Is this the Gay Germ? Part II

Courtyard with Lunatics, Francisco Goya (1746-1828). Why is HIV much more likely to cause cognitive impairment in the body of a gay man than in the body of an intravenous drug user? Has an unknown pathogen been caught in the dragnet of AIDS studies?



My last post focused on certain discrepancies in data on AIDS victims: as antiretroviral therapy becomes more widespread, there has been a decline in opportunistic infections, but the decline hasn't been the same for all pathogens. In particular, some brain infections have shown modest declines or no change at all. 

Has an unknown pathogen been caught in the dragnet of AIDS studies? This pathogen would coexist with HIV only because it, too, is associated with the gay lifestyle. It would not be a "cofactor" that makes the HIV infection worse. In fact, it probably precedes the HIV infection by many years. This unknown pathogen may target certain sites in the brain of its host early in life in order to change his sexual orientation and thereby increase its chances of transmission to another host. It thereafter remains in the background until its host has reached an age when he ceases to be useful. The pathogen is then no longer penalized if it causes damage to surrounding neural tissues. Various neurocognitive disorders could therefore develop in its host from late middle age onward.


AIDS in gay men and intravenous drug users

This post will focus on discrepancies in data from two other papers. The first one is a study of AIDS victims in the Italian city of Bologna. Some of them contracted AIDS via homosexual/bisexual behavior, and some via intravenous drug use. One finding strikes me as unusual: "Compared with injecting drug users, homosexual/bisexual and heterosexual participants had ORs of 9.6 (95% CI, 2.2-42.7) and 6.3 (95% CI, 2.2-18.3), respectively, for cognitive impairment" (De Ronchi et al. 2002).

In other words, when the researchers looked at AIDS victims, they found that cognitive impairment was ten times more strongly associated with homosexuality/bisexuality than with intravenous drug use. That finding is curious because the ratio of ten to one doesn't correspond at all to the ratio of homosexuals/bisexuals to intravenous drug users among Italian AIDS cases. In fact, intravenous drug users made up about 60% of those cases in 1997 (Wikipedia 2019). The Bologna study took place between 1994 and 1997.

Why is HIV much more likely to cause cognitive impairment in the body of a gay man than in the body of an intravenous drug user? Do druggies take better care of their mental health? The evidence actually suggests the reverse: HIV-associated dementia seems to progress more rapidly in intravenous drug users (Bouwman et al. 1998). The latter finding also points to a qualitative difference between the two groups: dementia seems to develop more slowly in gay men.


HAND and HAART

The second paper is a review of studies on HAND [HIV-associated neurocognitive disorders]. It notes that HAND can develop even in individuals on HAART [Highly active antiretroviral therapy] with no detectable traces of HIV:

Furthermore, 21% [of individuals in the CHARTER study] developed HAND despite effective HAART (although the precise number who were aviremic is unclear). Similarly, in a cohort of individuals with AIDS, 21% of aviremic individuals (who also had undetectable CSF HIV RNA) progressed to HAD [HIV-associated dementia]. A third prospective study also identified HAND in 8-34% (depending on the time point of the assessment) of aviremic patients without comorbidities and with a nadir CD4 cell count less than 200 cells/µl (McArthur and Brew 2010)

The authors suggest that HIV can produce irreversible neural damage that becomes noticeable only much later in life. Well, perhaps. Nonetheless, it seems to me more parsimonious to postulate a second pathogen.


Parting thoughts

Clearly, HIV does cause cognitive impairment. The Bologna study showed a strong association between HAND and low white cell counts. But it looks like a certain proportion of HANDs are due to a cause that exists independently of HIV infection.

Please note: I'm not arguing that HIV is interacting with an unknown pathogen to cause cognitive impairment. I am arguing that these two pathogens impair cognition independently of each other and in different ways. They share only one thing in common: they have a much higher incidence among gay men than in the general population.

