessarily ingenious or able to “confirm that transmission was within pairs” in the slightest.
If you want to get into the side discussion on “viral load” and viral DNA comparison based on PCR techniques, it’s critical that you understand Kary Mullis’s objection. Kary Mullis won the nobel for inventing PCR, and he is a strong critic of the whole HIV theory, and the entire interpretation of genetic data based on the technique he invented.
Basically, PCR-like techniques allow you to detect DNA sequences that match a partial fragment, and they allow you to massively amplify those matches—allowing one to find a needle in a haystack by duplicating the needle into a new haystack, so to speak. It’s more useful for qualitative vs quantitative results. The problem with the whole idea of using PCR to test for “HIV DNA” is multi-fold. First, HIV-DNA is allowed to be any of a vast set of sequences—presumably because of it’s massive “mutation” potential. The human body is floating in a sea of RNA and DNA sequences, most of which we know little about—large amounts of various types of RNA that is used to control gene expression, regulatory computation, and regulatory signaling between cells.
So out of that sea of DNA/RNA you get in a tube, a huge set of 10bp-ish sequences are rather arbitrarily determined to be “HIV”, and then one tests many partial sequences and usually finds some similar-ish matches. If you use this PCR test on anybody you will always get some positive results—everybody has some amount of “HIV-ish” genetic material circulating in their blood normally. Comparing sequences in this way is fraught with methodological problems—if you pick some random sequence you will probably find something similar in someone else’s blood, so there is a huge amount of potential sample bias—somewhat like looking for pictures of crystals in ice patterns or looking for coded messages in the bible. There is so many random sequences that it is easy to find some that match, focus on those, and then ignore all the non-matches. A real true similarity comparison would involve a tremendous amount of sequencing on a scale that is—as far as I can tell—never done or not even feasible today. It is not as if PCR gives us some complete snapshot pictureof all the DNA/RNA floating around.
And finally, keep in mind that any way you slice it—we should expect to see sequence similarities in these couples, as they are genetically related—from the same area in africa and much more related on average than two random samples of homo sapiens.
Strong claims shouldn’t hinge on a single study, but this study can be used to update probabilities for certain theories. You can think of it as eliminating possibilities.
That’s my issue — I don’t think Padian et al.’s zero seroconversions result is sufficiently strong to outright eliminate a possibility, unless one’s already assigned a low prior to that possibility. Personally, I walked into this discussion with a very high prior (something like 99%) for HIV being sexually transmissible to some nontrivial (more than, say, once in every million unsafe sex acts) extent, and the Padian et al. result is not a strong one, so my prior is essentially unchanged.
Namely it eliminates or vastly reduces any hypotheses involving a typical STD transmission route. It allows for a very small possible horizontal transmission rate, but the most likely cluster is centered around zero.
Since the prior estimates for sexual transmission I’ve seen are already very small (on the order of 0.01% to 0.1%), the Padian et al. result doesn’t really clash with them that much. I also doubt “the most likely cluster” is centred on zero if one accounts for all of the evidence in the study, rather than focusing exclusively on the zero seroconversions result.
That doesn’t prove it is zero, it is just that this evidence strongly favors zero transmission rate theories over all others.
It favours a zero transmission rate strongly only if one makes particular strong assumptions about the sexual behaviour of the study’s subjects, and disregards the evidence of risk factors.
The what? I don’t think there is a single “female HIV seroconversion” to be “explained away” in any of those studies.
Let’s return to one of the papers that kicked off this discussion, as it has a few examples. From page 810: “seroconversions occurred in three male and seven female contacts after enrolment in the study” (that’s not even counting whatever seroconversions had to have occurred in those subjects already HIV+ at the start of the study). There must be some explanation for those seven seroconversions.
From what I understand, and what Padian et al claim, the Padian study is the only properly controlled prospective study of heterosexual transmission. The other studies are just observational guesswork that are all circularly dependent on the notion that seropositivity is transmissible—they see a couple where both test positive and they just assume it was sexually transmissible—hardly anything resembling evidence for the theory—just circular logic.
Whether or not one believes HIV is sexually transmitted, seroconversions occurred. What were their causes, if not HIV infection due to sexual transmission?
First of all, in the other theories, there is no transmission to explain—and it certainly doesn’t have to involve iv drug use.
Where does the HIV come from if not an external source?
I glanced at the Madrid study and find it largely worthless compared to the Padin study. It is small, not properly controlled, and not prospective.
I do not see the Madrid study as “largely worthless”, though I’d give it less weight than the Padian et al. study for the reasons you give. (I should emphasize that I’m talking about the Padian et al. study as a whole there; I maintain my reservations about the zero seroconversions result.) Still, the Madrid study sample’s not particularly small compared to the number of Padian et al. couples who consistently had unprotected sex and were followed up prospectively.
Your “ingenious study” is not well controlled for drug use, and in fact barely even mentions it.
Yes. The point I was making was that with the sequence analysis confirming the source of the transmission, the probability of any given seroconverter having been infected by IV drug use with strangers is less than if the researchers hadn’t done the sequence analysis (although of course still more than zero). So, to have me agree that the HIV infections are due to IV drug use, I would have to be convinced that the seroconverters had been sharing needles with their partners. And...
As HIV/AIDS is highly correlated with drug use in all the epidemological data I have seen in the west,
...as the study took place in Uganda, I find it very unlikely that even half of the seroconverters were infected by sharing needles (especially since none of the subjects reported injection drug use). Unless you are now arguing that seroconversion doesn’t actually indicate HIV infection (and I can’t tell whether you are or not), I expect you can see why I’d want alternative explanations for each of these seroconversions.
So to show that lung cancer is caused by a sexually transmitted vector, you would need to focus on non-smokers. That is why the Padian study is useful, and this African study you point to is not useful.
The African study, I’d say, is weaker evidence than the Padian study. At the same time, I think it’s absurd to write it off as “not useful”. At the risk of repeating myself, my reasoning goes like this: some number of subjects acquired HIV during the Ugandan study; exposure to HIV is necessary for infection; it is not credible to suppose that every HIV exposure that led to seroconversion is attributable to IV drug use. If there were only four or five seroconversions, I’d say it was statistically possible. In fact, the study reports that out of 239 monogamous couples that were initially HIV-discordant, 72 “acquired HIV during follow-up”. The probability that all 72 of these Ugandans acquired HIV by IV drug use is surely astronomically small.
