Diversity in the MHC
has been identified as the most significant AIDS-regulating genetic factor [3
]. Well-documented evidence has indicated that HLA
class I polymorphism specifically plays an important role in varied outcomes across individuals following HIV-1 infection [2
]. However, analyses based on general populations comparing HIV- to HIV+ individuals have shown little consistent evidence of HLA
association with HIV infection. In general, the identification of appropriate HIV- and HIV+ groups for comparison requires careful consideration, as the available groups have great potential for selection biases that may erroneously result in significant differences between the two groups. For example, the loss of rapid progressors amongst HIV+ individuals, which is common across cohorts, may artificially result in a high frequency of variants that associate with longer term nonprogression. Analyses of sero-discordant sexual partners examine both viral transmitters and recipients, providing a better-controlled research design for examining the potential influence of HLA
class I on HIV-1 transmission and susceptibility to infection.
We recently reported that HLA-Bw4
was associated with a lower risk for HIV-1 transmission from hemophiliac patients to their female partners [13
]. The two low-risk alleles for HIV-1 transmission, B*27
, that we detected in the present study both belong to the Bw4 antigen group. The Bw4 epitope on the alpha-1 domain of the class I HLA molecule forms part of the F-pocket that accommodates the C-terminal anchor residue of the bound peptide. This complex is recognized by the natural killer cell receptor KIR3DL1, which may explain the general protection of the group of alleles containing the Bw4 epitope. In addition, B*27 and B*57 are known to have characteristics that can delay HIV-1 adaptation to the host MHC [16
], explaining in part why these two alleles exhibit the strongest protective effect on AIDS progression, as well as HIV transmission, relative to all other Bw4 bearing HLA-B alleles.
HIV-1 transmitters (men with hemophilia) and recipients (their female partners) showed different patterns of HLA
associations. In the men, B*35
, though B*35PY
also tended in the same direction) was detected as a high-risk allele for HIV-1 transmission, whereas B*27
were associated with low risk. In female partners, none of the previously detected AIDS-regulating HLA
alleles showed an association with susceptibility to HIV-1 infection, consistent with a model in which HLA
class I diversity affects outcome after HIV infection, but not infection itself. While our sample size was small, there were no consistent tendencies for effects of these alleles on infection with those observed for viral load control, AIDS progression, and transmission. Our study was largely composed of European Americans infected with clade B virus, such that our results pertain to this ethnic group. Nevertheless, our data concur with a recent report showing that HLA
alleles/haplotypes associated with transmission in an African cohort do not associate with acquisition in their heterosexual partners [12
]. The different patterns of genetic associations illustrate that HIV-1 transmission and susceptibility to infection involve different host/viral mechanisms and therefore are subject to different genetic influences.
Our null data on susceptibility of heterosexual acquisition of HIV-1 infection among women are also consistent with a study on HLA
and mother-to-infant HIV-1 transmission in which the HLA-B
genotype of the recipient (the infant) did not alter the risk of transmission, whereas the HLA-B
genotype of the HIV transmitter (the mother) was associated with varied risks for HIV-1 transmission [9
]. If there is indeed an effect of HLA
polymorphism on susceptibility to HIV-1 infection, it may very well differ from that for viral transmission. For example, MHC
polymorphism might affect susceptibility by influencing innate immunity against HIV-1 infection through specific interactions with KIR. A larger sample with more HIV-1 infected women is needed to test this hypothesis.
B*35 showed consistent, significant associations with AIDS progression, HIV transmission, and HIV viral load levels, suggesting that the molecular variation of B*35 impacts these related processes in a coherent manner. While these associations appeared to be driven primarily by B*35Px for both progression to AIDS and HIV infectivity, lack of viral load control was observed for both B*35Px and B*35PY. Thus, both subgroups of B*35 may confer some level of susceptibility, especially in terms of viral load control, though B*35Px appears to have a stronger effect on AIDS progression and infectivity.
The consistent effects of B*35Px, B*27
on AIDS progression and transmission suggest that HLA
polymorphism may influence these events through a common mechanism. A likely explanation is the control of HIV viremia. In support of this model, the high risk B*35Px
was associated with higher setpoint HIV RNA levels, an indicator of more rapid AIDS progression [19
], while the two protective alleles B*27
were associated with lower setpoint HIV RNA levels. Furthermore, an association between HIV RNA level in blood and heterosexual transmission has been reported previously [21
], as has faster progression to AIDS with higher likelihood of heterosexual transmission [22
]. Our analysis suggests that HLA
class I polymorphisms contribute to these relationships.