Finally, I'm not arguing that this unknown pathogen is the only cause of male homosexuality. There are likely multiple causes. In a nutshell, male homosexuality seems to be due to a genetic predisposition interacting with something in the environment. The genetic predisposition is a smaller-than-average neuronal population that promotes a heterosexual orientation. Normally, natural selection keeps it from falling below the threshold needed to sustain attraction to women. Certain environmental agents, however, can cause this neuronal population to fall below the threshold: fraternal birth order effects, stressful events during pregnancy, exposure to environmental estrogens during childhood, and, yes, a pathogen.

I don't know whether my views on the "gay germ theory" are consistent with Greg Cochran's. I hope he will deign to provide his comments.


References

Bouwman, F., R. Skolasky, D. Hes, O. Selnes, J. Glass, T. Nance-Sproson, W. Royal, G. Dal Pan,  and J. McArthur. (1998). Variable progression of HIV-associated dementia. Neurology 50(6): 1814-1820.
https://insights.ovid.com/article/00006114-199806000-00048 

Cochran, G.M., Ewald, P.W., and Cochran, K.D. (2000). Infectious causation of disease: an evolutionary perspective. Perspectives in Biology and Medicine 43: 406-448.
https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.182.5521&rep=rep1&type=pdf 

De Ronchi, D., I. Faranca, D. Berardi, et al. (2002). Risk Factors for Cognitive Impairment in HIV-1-Infected Persons with Different Risk Behaviors. Archives of Neurology 59(5): 812-818.
https://jamanetwork.com/journals/jamaneurology/article-abstract/781960

McArthur, J.C., and B.J. Brew. (2010). HIV-associated neurocognitive disorders: is there a hidden epidemic? AIDS 24(9): 1367-1370
https://journals.lww.com/aidsonline/Fulltext/2010/06010/Circulating_proviral_HIV_DNA_and_HIV_associated.17.aspx?Ppt=Article|aidsonline:2010:06010:00017|| 

Wikipedia (2019). HIV/AIDS Public Health Campaigns in Italy
https://en.wikipedia.org/wiki/HIV/AIDS_Public_Health_Campaigns_in_Italy

Is this the Gay Germ?

Poster for 1997 World AIDS Day (Wikicommons - Neil Curtis, Christian Michelides). Antiretroviral therapy has reduced infections in AIDS victims, but the decline hasn't been the same for all pathogens. Some infections have shown modest declines or no change at all. Could they be due to the "gay germ"?



Male homosexuality has low to moderate heritability (30 to 45%). A recent study in the UK Biobank and 23andMe has identified a number of genetic variants associated with same-sex sexual behavior. Together, they account for 8 to 25% of variation in male and female same-sex behavior (Ganna et al. 2019). There is thus a genetic predisposition, but it's weak and may simply reflect a smaller population of neurons for heterosexual orientation.

So this genetic predisposition seems to be interacting with something in the environment. But what?

There may be different environmental factors. One possibility would be a pathogen that alters its host's sexual orientation in order to enhance its chances of spreading to other hosts. This is Greg Cochran's "gay germ" theory (Cochran et al. 2000).

With the introduction of antiretroviral therapy for AIDS, we may have a chance to identify candidates for the "gay germ." Over time this therapy should reduce the incidence of infections in AIDS victims. Indeed it has, but the decline has been uneven.  A retrospective study of AIDS autopsies in Vienna between 1984 and 1999 found a lower rate of decline for infections due to fungi and most bacteria than for infections due to protozoa, viruses, and mycobacteria:

Extracerebral protozoal (Pneumocystis carinii, toxoplasmosis), Mycobacterium avium complex, viral [e.g., cytomegalovirus (CMV)], multiple opportunistic organ and CNS infections, and Kaposi sarcoma significantly decreased over time. There was less decrease in fungal infections, while bacterial organ and CNS infections (except for mycobacteriosis), lymphomas, HIV-associated CNS lesions (around 30%), non HIV-associated changes (vascular, metabolic, etc.) and negative CNS findings (10-11%) remained unchanged. (Jellinger et al. 2000)

These findings are in line with those of a retrospective study of AIDS autopsies in San Diego between 1982 and 1998:

Pneumocystis carinii pneumonia and Mycobacterium avium complex decreased, whereas bacterial infections increased and the frequency of fungal infection remained unchanged over time. (Eliezer et al. 2000)

After the lungs, such pathogens most often target the brain:

This study suggests that despite the beneficial effects of antiretroviral and anti-opportunistic infection therapy, involvement of the brain by HIV continues to be a frequent autopsy finding. (Eliezer et al. 2000).