If you want to get into the side discussion on “viral load” and viral DNA comparison based on PCR techniques,
Not especially, to be honest.
it’s critical that you understand Kary Mullis’s objection. Kary Mullis won the nobel for inventing PCR, and he is a strong critic of the whole HIV theory, and the entire interpretation of genetic data based on the technique he invented.
I’m not much impressed by Mullis’s Nobel credentials. There are quiteafewNobelists who got the prize and promptly started dabbling in crankery. (Including, as it happens, Luc Montagnier, so this isn’t just an issue for people who downplay the links between HIV & AIDS.) Jim Watson co-discovered DNA’s structure, but I’m not about to take all his proclamations about genetics at face value.
Anyway, I haven’t seen anything in the Uganda study report to suggest they used PCR in so sloppy a way as you’re suggesting, and I doubt they’d have much to report if they had. As such, it’s hard for me to avoid the feeling that your remarks about PCR are something of a fully general counterargument against HIV sequencing.
And finally, keep in mind that any way you slice it—we should expect to see sequence similarities in these couples, as they are genetically related—from the same area in africa and much more related on average than two random samples of homo sapiens.
Right, but two samples of virus from a couple where one member infected the other will nonetheless be far more genetically similar on average than two samples of virus from randomly selected infected people in Rakai.
Whether or not one believes HIV is sexually transmitted, seroconversions occurred. What were their causes, if not HIV infection due to sexual transmission?
First of all, in the other theories, there is no transmission to explain—and it certainly doesn’t have to involve iv drug use.
Where does the HIV come from if not an external source?
I’m having difficulty squaring some of your comments on seropositivity and HIV testing with the high reported sensitivity & specificity of properly conducted HIV tests.
First off, before we get into anything else, we need to understand and agree on what seropositivity actually means. Seropositivity means a positive result on an antibody test such as western blot, to some combination of antigens identified by Gallo in 1985 in his large scale blood screening tests. He did a large number of tests on transformed (immortalized) cell lines derived from AIDS patients and found a combination of antigens that could screen blood—separating AIDS and pre-AIDS blood from regular blood.
The problem is he (like Motagnier) failed to isolate the ‘virus’, and most or all of the antibodies in the test react or cross-react with antigens to opportunistic microbes (candida namely) and cellular debris. The p24 protein in particular is essentially just a normal cellular wall or microvescile component—so the ‘HIV’ test is really just a general test of opportunistic infection and apoptosis or immune directed killing of CD4 cells (possibly due to widespread viral parasite burden). It is not a measure of ‘HIV’, it is a direct measure of declining CD4 cells and AIDS or pre-AIDS.
The antibody tests are not standardized geographically or temporarily, so it also makes it very difficult to compare across studies—“seropositivity” means different things in different places and times.
As just one random example—most dogs typically have a mix of ‘HIV’ antigens, and are HIV ‘seropositive’ in whole or in part:
reported that 72⁄144 (50%) of dog blood samples “obtained from the Veterinary Medical Teaching Hospital, University of California, Davis” tested in commercial Western blot assays, “reacted with one or more HIV recombinant proteins [gp120--21.5%, gp41--23%, p31--22%, p24-- 43%]”
You post a link to a paper which supposedly shows the ” high reported sensitivity & specificity” of HIV tests. This is not actually what that paper is about, but it references several other papers for this claim—the first I investigated being this. The important quote:
Thirty-fourwomentested HIV-1 positive
with both rapid test and EIA, and all
were confirmed by Western blot
(prevalence=7/1000).
So they are just using Western blot as ‘confirmation’. So they are just using one antibody test to confirm another antibody test—which of course is rather ridiculous.
To actually compute the sensitivity and specificity for a “HIV” test, one needs a gold standard such as viral isolation or perhaps a DNA test. Unfortunately HIV can not be isolated, either because it doesn’t exit or it exists in only minute quantities.
But one can attempt to use the presumed viral DNA as a gold standard, and the result is extremely poor sensitivity and specificity:
Poor sensitivity is perhaps a gross understatement—the study actually shows that around 18-25% of the population at large test positive for ‘HIV DNA’, and this is only weakly correlated with seropositivity.
You completely dismiss Mullis’s argument based solely on an ad hominem “not much impressed by Mullis’s nobel credentials” without seeming to acknowledge or understand the argument itself.
Seroconversion in the west is closely correlated with AIDS or pre-AIDS. This does not appear to be as true in Africa, so we are generally talking about two different worlds. Part of this may be genetic (black americans have amazingly higher seropositvity in general), the other part may relate simply to higher precedence of opportunistic infections and antigens that seropositivity measures. KS for example is vary rare in the west and along with systemic candidaisis was part of the original AIDS definition, but it is one of the most common cancers in Africa.
Unless you are now arguing that seroconversion doesn’t actually indicate HIV infection (and I can’t tell whether you are or not),
I am arguing that.
Seropositivity does not strongly correlate with ‘HIV’ infection (by DNA test), which is why it is better to discuss AIDS itself as being sexually transmittable or not.
The Gallo blood test is tightly correlated with AIDS (at least in the west) - simply because that is what it was designed to do, so you can use that as data for AIDS transmission discussions.
Unless you are now arguing that seroconversion doesn’t actually indicate HIV infection (and I can’t tell whether you are or not),
I am arguing that.
OK. At this point, I’m going to have to disengage and walk away from this debate. I’m realizing that the inferential distance between us is far bigger than I originally thought, and trying to bridge it would need me to considerably ramp up the effort I’m already putting into this. (Even then I can imagine this going on indefinitely, which isn’t a very appealing prospect to me, nor to other Less Wrong posters, by the looks of it.)
I’d still like to respond briefly to one part of your comment, which comments on my own words rather than HIV/AIDS:
You completely dismiss Mullis’s argument based solely on an ad hominem “not much impressed by Mullis’s nobel credentials” without seeming to acknowledge or understand the argument itself.
It’s wholly legitimate for me to respond to someone citing Mullis’s credentials (as if I didn’t know about them already) by explaining why I give them little weight, and my next paragraph was meant to summarize why I gave “your remarks about PCR” (that is, those you paraphrased from Mullis) short shrift. In other words, I acknowledged the argument by rejecting it.
