While there has been a large amount of research conducted on the mechanisms of HLA-mediated immune control of HIV, there are still many unknowns. For example, protective alleles, such as HLA-B*81, are associated with profound protection from CD4+ T cell decline but in the absence of robust control of early plasma viraemia. The authors identified additional HLA class I (B*1401, B*57, B*5801, as well as B*81) and class II (DQB1*02 and DRB1*15) alleles that also display such a discordant virologic and immunologic phenotype in a Zambian early infection cohort. They found that such HLA class I alleles were also associated with an enhanced immune response to conserved epitopes in Gag. In addition, these HLA class I alleles were associated with reduced levels of lipopolysaccharide (LPS) in the plasma during acute infection. The authors found that elevated LPS levels early in infection predicted accelerated CD4+ T cell decline, immune activation and exhaustion. Therefore this suggests that there are novel mechanisms underlying the HLA-mediated immune control of HIV pathogenesis that do not necessarily involve significant control of early viraemia, with microbial translocation being a potential direct driver of HIV-1 pathogenesis rather than simply a consequence.
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