MHC Heterozygote Advantage in Simian Immunodeficiency Virus–Infected Mauritian Cynomolgus Macaques

This manuscript demonstrates unambiguous major histocompatibility complex heterozygote advantage in macaque monkeys infected with the same strain of simian immunodeficiency virus, suggesting that a prophylactic HIV vaccine should elicit a population of CD8+ T cells with broad specificity. A Broad View of HIV Some studies of HIV-infected people have suggested that HIV is better controlled when the individual’s immune response is broader, that is, when more parts of the HIV virus are recognized by T cells. Indeed, the lack of a broad immune response may explain why HIV vaccines have generally not been successful. Despite the importance of this question for vaccine design, it has been difficult to answer definitively because of diversity in HIV strain, sampling time after infection, individual genetics, and other variables. Now, O’Connor et al. use genetically defined Mauritian cynomolgus macaques to get around these issues and test whether a broader immune response does in fact lead to better disease control. The immune response to a virus is determined in part by the genetics at the HLA locus. This locus is important because variability in HLA class I genes determines the number of major histocompatibility complex (MHC) molecules generated; the number of MHC molecules then determines the number of epitopes that can be presented to immune CD8 T cells. Individuals who are heterozygotes at this locus are expected to have a broader immune response than do homozygotes because they have the potential to present a more diverse set of epitopes to immune cells. O’Connor and colleagues measured viral blood concentrations and cellular immune responses in cynomolgus macaques harboring identical MHC genetics and infected with the same strain of simian immunodeficiency virus; this enabled them to unambiguously define the relationship among MHC diversity, CD8 T cell breadth, and disease outcome. They found that the vast majority of macaques homozygous for MHC had viral loads nearly 80 times those of their heterozygote counterparts; the associated CD8 T cell responses, measured by immune assays that rely on visualization techniques, were inconsistent. Therefore, to better understand their results, the authors examined how the animals’ CD8 T cell epitopes changed with time. They found that viral sequences isolated from MHC heterozygotes collected 1 year after infection matched variants observed in each of their MHC homozygote counterparts at 1 year after infection, which suggested that the CD8 T cell responses in MHC heterozygotes were an assemblage of the responses from their MHC homozygote counterparts. These data collectively indicate that the potential breadth of the immune response determines viral replication: The broader the response, the less replication. This study builds on previous observational studies showing heterozygote advantage in HIV-infected people, and sets the stage for future studies exploring the mechanisms responsible for this immunological control of immunodeficiency viruses. Furthermore, through the use of these macaques with identical MHC genetics, vaccine candidates can be tested for their effectiveness in the presence of limited CD8 T lymphocyte diversity. The importance of a broad CD8 T lymphocyte (CD8-TL) immune response to HIV is unknown. Ex vivo measurements of immunological activity directed at a limited number of defined epitopes provide an incomplete portrait of the actual immune response. We examined viral loads in simian immunodeficiency virus (SIV)–infected major histocompatibility complex (MHC)–homozygous and MHC-heterozygous Mauritian cynomolgus macaques. Chronic viremia in MHC-homozygous macaques was 80 times that in MHC-heterozygous macaques. Virus from MHC-homozygous macaques accumulated 11 to 14 variants, consistent with escape from CD8-TL responses after 1 year of SIV infection. The pattern of mutations detected in MHC-heterozygous macaques suggests that their epitope-specific CD8-TL responses are a composite of those present in their MHC-homozygous counterparts. These results provide the clearest example of MHC heterozygote advantage among individuals infected with the same immunodeficiency virus strain, suggesting that broad recognition of multiple CD8-TL epitopes should be a key feature of HIV vaccines.