I’m glad you can walk away, I have a harder time initiating that. I’m curious though about the direction of the inferential distance you see—do you have a biology background?
The dissidents point to a rather surprising pile of evidence that the serological HIV tests are based on rather general, cross-reactive antibodies, and this is essentially a fundamental flaw in HIV science which has never been corrected. Now it may be that the orthodoxy has a really good counter to this, but if they do I have yet to find it. The orthodox position on this, from papers linked to wikipedia, points to studies which measure the sensitivity of various HIV antibody tests by comparing them to . . other HIV antibody tests.
The few large double-blind meta-studies that compare the different antibody tests to PCR tests show terrible sensitivity and specificity between the two, and I haven’t seen the orthodox counter to this. So something is wrong with the antibody tests, the PCR tests, or the whole thing. I imagine it’s a little bit of both—the antibody tests are cross-reactive (hence many dogs test positive), and PCR tests are difficult and subject to experimenter bias.
Perhaps the orthodox counter is that there are a whole big host of HIV related viruses, and the antibody tests are cross-reactive across these related species. This seems to then just beg more questions than it answers, and doesn’t circumvent some of the specific non-viral cross-reactions the dissidents point to.
My paraphrase of Mullis’s argument may actually be a mix of other dissident positions. I just rechecked that part of his book and he covers the difficulty of PCR and the confirmation bias but largely in regards to the OJ trial. On HIV he mainly rehashes Deusberg’s argument.
I’m curious though about the direction of the inferential distance you see—do you have a biology background?
None at all. (I expect the inferential distance would be even greater if I did. If I had personal experience of working with retroviruses, for instance, I reckon my prior probabilities for claims like “HIV can not be isolated” or “HIV doesn’t exist” would be far, far less than they are. And they are already very low.)
To actually compute the sensitivity and specificity for a “HIV” test, one needs a gold standard such as viral isolation or perhaps a DNA test. Unfortunately HIV can not be isolated, either because it doesn’t exit or it exists in only minute quantities.
When ‘HIV’ was first ‘discovered’ in the original papers by Gallo and Montagnier, they had difficulty isolating and didn’t publish pictures from what I understand—that didn’t happen until years later. Gallo’s great discovery for HTLVIII was based on running a lager number of antigen/antibody tests with an immortalized cell line to find an antibody test that could screen AIDS and pre-AIDS blood from regular blood. That is the basis of all the current HIV tests.
The first published pictures came more than a decade later, and they showed that “HIV isolate” really consists largely of cellular debris and microvesciles. In these EM photos, they do find some occasional particles of roughly the right size and label them as “HIV”, but they could also just be any of a number of other things, and for all intents and purposes, HIV ‘particles’ look like regular microvesciles.
The titles of the papers say it all:
“Cell membrane vesicles are a major contaminant of gradient-enriched human immunodeficiency virus type-1 preparations”
“Microvesicles are a source of contaminating cellular proteins found in purified HIV-1 preparations”
I have lost the link, but there are better more recent pictures taken with ATM, and they show that for all intents and purposes, it’s impossible to distinguish ‘HIV’ from regular microvesicles that bud from the cell wall naturally. If HIV can be said to exist at all as a unique exogenous virus, it is only because of unique RNA content in the microvesicle, and in this sense is very much unlike all other known viruses.
Of course, the part of HIV’s genome which is supposed to code for the outer envelope is pretty much the same as the endogenous sequences that already exist in the human genome—the HERVs.
What you’re saying about Padian et al. just clicked for me. I’d got it into my head that they were allocating each recruited couple to either a retrospective track or a prospective track, with couples switching from the retrospective track to the prospective track after 1990, but without their data being carried over. But you’re saying the couples already enrolled in the study pre-1990 were automatically entered into the prospective part with their earlier questionnaires & lab work retained, right? That’d make more sense than how I first interpreted the paper. (Serves me right for skipping the abstract and diving straight into the methods section. Twice.)
Alright, let’s crunch some numbers.
Using the midpoints of the ranges is a good first guess in the absence of other information. However, I think there’s a good reason to use estimates much closer to the follow-up percentages (14.5%, 74% & 8%) than the baseline percentages (0%, 32% & 37%). The prospective results section says that “approximately 97 percent of behavior change was reported between baseline and the first follow-up visit”. That is, when couples started/stopped using condoms consistently (or abstaining, or having anal sex), they almost always did so before their first follow-up visit, suggesting the couples changed their behaviour shortly after counselling, not gradually. If so, then the baseline percentages only represent the couples’ behaviour distribution for a few weeks; after that, the distribution would be much better represented by the rates at final follow-up.
This could have a big impact on the surprisingness of the zero seroconversions result. Switching from the midpoint rates to the final follow-up rates boosts the abstinence rate to 14.5% and the consistent condom use rate to 74%, while cutting the “[a]ny anal intercourse” rate from 22.5% to 8%. So the neither-abstinent-nor-consistently-condom-using rate sinks from 39.7% to 11.5%. Carrying that forward, I get an unsafe act count ≈1600 instead of ≈5600 (assuming 50% condom use in that 11.5% of couples).
That of course makes a big difference: with a 0.1% risk per act (and I’d peg the risk as being far closer to 0.1% than 0.5%, given the low rate of couples admitting to any anal sex, let alone repeated anal sex), 1600 sex acts have a 20% chance of not causing any transmissions, but 5000 sex acts have only a 0.03% chance. Evidently the unlikeliness of getting no seroconversions under a hypothesis of low-but-nonzero transmission rates hinges on the numerical assumptions made about sexual behaviours. (And there are yet more tweaks one could make to the numbers: whether to adjust for the couples that were female HIV+ instead of male HIV+, how much to adjust for condom unreliability, how much to adjust for the time lag between HIV infection and showing up as HIV+ on a blood test, and so on.) A claim that HIV isn’t an STI is a hefty claim to hang on this single result.
If I’m remembering correctly, the only pieces of specific negative evidence I’ve seen cited here were the transmission rates’ small sizes (which I don’t see as evidence that HIV isn’t an STI, because the fact that a number is small doesn’t mean I can safely assume it’s nil), and the zero seroconversions result from Padian et al., the strength of which is arguable.
