Differential levels of immune control of HIV and highly variable disease course suggest that host genetics influence HIV disease progression. Since HLA A, B, and DRB1 gene loci specify immune cell recognition and activation, potentially influencing both protective and pathogenic responses, HLA genes are logical genetic candidates. HLA association studies are complicated by the extensive diversity at the 3 main loci (A, B, DRB1) and the requirement for large sample sizes.
Despite these obstacles, independent studies have now linked specific HLA types with high or low risk for HIV seroconversion, immunologic control, and disease progression. Findings from a number of groups agree that certain HLA A and B alleles (HLA B*27 B*57, 58, in US and Western European cohorts) present conserved regions of HIV gag and nef to T-cells. The hypothesis is that individuals with these alleles have effective anti-HIV CD8 T-cells that maintain immune control of HIV because virus escape mutations in these conserved regions result in significant loss of replicative fitness. Therefore the CD8 T-cells in these individuals tend to remain effective and if escape mutants are viable, they grow slowly. In either case, individuals with such alleles tend to have a slower rate of HIV disease progression. However, it is not yet clear whether there are specific alleles that increase or decrease risk of HIV associated neurocognitive disorder (HAND) or whether alleles that are linked to slow disease progression in general also protect from HAND.
Mild to moderate neuropsychological impairment can be detected in 30–40% of HIV infected cohorts, and affects an individual’s ability to work, day to day functioning, and quality of life. Antiretroviral treatment (ART), while significantly reducing incidence of HIV encephalitis, plasma HIV RNA, and reconstituting CD4 numbers and resistance to opportunistic infections, has had a less dramatic impact on chronic HAND, increasing the relative visibility of moderate cognitive impairment in otherwise well managed cohorts. As it becomes feasible to target CNS infection therapeutically, there is increasing interest in identifying genetic phenotypes that either predispose or protect the host from HAND. In an earlier cohort of 191 HIV-infected, HLA typed persons in the United States, HLA DR alleles that presented relatively few HIV peptides (especially HLA DR*04) were associated with a higher risk of HAND, but also, unexpectedly, low plasma HIV RNA levels. In contrast, those individuals with HLA DR types with broad peptide recognition had a lower risk of HAND, but comparatively higher HIV RNA levels. Our explanation for the differences in HIV RNA levels was that individuals with broad response alleles had more activated CD4 T-cells to host HIV replication, while those with low CD4 responses (and activation) had fewer permissive host cells and consequently less HIV replication. The higher risk of HAND in the low CD4 response subgroup could be due to a lack of CD4 help for HIV specific CD8 T-cells, whose role is to migrate into the CNS and destroy HIV infected cells. Lack of CD4 support for CD8 T-cells would permit spread of HIV and associated inflammation, leading to greater risk of neurocognitive impairment.
Recent studies from other groups are relevant to our initial report. HLA DR*04, which was linked to low (and narrow) CD4 T-cell responses to HIV is also reportedly associated with low CD4 T-cell responses to mitogens in Autism Spectrum Disorder. In the HIV field, specific HLA Class I (A and B) alleles that encode for protective CD8 recognition have been identified. HLA Class I alleles (B*27, B*57, B*58) that present conserved regions (mostly gag and nef) of HIV appear to protect against HIV disease progression and are at higher frequencies in long term non progressor and virus controller groups.
A robust method of testing genetic hypotheses is to re-examine the allele associations in a new, non-overlapping cohort. Our research group’s study in China presented an opportunity to validate our previous findings concerning HLA and HAND and extend our investigation in a new and ethnically different population. Several studies in China have reported on associations between HLA genes, HIV seroconversion and progression to an AIDS diagnosis, as well as T-cell recognition, providing important information on local allele frequencies for updating hypotheses. Based on our previous results and (other’s) findings for Class I alleles, we proposed to assess whether the HLA Class II allele previously identified, HLA DR*04, was associated with neurocognitive impairment, decline, and low HIV RNA levels. We also asked whether Class I alleles that present conserved peptides of HIV and are associated with slow disease progression (in the US and China) are also associated with protection from neurocognitive impairment. In addition, because a previous study of genetic variants associated with neurocognitive impairment in this cohort identified an association with ApoE4, the role of ApoE4 in mediating the HLA effects was also examined.