While it has been important to focus down on the specific details of how transmission occurs at a cellular and bodily level, it is important for the purposes of prevention and reassurance in the real world to be aware that all transmission is by definition always interpersonal i.e. it involves two or more people. As such, it needs to be understood as a social phenomenon as much as a biological one.

Resistance to infection

Research in Kenya has identified a particular genetic tissue type which is associated with a low risk of HIV infection despite repeated exposure to HIV. Women with the HLA–28 genetic marker were much more likely to be seronegative in the Nairobi sex workers study.

Some of the genetic patterns seen in persistently seronegative women in Nairobi have not been seen in North Americans or Europeans. These patterns are rare in the Nairobi cohort; however, they have also been seen amongst men persistently seronegative despite repeated exposure to HIV–positive partners.

The more dissimilar the mother and baby's MHC 1 profile, the lower the chance of transmission from mother to baby. The closer the fit, the greater the likelihood of transmission.

More recently a number of studies in Africa have found that different MHC 1 profiles vary in their reactivity to HIV by as much as eleven-fold (Frahm 2004; Kiepiela 2004), and that there was a strong correlation between subject’s reactivity to HIV and their viral load, which varied from 200,000 and above in those with the least reactive MHC types to a few hundred with the most reactive. These surveys are the most comprehensive yet that map out a huge degree of genetic variability in susceptibility ti HIV infection and progression to AIDS.

Cytotoxic T-cell protection against HIV

In Gambia, British researchers have found female prostitutes with immune responses to HIV yet no evidence of infection. The researchers took samples of CD8 lymphocytes (cytotoxic lymphocytes or CTL) from women persistently seronegative despite a high risk of exposure. These lymphocytes were then exposed to genetic material from HIV to determine whether they recognised this material. If the CD8 lymphocytes had encountered these genetic sequences in the past, they would show a response. In three out of six women they observed immune responses to HIV despite no evidence of infection.

In Nairobi, British vaccine researchers have identified a similar group of women, and have also made a disturbing discovery about the mechanisms which maintain this form of immune response. The group found that 6 persistently seronegative women with cytotoxic T-lymphocyte responses to HIV seroconverted after they stopped commercial sex work for a period (and therefore reduced the amount of unprotected sex they engaged in). This finding implies that repeated exposure to HIV might be necessary in order to maintain the cytotoxic response (Kaul).

Investigations are now going on to determine what degree of overlap exists between the two forms of resistance. For example, does a strong immune response to HIV depend on possessing a particular genetic type? Or is a CTL response to HIV a function of exposure to very small amounts of HIV which `prime' the immune system to recognise HIV in the future?

Another interesting observation is the finding that nearly 50% of seronegative Ethiopians tested in Israel have specific immunity to HIV, but no evidence of HIV infection or HIV antibodies. Furthermore, specific cellular immunity was found to increase over the course of one year in these individuals, although 5 of the 21 had evidence of HIV RNA after one year of follow–up. It is possible that all 21 have undetectable HIV infection which is extremely well controlled, to the extent that viral expression has been halted (hence the lack of antibody response), rather than resistance to HIV.

The authors speculate that a high burden of parasitic infections in these individuals could have enhanced their ability to mount an immune response to HIV, but if this were the case one would expect to see this degree of HIV–specific immunity on a far larger scale in Africa. It is more plausible that this group of individuals were exposed to a geographically confined, defective strain of HIV, resulting in either immunity or very easily controllable infection (Bar–Yehuda).

In 2003 a UK team published findings showing that the negative partner in serodiscordant couples in long-term relationships who had unprotected sex acquired a degree of immunity to their partner’s HIV (Peters 2003).

Dr Peters’ team studied 29 monogamous heterosexual serodiscordant couples who had had frequent unprotected intercourse for more than six months. They compared the anti-HIV immune responses in the negative partner to those in a control group of 15 HIV-negative women and 10 Hiv-negative men who had had no sex, or only protected sex, for at least the previous six months.

They took CD4 cells from all the subjects and attempted to infect them with various different strains of HIV in the test tube.

It was found that CD4 cells in women who had had unprotected sex with HIV-positive men were only 10% as likely to be infected with CCR5-tropic HIV as CD4 cells from women who had had protected or no sex.

The HIV-negative men who had had unprotected sex with positive women had half that degree of protection: their CD4 cells were 20% as likely to be infected with HIV as cells from men who’d had protected or no sex.

A study, presented by Dr Tuofu Zhu (see reference) at the 2004 Bangkok World AIDS Conference found evidence of the same immunity in gay men.

Zhu was studying “long-term exposed seronegative" partners of HIV-positive gay men. The group consisted of the HIV-negative partners of HIV-positive men who had been diagnosed between 1994 and 1998.

Out of 94 HIV-negative regular partners of positive men, he found 14 who had become HIV-positive.