I think the other studies of heterosexual transmission are at least suggestive. Explaining away the hundreds of female HIV seroconversions detected in those studies by assuming that each case of male-to-female transmission “involves iv drug use” does not seem credible to me. IV drug use is more common that it once was, but surely it’s not that common!
My scepticism is stronger still because a few of the studies have methodological features that would make transmission via needle sharing even less likely. I mentioned this Madrid study before. There’s also this ingenious study, which used sequence analysis on the subjects’ HIV samples to confirm that transmission was within pairs, making it less likely that non-index partners who seroconverted caught HIV from sharing needles with strangers.
It’s not as if these are the only studies that’re informative, either. This meta-analysis finds that male circumcision reduces HIV transmission risks, a conclusion bolstered by this randomized trial, a second randomized trial, and a third randomized trial. I’m not sure how I could explain these results without invoking sex as a way to transmit HIV.
Immunosuppressed or not, a person won’t get infected by a virus unless that virus makes it into their body. Even with immunosuppression as a cofactor for HIV transmission, it can’t substitute for HIV transmission.
I almost forgot to ask for a reference for this:
I’m unwilling to take Duesberg’s synopsis of these data on trust, and would want to see where he got his numbers from, and which methodological issues he might’ve glossed over. I can think of a few issues already, without even looking. The fact that the couples were having sex for years before getting tested in the 1980s wouldn’t mean much if HIV hadn’t been circulating in the blood supply for long. Different AIDS risk groups often have different constellations of AIDS-defining illness: Haitians often present with diarrhoea & TB, whereas US gay men often present with KS, for example, so I would guess haemophiliacs & their wives might have their own distinct AIDS-associated illnesses. Counting AIDS cases would underestimate HIV transmissions, because only some HIV+ wives would have progressed to AIDS. And so forth.
Also note this ‘ingenious’ study has an important point of evidence that does agree with the Padian study and points to a non-sexually transmitted etiology:
The circumcision studies from Africa don’t tell us much either, as circumcision is associated with ethnic/cultural groups and thus drug use and other factors.
There are other more parsimonious explanations that don’t rely on a ‘virus’ at all, and HIV—as far as it exists as a rather arbitrary collection of DNA/RNA sequences, may not be a virus at all. It could just as easily be trash RNA being secreted in exosomes tagged for immune system garbage collection. It could be regulatory RNA exosome messages intended for other cells. It could be a mutant form of an endogenous regulatory RNA exosome. It could be an endogenous ‘virus’ that forms as a cancer-like mutation of normal endogenous regulatory RNA exosome communication. And yes, it could actually be a true exogenous RNA virus that just happens to be remarkably similar to sequences embedded in the human genome (such as the so called “HERV” sequences) - and just happens to look like typical RNA exosomes in the microscope.
But even if it is a true exogenous virus that can jump between cells and that is a huge if, there is astonishingly little evidence it causes much harm.
There is a mountain of evidence that drug use causes harm, and specifically that particular drugs linked especially to the gay community cause specific types of chronic accumulated immune damage.
Methanphetamine (speed) and its derivatives for example is tightly correlated with HIV/AIDS, it is endemic in the “party and play” gay community, and we have a large amount of evidence that Meth does significant long term harm.
Firstly, Meth is a hyper-stimulant of the “flight or fight” stress response. This stress response essentially temporarily shuts down the immune system and digestion to focus the body on a temporary threat. A lion may kill you in a matter of minutes, while your body’s normal symbiotes/parasites such as fungal candida are not going to do much in this time frame—so stress is bad for the immune system, but this is ok because stress normally is temporary.
What happens when go on a multi-day meth binge and hyper-stimulate your stress response? Well, we don’t entirely know, but it appears to be pretty bad for your immune system. And finally, the drug itself has potential DNA damaging effects through oxidative free radicals. This is a particular problem for any drugs that are often heated up and burnt in either the consumption or production phases, resulting in oxidative byproducts. The typical crack-cocaine ‘cooking’ procedure is especially bad in this respect.
The ‘immune system’ - which really should be called the ‘regulatory system’, is second only to the brain in complexity. It is responsible for not only protecting the body from foreign invaders, but also for general regulation of symbiotes/parasites in the gut, identification and control of rebellions (cancer), as well as normal tissue generation and regeneration (healing).
The CD4 cell pathway in particular is especially complex, and these cells are responsible for identification and long-term memory of particular antigens. They go through an extensive selection process to eliminate possible identification errors (auto-immune disorders). This system is especially sensitive to DNA damage, which is happening all the time—and these cells are expected to stick around for many years to hold antigen memory. They also use a random DNA shuffling process early on to generate their antigen recognition system, and these cells are bouncing around constantly in the blood in such a way that makes essential complex DNA repairs—double strand break repairs—much more difficult.
Consider the insults that AIDS patients are inflecting on this system: known potent stress inducing immuno-suppressants such as Meth and Cocaine type drugs, and oxidized byproducts of cooked drugs directly injected or smoked. Also consider that the rectum is second only to injection as a route into the bloodstream, and associated with anal sex are lubricants which can be absorbed. Has anybody seriously evaluated the long-term health effects of anal lubricants? I haven’t seen such a study. Consider that earlier in the AIDS era more toxic oil based lubricants, possibly containing benzoprene deriatives, were more common. Fortunately presumably safer water based lubricants are more common today, as the oil-lubricants can destroy condoms. All of this stuff goes—right up into the bloodstream.
And finally we should look at gay related intestinal disorders—as most of the CD4 cells are actually in the gut, and gut problems are endemic in gay men. Whether it’s semen absorption, lubricants, or anal douching is unclear, but it appears to cause some chronic gut problem—and possibly leaky gut syndrome, allowing more foreign antigens to pass directly into the blood. Exposure to all these strange antigens may simply confuse the immune system. Now combine that with chronic meth use and you have a clear recipe for AIDS which doesn’t require a virus. Overall, the gut/immune system is designed for forward entry.
The hetero groups that get AIDS in the west tend to be hardcore drug users. The other known group is hemophiliacs. The “AIDS” each of these groups gets are quite different and really only have the low CD4 count and blood reaction test in common—which really are just general markers of a dysfunctional immune system. Hemophilliacs have a genetic disorder of the blood and never lived long until the AIDS era anyway, and injecting foreign protein for the clotting agent is immuno-suppressive in itself.
