Acute-phase CD4+ T cell responses targeting invariant viral regions are associated with control of live-attenuated simian immunodeficiency virus

Abstract

We manipulated SIVmac239{Delta}nef, a model of MHC-independent viral control, to evaluate characteristics of effective cellular responses mounted by Mauritian cynomolgus macaques (MCMs) who express the M3 MHC haplotype that has been associated with poor control of pathogenic SIV. We created SIV{Delta}nef-8x to test the hypothesis that effective SIV-specific T cell responses targeting invariant viral regions can emerge in the absence of immunodominant CD8+ T cell responses targeting variable epitopes, and that control is achievable in individuals lacking known protective MHC alleles. Full proteome IFN{gamma} ELISPOT assays identified six newly targeted immunogenic regions following SIV{Delta}nef-8x infection of M3/M3 MCMs. We deep sequenced circulating virus and found that four of the six newly targeted regions rarely accumulated mutations. Six animals infected with SIV{Delta}nef-8x targeted at least one of the four invariant regions and had a lower set point viral load compared to two animals that did not target any invariant regions. We found that MHC class II molecules restricted all four of the invariant peptide regions, while the two variable regions were restricted by MHC class I molecules. Therefore, in the absence of immunodominant CD8+ T cell responses that target variable regions during SIVmac239{Delta}nef infection, individuals without protective MHC alleles developed predominantly CD4+ T cell responses specific for invariant regions that may improve control of virus replication. Our results provide some evidence that antiviral CD4+ T cells during acute SIV infection can contribute to effective viral control and should be considered in strategies to combat HIV infection.\n\nImportanceStudies defining effective cellular immune responses to human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have largely focused on a rare population that express specific MHC class I alleles and control virus replication in the absence of antiretroviral treatment. This leaves in question whether similar effective immune responses can be achieved in the larger population. The majority of HIV-infected individuals mount CD8+ T cell responses that target variable viral regions that accumulate high-frequency escape mutations. Limiting T cell responses to these variable regions and targeting invariant viral regions, similar to observations in rare elite controllers, may provide an ideal strategy for the development of effective T cell responses in individuals with diverse MHC genetics. Therefore, it is paramount to determine whether T cell responses can be redirected towards invariant viral regions in individuals without protective MHC alleles and if these responses improve control of virus replication.