Two of the partners appeared to have caught HIV from their partners early on in their relationship, but to have mounted a successful immune response to it. They had no antibodies to HIV - in other words, they did not test HIV-positive by conventional tests. The fact that they had HIV at all could only be detected by hypersensitive viral-load testing, which picked up HIV in their blood at a count of 0.05 copies - one thousandth of the amount usually called "undetectable" by standard tests. There were no infections from regular partners more than 18 months after the start of the relationship.

The other 12 of the 14, however, had recognizable HIV infections with positive antibody responses. Some maintained low viral loads in the 500-2,000 range and showed some evidence of an immune response to HIV; others had standard viral loads in the tens of thousands. But all 12 had clearly not caught HIV from their regular partners. Genetic analysis of the virus they carried showed that not only was it completely different in each case from the virus their partner carried, but that on average it was more different than any randomly selected North American strain would have been.

When they had a strong immune response to HIV, their virus tended to change in a completely different way to their partner's and become more unlike it as time went on. When people only had a weak response to their partner's HIV, their viruses became more similar.

Chemokine receptor mutations and resistance to infection

Viruses have a particular host cell in the host animal or plant and HIV is no exception. Hepatitis viruses have host cells in the liver and herpes simplex virus (causing cold sores) live in peripheral nerve cells. The host cells for HIV are those carrying CD4 molecules – macrophages and CD4 T lymphocytes (CD4 cells). HIV uses proteins on its surface called gp120 and gp41 to attach to the CD4 molecule on cells. Specific antibodies to gp120 can block the attachment to CD4 molecules.

In 1996 it was discovered that HIV also binds to a second protein on the surface of human cells, called chemokine receptor 5 or CCR5, as part of the process of infecting a cell. The genetic instructions for producing this protein are contained in a gene called the CCR5 gene. Everyone has two copies of this gene, but a significant proportion of the population (about one in seven US whites, and one in 59 US blacks) have a mutation in one or both of these genes which interferes in the production of the protein.

People who have two mutant CCR5 genes may be partially protected against infection with NSI strains of HIV. However, they are not completely protected against HIV infection, since they remain susceptible to SI strains of HIV. There have now been four separate papers describing cases in which people with two mutant CCR5 genes have become infected with HIV.

Studies have found that among HIV–positive people who were infected sexually, those who have one mutant CCR5 gene experience slightly slower HIV disease progression (characterised by one researcher as `only a couple of years'). No reduction in disease progression was seen among people infected by other routes, such as blood products or drug injecting, perhaps because they were probably exposed to larger amounts of HIV when they became infected.

The CCR5 protein is believed normally to act as a receptor for three chemokines (immune system chemicals) known as RANTES, MIP–1 alpha and MIP–1beta. Studies have shown that HIV–positive people who do not progress, and HIV–negative people who have been repeatedly exposed to the virus through unprotected sex yet do not become infected, often have unusually high levels of these chemokines. They are thought to inhibit HIV either because they bind to the CCR5 protein on CD4 cells and `block' it, or because their presence causes the shape of the CCR5 protein to change, or because they cause the cell to display fewer CCR5 proteins on its surface. In any event, this prevents HIV from using the receptor and so reduces the chance that the cells will be infected. It is speculated that levels of these chemokines may fall with age, which might explain why older people tend to experience faster HIV disease progression than younger people.

The level of CCR5 expression per CD4 cell appears to be increased in an environment of high immune activation, which may explain why HIV infection is more frequent in Africa and Asia. A research team in Israel compared levels of CCR5 expression in HIV-negative Ethiopians and an HIV-negative Israeli control group and found significantly higher levels of CCR5 expression. However, they also found higher levels of CCR5 expression in Ethiopian immigrants resident in Israel for more than five years, despite no differences in immune activation levels when compared to an Israeli control group. This finding suggests that there may be a genetic predisposition to increased CCR5 expression in some African populations that could also account for higher prevalence (Kalinkovich).

CXCR4 (Fusin)

References

Dean M et al. Genetic restriction of HIV–1 infection and progression to AIDS by a deletion allele of the CCR5 structural gene. Science 273: 1856–1862, 1996.

Deng HK et al. Identification of a major co–receptor for primary isolates of HIV–1. Nature 381: 661–666.

Frahm N et al. Consistent CTL targeting of immunodominant regions in HIV across different ethnicities. J. Virol. 78(5), 2004.

Kalinkovich A et al. Increased CCR5 expression in Ethiopians: Relevance to the rapid spread of HIV infection in Africa? XIII International AIDS Conference, Durban, abstract MoPeA2016, 2000.

Kaul R et al. Late seroconversion in HIV ‘resistant’ Nairobi prostitutes is associated with a preceding decrease in HIV exposure. Seventh Conference on Retroviruses, San Francisco, abstract 489, 2000.

Kiepiela P et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature, 432(7018): 769-775. 2004.

Peters B et al. Study of Allo-immunization in Humans During Sexual Intercourse and Effects on HIV Infectivity. Tenth CROI, Boston, abstract 424, 2003. 

Zhu T. Breakthrough HIV-1 infection in long-term exposed seronegative individuals. 15^th International AIDS Conference, Bangkok, abstract TuOrA1141, 1994.