AIDS, like cancer, is something that anybody can get—but most will not progress to AIDS or cancer until they are already quite old, and will usually die of something else well before that. AIDS is really just a common immune disorder—the elderly often have it to some degree—lower CD4 counts and opportunistic infections. You can accelerate the aging of your immune system and progress to AIDS faster by chronic use of immune supressing hyper-stressors such as Meth/coke drugs and or direct toxic DNA damage through injecting or absorbing (anally) foreign matter into the blood.
None of this causes much immediate damage, but like smoking it ages particular vulnerable systems, probably through accumulated DNA damage, and this is why many people who quit eventually will progress to AIDS anyway a decade later or so—the damage has already been done, just as many smokers who quit will still progress to lung cancer at an accelerated rate.
But the insults that these risk groups are doing to their blood and lymph are considerably worse than smoking. Although notice there is a huge amount of overlap—someone who chronically smokes crack cocaine is much more likely to die of some lung infection than say karposi’s sarcoma.
Flicking to page 354 of Padian et al. I see this: “the practice of anal sex and lack of condom use have remained strong predictors of transmission since the beginning of the study”. And table 2 of the paper suggests that not using condoms is a statistically significant transmission risk factor, after adjusting for number of contacts (as I previously mentioned). I would not interpret that as agreement with a finding of “no significant difference”.
This argument might go through for observational studies, although even there I’d want a quantitative argument for why I should expect those confounders to have as strong (or stronger) an effect as circumcision’s apparent effect. But I also referred to three large randomized trials, and randomization reduces the association between confounders and treatment effects to statistical noise — that’s why people conduct randomized trials. So I still regard the trials as strong evidence for circumcision having an effect on HIV transmission; confounders don’t have a substantial effect on the results of randomized trials unless the randomization process was faulty.
(Incidentally, my original links to the 2nd & 3rd trials are now broken. Here are alternative links, although they may be paywalled.)
I’m skipping over the paragraphs on whether or not HIV is a virus since what HIV is specifically doesn’t bear on the point I was trying to make, which is that cofactors can’t subtitute for exposure to HIV (whatever one thinks HIV is).
Agreed.
Even if I grant you that, it doesn’t mean much to me unless one of those “specific types” of immune damage is the massive reduction in CD4 cell counts characteristic of AIDS. There are different kinds of immunosuppression, and it won’t do to presume that because something causes one kind of immunosuppression, it causes the kind of immunosuppression associated with AIDS.
At any rate, I suspect properly accounting for HIV+ status eliminates the link between whichever drugs you have in mind and AIDS. (Note that I am not denying any association between drug use and some form of immunosuppression — just non-spurious associations between drug use and substantial depletion of CD4 counts.) This 1993 Nature report describes results from the Multicenter AIDS Cohort Study. Check out the graph: there is a clear difference in CD4 count between seronegatives & seropositives, and only the seropositives suffer a downward slide in CD4 counts over the years, whereas differing levels of drug use show only meagre effects on CD4 count trajectories.
But how much does it affect CD4 counts?
But how much do they affect CD4 counts?
Skipping the background commentary on the immune system and the speculation about lubricants & intestinal disorders.
CD4 counts below 200-400 are AIDS’ key feature. The Nature paper I linked refers to “CD4+ T-lymphocyte depletion” as “the primary pathognomonic feature of AIDS”. Opportunistic infections of course vary in prevalence across subpopulations, but that doesn’t somehow negate the common symptom that allows them to get a foothold: low CD4 counts.
Do you have references for this?
But how much does it affect CD4 counts?
If they have HIV. Or idiopathic CD4+ T-lymphoctyopenia, come to think of it. Other than that...?
Hedging with the phrase “to some degree” makes that statement too vague for me to get a handle on, and it’d help to put a number on it. At any rate, CD4 counts don’t appear to be much lower among the elderly than among younger adults. A quick poke around for CD4 reference counts brings up this Mayo Medical Laboratories page, which gives a range of 424-1509 for people aged 18-55, and a range of 430-1513 for people aged 55+.
You can probably anticipate what I’d say/ask for the rest of the parent post, so I’ll save you the repetition.
You people are still going at it on the HIV thing?
This thread is now at 4.5*10^4 words (counted by copying into a text editor, and find/replacing to delete words that’re actually headers or vote/navigation links). I believe it should have been taken off-line at approximately the 5*10^3 word mark, if not sooner.
I admit I’m obsessively addicted. The more I look into it, the more I have found that HIV science has gone horribly, horribly wrong, and ‘HIV’ - whatever it is—if it even exists—is neither necessary nor sufficient to cause AIDS.
Considering that we have spent hundreds of billions of dollars on this hypothesis, this has larger implications for rationality and the scientific establishment in general.
This is absolutely true, and is a very good point. However, keep in mind that seropositivity is not a direct measure of HIV, and isn’t even especially correlated with HIV (see my reply in the other thread). Seropositivity is a rather good measure of CD4 cell decline—simply glance at that graph in the Nature paper and you can see that. Although I should point out I’m not sure if it’s actual cell loss that is measured or simply more CD8 expressing T-cells vs CD4.
Also note that there was no body of non-users of nitrates in the homo risk group in this study—they were split simply into ‘light’ and ‘heavy’, and the heavy users were twice as likely to get KS—I’d say that is a rather significant correlation.
This study has some flaws for looking at toxological causes though, as it was only looking at rather recent drug use (24 months), which is not quite the same as use history overall.
I’m not sure about Meth’s effects on CD4 counts in particular, but heavy cocaine use has a strong depleting effect on CD4 counts. First google result
But there are other factors in the homosexual risk group, the most important of which is simply semen. Semen is loaded with immunosuppressants that are designed to temporarily and locally deactivate the female immune system in the vaginal tract. One of those components are the prostglandins. It appears that evolution has struck a balance between semen’s need to disable immunity and the female’s need to regulate opportunistic microbes in the vagina (namely candida) - this balance sometimes fails and yeast infections result.
AIDS is in general associated with candidiasis—yeast infections—which overgrows in the rectal tract and eventually in the blood, and some of the seminal components absorb into the blood. Large-scale overuse of antibiotics to combat STD’s in the gay community is another significant cofactor, but semen itself may be a major part of the problem.