Similar to a recent autopsy study from San Diego, these data suggest that despite the beneficial effects of modern antiretroviral combination therapy, involvement of the brain in AIDS subjects continues to be a frequent autopsy finding. (Jellinger et al. 2000)

Subjects with brain alterations at an early stage otherwise seemed almost normal:

Of the cases with early brain alterations, systemic opportunistic infections were present in only 5.9% of the cases, neoplasms in 0.5%, and neoplasms and opportunistic infections in 1.7%. (Eliezer et al. 2000)

A few caveats

The change in incidence over time partly reflects differences between fast-developing infections and slow-developing ones. By definition, people succumb more quickly to the former than to the latter. When antiretroviral therapy was still unavailable those infections were the ones that generally killed people with AIDS. Better control of aggressive infections may have also created a better environment for the growth of less aggressive infections.


But ...

It is harder to explain why the brain should remain a major pathogenic target. It is especially hard to explain why subjects with brain alterations at an early stage otherwise seemed almost normal.

Eggers et al. (2017) pointed out another apparent contradiction: HIV-associated neurocognitive disorders (HAND) are continuing to develop in people whose HIV infection is under control.

Despite the brain infection taking place in the days after primary infection, the development of HAND takes years. As an explanation for this ostensible contradiction, it has been suggested that initially, the brain infection is relatively well controlled, while later, there is a quantitative and qualitative breakdown of immune control in the CNS (Eggers et al. 2017)

Some authors have suggested co-infection by the Hepatitis C virus, but Eggers et al. (2017) ruled this out:

While some authors implicated HCV co-infection in the pathogenesis of HAND, a recent large and well-controlled study found no evidence for worse cognitive function in HCV co-infected patients, at least in the absence of liver dysfunction. (Eggers et al. 2017)

Pathogen "X"

Could we be looking at an unknown pathogen that exists independently of HIV? Over the years some have suggested that HIV is not the only pathogen involved in AIDS. In this case, pathogen "X" may cause adverse effects that get blamed on HIV, but its relationship with HIV is incidental, the only common denominator being the gay lifestyle.

I would propose the following scenario. Pathogen "X" enters its host early in life, just in time to alter that person's psychosexual development. From then on it remains in the background and reaps whatever benefit it gets from its behavior manipulation. Past the age of 40 the host becomes less useful, and the pathogen begins to cause more adverse effects, including neurocognitive disorders that are wrongly attributed to HIV.

Pathogen "X" is most likely a fungus. If we go back to the two retrospective studies, the fungal infections were the ones that seemed the least influenced by the introduction of antiretroviral therapy.


References

Cochran, G.M., Ewald, P.W., and Cochran, K.D. (2000). Infectious causation of disease: an evolutionary perspective. Perspectives in Biology and Medicine 43: 406-448.
https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.182.5521&rep=rep1&type=pdf 

Eggers, C., G. Arendt, K. Hahn, K., I.W. Husstedt, M. Mashke, et al. (2017). HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment. Journal of Neurology 264: 1715-1727
https://link.springer.com/article/10.1007/s00415-017-8503-2

Eliezer, M., R.M. DeTeresa, M.E. Mallory, and L.A. Hansen. (2000). Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 14(1): 69-74.
https://journals.lww.com/aidsonline/Fulltext/2000/01070/HIV_associated_brain_pathology_in_the_United.8.aspx

Ganna, A., K.J.H. Verweij, M.C. Nivard, R. Maier, R. Weddow, et al. (2019). Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior. Science 365(6456)
https://science.sciencemag.org/content/365/6456/eaat7693 

Jellinger, K.A., U. Setinek, M. Drlicek, G. Böhm, A. Steurer, and F. Lintner. (2000). Neuropathology and general autopsy findings in AIDS during the last 15 years. Acta Neuropathologica 100(2): 213-220.
https://www.ncbi.nlm.nih.gov/pubmed/10963370