Many papers about semen’s immune suppression effects are a simple google search away—here is one typical example.
One of the most interesting though was this study of semen’s effects on rats from 1985.
They found that just seven daily rectal semen insertions had a marked immune suppression effect, but only in male rats, female rats didn’t seem to be particularly effected.
You seem to think that the CD4 count decline is somehow completely explained by HIV theory. It is not. The CD4 count decline is the defining feature of AIDS, but HIV’s role, if any, is theoretical and not well understood. So it makes sense to look at all the factors involved—for there are many independent immune suppressing factors in the primary AIDs risk groups—homosexuals and injection drug users.
In the original AIDS defining population of homosexuals, AIDS is associated with a tightly bundled set of cofactors:
passive anal sex
drug use
a history of a large number of past sexual partners and STD’s
a history of heavy antibiotic treatment
More on all the known immune suppressing factors in the gay cohort here. All of this needs to be taken into consideration before one starts chasing some new ‘virus’.
The drugs have changed over time (meth and MDMA being more popular now), but the correlation has remained.
The second significant risk group of AIDS patients appears to be injection drug users—really crack cocaine injectors in particular, and cocaine is known to deplete CD4 cells and cause AIDS all by itself.
I don’t know. Do you know? Do you want to investigate this? How? Keep in mind that before the AIDS era, hemophiliacs didn’t live all that long. We simply didn’t have much data on their longer term health problems. Then in 1985 the HIV panic mania spread, and the hemophiliac population was tested with Gallo’s “HIV’ test—which really is just a CD4 decline surrogate test. And we found that a big % of this population had declining CD4 counts and somewhat AIDS-like blood. What does this really mean?
And their wives don’t get it, btw. Neither do non-drug using prostitutes. Porn actresses in general do not appear to be at an elevated risk of developing AIDS either. None of this makes any sense for a sexually transmittable viral theory, but it makes perfect sense if AIDS is caused by primarily toxological chronic immune suppression.
I’m not so sure about that. I’m not sure that low CD4 counts in particular is common in the elderly, but compromised immune function is a typical problem of the elderly:
from the CDC: Opportunistic Infections in Immunodeficient Populations
“Opportunistic infections occur with greater frequency or severity in patients with impaired host defenses. Growing numbers of HIV-infected persons, transplant recipients, and elderly persons are at increased risk.”
“Elderly persons have defects in T-cell immunity that result in increased incidence and death from TB”
?
I won’t reply to this comment in full, but there’s a little loose end of my own making here, and I should tie it up:
“But how much does it affect CD4 counts?” (In response to the references to meth, cocaine, direct DNA damage due to injection and rectal absorption of foreign matter, and smoking.)
Strong claims shouldn’t hinge on a single study, but this study can be used to update probabilities for certain theories. You can think of it as eliminating possibilities.
Namely it eliminates or vastly reduces any hypotheses involving a typical STD transmission route. It allows for a very small possible horizontal transmission rate, but the most likely cluster is centered around zero. That doesn’t prove it is zero, it is just that this evidence strongly favors zero transmission rate theories over all others.
The what? I don’t think there is a single “female HIV seroconversion” to be “explained away” in any of those studies. From what I understand, and what Padian et al claim, the Padian study is the only properly controlled prospective study of heterosexual transmission. The other studies are just observational guesswork that are all circularly dependent on the notion that seropositivity is transmissible—they see a couple where both test positive and they just assume it was sexually transmissible—hardly anything resembling evidence for the theory—just circular logic.
First of all, in the other theories, there is no transmission to explain—and it certainly doesn’t have to involve iv drug use.
You have to understand what exactly seropositivity actually means. It is a blood test that was specifically designed to classify “aids-like” blood. Gallo developed it by comparing and testing a large amount of antibody combinations (biological IDs essentially), until he found a combination which successfully partitioned the AIDS-like and pre-AIDS-like blood from the normal blood. There are a host of other conditions that can cause full or partial seropositivity—think of it as a semi-general measure of CD4 immune malfunction. And actually, ‘malfunction’ is not even the right term, as one can test positive under some normal circumstances as well—such as pregnancy or during the course of some illnesses.
Testing positive multiple times, for no other apparent reasons, is a clear sign of some persistent CD4 immune malfunction which is highly correlated with full-blown AIDS in the future.
I glanced at the Madrid study and find it largely worthless compared to the Padin study. It is small, not properly controlled, and not prospective. They found higher “viral load” in couples that were both positive vs couples where only one partner was positive? That makes sense simply because as viral load loosely correlates with degree of sickness, we expect that to be correlated in couples. More sick people are more likely to not have partners at all or have sick partners.
You would see the exact same effect in smokers, and keep that analogy in mind when looking at any of this data.
Your “ingenious study” is not well controlled for drug use, and in fact barely even mentions it. As HIV/AIDS is highly correlated with drug use in all the epidemological data I have seen in the west, I don’t think this study allows us to differentiate much of anything.
For example, if you want to determine if lung cancer is predominantly caused by a sexually transmittable virus or toxicological effects of smoking, you need to design studies that carefully differentiate between the two. If you don’t screen for drug use (or smoking) you won’t learn much. Smoking (and drug use) are both highly correlated in long-term couples. If you just simply assume from the get go that the sexually transmitted viral theory is correct, you would naturally see an apparent low rate of transmission proportional to the length of time the couple is together (because this correlates with the smoking behavior ‘catching’.)
So to show that lung cancer is caused by a sexually transmitted vector, you would need to focus on non-smokers. That is why the Padian study is useful, and this African study you point to is not useful.
The part that you seem to think is ingenious—the so called “sequence analysis”, I do not find necessarily ingenious or able to “confirm that transmission was within pairs” in the slightest.
If you want to get into the side discussion on “viral load” and viral DNA comparison based on PCR techniques, it’s critical that you understand Kary Mullis’s objection. Kary Mullis won the nobel for inventing PCR, and he is a strong critic of the whole HIV theory, and the entire interpretation of genetic data based on the technique he invented.
Basically, PCR-like techniques allow you to detect DNA sequences that match a partial fragment, and they allow you to massively amplify those matches—allowing one to find a needle in a haystack by duplicating the needle into a new haystack, so to speak. It’s more useful for qualitative vs quantitative results. The problem with the whole idea of using PCR to test for “HIV DNA” is multi-fold. First, HIV-DNA is allowed to be any of a vast set of sequences—presumably because of it’s massive “mutation” potential. The human body is floating in a sea of RNA and DNA sequences, most of which we know little about—large amounts of various types of RNA that is used to control gene expression, regulatory computation, and regulatory signaling between cells.
So out of that sea of DNA/RNA you get in a tube, a huge set of 10bp-ish sequences are rather arbitrarily determined to be “HIV”, and then one tests many partial sequences and usually finds some similar-ish matches. If you use this PCR test on anybody you will always get some positive results—everybody has some amount of “HIV-ish” genetic material circulating in their blood normally. Comparing sequences in this way is fraught with methodological problems—if you pick some random sequence you will probably find something similar in someone else’s blood, so there is a huge amount of potential sample bias—somewhat like looking for pictures of crystals in ice patterns or looking for coded messages in the bible. There is so many random sequences that it is easy to find some that match, focus on those, and then ignore all the non-matches. A real true similarity comparison would involve a tremendous amount of sequencing on a scale that is—as far as I can tell—never done or not even feasible today. It is not as if PCR gives us some complete snapshot pictureof all the DNA/RNA floating around.
And finally, keep in mind that any way you slice it—we should expect to see sequence similarities in these couples, as they are genetically related—from the same area in africa and much more related on average than two random samples of homo sapiens.
That’s my issue — I don’t think Padian et al.’s zero seroconversions result is sufficiently strong to outright eliminate a possibility, unless one’s already assigned a low prior to that possibility. Personally, I walked into this discussion with a very high prior (something like 99%) for HIV being sexually transmissible to some nontrivial (more than, say, once in every million unsafe sex acts) extent, and the Padian et al. result is not a strong one, so my prior is essentially unchanged.
Since the prior estimates for sexual transmission I’ve seen are already very small (on the order of 0.01% to 0.1%), the Padian et al. result doesn’t really clash with them that much. I also doubt “the most likely cluster” is centred on zero if one accounts for all of the evidence in the study, rather than focusing exclusively on the zero seroconversions result.
It favours a zero transmission rate strongly only if one makes particular strong assumptions about the sexual behaviour of the study’s subjects, and disregards the evidence of risk factors.
Let’s return to one of the papers that kicked off this discussion, as it has a few examples. From page 810: “seroconversions occurred in three male and seven female contacts after enrolment in the study” (that’s not even counting whatever seroconversions had to have occurred in those subjects already HIV+ at the start of the study). There must be some explanation for those seven seroconversions.
Whether or not one believes HIV is sexually transmitted, seroconversions occurred. What were their causes, if not HIV infection due to sexual transmission?
Where does the HIV come from if not an external source?
I’m having difficulty squaring some of your comments on seropositivity and HIV testing with the high reported sensitivity & specificity of properly conducted HIV tests.
I do not see the Madrid study as “largely worthless”, though I’d give it less weight than the Padian et al. study for the reasons you give. (I should emphasize that I’m talking about the Padian et al. study as a whole there; I maintain my reservations about the zero seroconversions result.) Still, the Madrid study sample’s not particularly small compared to the number of Padian et al. couples who consistently had unprotected sex and were followed up prospectively.
Yes. The point I was making was that with the sequence analysis confirming the source of the transmission, the probability of any given seroconverter having been infected by IV drug use with strangers is less than if the researchers hadn’t done the sequence analysis (although of course still more than zero). So, to have me agree that the HIV infections are due to IV drug use, I would have to be convinced that the seroconverters had been sharing needles with their partners. And...
...as the study took place in Uganda, I find it very unlikely that even half of the seroconverters were infected by sharing needles (especially since none of the subjects reported injection drug use). Unless you are now arguing that seroconversion doesn’t actually indicate HIV infection (and I can’t tell whether you are or not), I expect you can see why I’d want alternative explanations for each of these seroconversions.
The African study, I’d say, is weaker evidence than the Padian study. At the same time, I think it’s absurd to write it off as “not useful”. At the risk of repeating myself, my reasoning goes like this: some number of subjects acquired HIV during the Ugandan study; exposure to HIV is necessary for infection; it is not credible to suppose that every HIV exposure that led to seroconversion is attributable to IV drug use. If there were only four or five seroconversions, I’d say it was statistically possible. In fact, the study reports that out of 239 monogamous couples that were initially HIV-discordant, 72 “acquired HIV during follow-up”. The probability that all 72 of these Ugandans acquired HIV by IV drug use is surely astronomically small.
Not especially, to be honest.
I’m not much impressed by Mullis’s Nobel credentials. There are quite a few Nobelists who got the prize and promptly started dabbling in crankery. (Including, as it happens, Luc Montagnier, so this isn’t just an issue for people who downplay the links between HIV & AIDS.) Jim Watson co-discovered DNA’s structure, but I’m not about to take all his proclamations about genetics at face value.
Anyway, I haven’t seen anything in the Uganda study report to suggest they used PCR in so sloppy a way as you’re suggesting, and I doubt they’d have much to report if they had. As such, it’s hard for me to avoid the feeling that your remarks about PCR are something of a fully general counterargument against HIV sequencing.
Right, but two samples of virus from a couple where one member infected the other will nonetheless be far more genetically similar on average than two samples of virus from randomly selected infected people in Rakai.
First off, before we get into anything else, we need to understand and agree on what seropositivity actually means. Seropositivity means a positive result on an antibody test such as western blot, to some combination of antigens identified by Gallo in 1985 in his large scale blood screening tests. He did a large number of tests on transformed (immortalized) cell lines derived from AIDS patients and found a combination of antigens that could screen blood—separating AIDS and pre-AIDS blood from regular blood.
The problem is he (like Motagnier) failed to isolate the ‘virus’, and most or all of the antibodies in the test react or cross-react with antigens to opportunistic microbes (candida namely) and cellular debris. The p24 protein in particular is essentially just a normal cellular wall or microvescile component—so the ‘HIV’ test is really just a general test of opportunistic infection and apoptosis or immune directed killing of CD4 cells (possibly due to widespread viral parasite burden). It is not a measure of ‘HIV’, it is a direct measure of declining CD4 cells and AIDS or pre-AIDS.
more on this
and a longer, more detailed analysis of cross-reactivity for the different ‘HIV’ proteins
The antibody tests are not standardized geographically or temporarily, so it also makes it very difficult to compare across studies—“seropositivity” means different things in different places and times.
As just one random example—most dogs typically have a mix of ‘HIV’ antigens, and are HIV ‘seropositive’ in whole or in part:
from this paper
You post a link to a paper which supposedly shows the ” high reported sensitivity & specificity” of HIV tests. This is not actually what that paper is about, but it references several other papers for this claim—the first I investigated being this. The important quote:
So they are just using Western blot as ‘confirmation’. So they are just using one antibody test to confirm another antibody test—which of course is rather ridiculous.
To actually compute the sensitivity and specificity for a “HIV” test, one needs a gold standard such as viral isolation or perhaps a DNA test. Unfortunately HIV can not be isolated, either because it doesn’t exit or it exists in only minute quantities.
But one can attempt to use the presumed viral DNA as a gold standard, and the result is extremely poor sensitivity and specificity:
Poor sensitivity, specificity, and reproducibility of detection of HIV-1 DNA in serum by polymerase chain reaction. The Transfusion Safety Study Group.
Poor sensitivity is perhaps a gross understatement—the study actually shows that around 18-25% of the population at large test positive for ‘HIV DNA’, and this is only weakly correlated with seropositivity.
You completely dismiss Mullis’s argument based solely on an ad hominem “not much impressed by Mullis’s nobel credentials” without seeming to acknowledge or understand the argument itself.
Seroconversion in the west is closely correlated with AIDS or pre-AIDS. This does not appear to be as true in Africa, so we are generally talking about two different worlds. Part of this may be genetic (black americans have amazingly higher seropositvity in general), the other part may relate simply to higher precedence of opportunistic infections and antigens that seropositivity measures. KS for example is vary rare in the west and along with systemic candidaisis was part of the original AIDS definition, but it is one of the most common cancers in Africa.
I am arguing that.
Seropositivity does not strongly correlate with ‘HIV’ infection (by DNA test), which is why it is better to discuss AIDS itself as being sexually transmittable or not.
The Gallo blood test is tightly correlated with AIDS (at least in the west) - simply because that is what it was designed to do, so you can use that as data for AIDS transmission discussions.
OK. At this point, I’m going to have to disengage and walk away from this debate. I’m realizing that the inferential distance between us is far bigger than I originally thought, and trying to bridge it would need me to considerably ramp up the effort I’m already putting into this. (Even then I can imagine this going on indefinitely, which isn’t a very appealing prospect to me, nor to other Less Wrong posters, by the looks of it.)
I’d still like to respond briefly to one part of your comment, which comments on my own words rather than HIV/AIDS:
It’s wholly legitimate for me to respond to someone citing Mullis’s credentials (as if I didn’t know about them already) by explaining why I give them little weight, and my next paragraph was meant to summarize why I gave “your remarks about PCR” (that is, those you paraphrased from Mullis) short shrift. In other words, I acknowledged the argument by rejecting it.
I’m glad you can walk away, I have a harder time initiating that. I’m curious though about the direction of the inferential distance you see—do you have a biology background?
The dissidents point to a rather surprising pile of evidence that the serological HIV tests are based on rather general, cross-reactive antibodies, and this is essentially a fundamental flaw in HIV science which has never been corrected. Now it may be that the orthodoxy has a really good counter to this, but if they do I have yet to find it. The orthodox position on this, from papers linked to wikipedia, points to studies which measure the sensitivity of various HIV antibody tests by comparing them to . . other HIV antibody tests.
The few large double-blind meta-studies that compare the different antibody tests to PCR tests show terrible sensitivity and specificity between the two, and I haven’t seen the orthodox counter to this. So something is wrong with the antibody tests, the PCR tests, or the whole thing. I imagine it’s a little bit of both—the antibody tests are cross-reactive (hence many dogs test positive), and PCR tests are difficult and subject to experimenter bias.
Perhaps the orthodox counter is that there are a whole big host of HIV related viruses, and the antibody tests are cross-reactive across these related species. This seems to then just beg more questions than it answers, and doesn’t circumvent some of the specific non-viral cross-reactions the dissidents point to.
My paraphrase of Mullis’s argument may actually be a mix of other dissident positions. I just rechecked that part of his book and he covers the difficulty of PCR and the confirmation bias but largely in regards to the OJ trial. On HIV he mainly rehashes Deusberg’s argument.
All right, enough.
None at all. (I expect the inferential distance would be even greater if I did. If I had personal experience of working with retroviruses, for instance, I reckon my prior probabilities for claims like “HIV can not be isolated” or “HIV doesn’t exist” would be far, far less than they are. And they are already very low.)
So those electron microscope pictures are fakes?
Which electron microscope pictures?
When ‘HIV’ was first ‘discovered’ in the original papers by Gallo and Montagnier, they had difficulty isolating and didn’t publish pictures from what I understand—that didn’t happen until years later. Gallo’s great discovery for HTLVIII was based on running a lager number of antigen/antibody tests with an immortalized cell line to find an antibody test that could screen AIDS and pre-AIDS blood from regular blood. That is the basis of all the current HIV tests.
The first published pictures came more than a decade later, and they showed that “HIV isolate” really consists largely of cellular debris and microvesciles. In these EM photos, they do find some occasional particles of roughly the right size and label them as “HIV”, but they could also just be any of a number of other things, and for all intents and purposes, HIV ‘particles’ look like regular microvesciles.
The titles of the papers say it all:
“Cell membrane vesicles are a major contaminant of gradient-enriched human immunodeficiency virus type-1 preparations”
“Microvesicles are a source of contaminating cellular proteins found in purified HIV-1 preparations”
more on HIV ‘pictures’
I have lost the link, but there are better more recent pictures taken with ATM, and they show that for all intents and purposes, it’s impossible to distinguish ‘HIV’ from regular microvesicles that bud from the cell wall naturally. If HIV can be said to exist at all as a unique exogenous virus, it is only because of unique RNA content in the microvesicle, and in this sense is very much unlike all other known viruses.
Of course, the part of HIV’s genome which is supposed to code for the outer envelope is pretty much the same as the endogenous sequences that already exist in the human genome—the HERVs.
Huh. While I still think that the HIV explanation is the most likely one for AIDS, I am slightly less convinced.