The inhibitory receptor Programmed Death-1 (PD-1) has been shown to regulate CD8 T cell function during chronic SIV infection, however its role on CD4 T cells, specifically in the gut associated lymphoid tissue, is less well understood. Here, we show that a subset of CD4 T cells express high levels of PD-1 (PD-1hi) in the rectal mucosa, a preferential site of virus replication. The majority of these PD-1hi CD4 T cells expressed Bcl-6 and CXCR5, markers characteristic of T follicular helper cells in the lymph nodes. Following a pathogenic SIV infection, the frequency of PD-1hi cells (as a percent of CD4 T cells) dramatically increased in the rectal mucosa, however a significant fraction of them did not express CXCR5. Furthermore, only a small fraction of PD-1hi cells expressed CCR5 and despite this low level of viral co-receptor expression a significant fraction of these cells were productively infected. Interestingly, vaccinated SIV controllers did not present with this aberrant PD-1hi CD4 T cell enrichment and this lack of enrichment was associated with the presence of higher frequencies of SIV-specific granzyme B+ CD8 T cells within the lymphoid tissue, suggesting a role for anti-viral CD8 T cells in limiting aberrant expansion of PD-1hi CD4 T cells. These results highlight the importance of developing vaccines that enhance anti-viral CD8 T cells at sites of preferential viral replication and support the need for developing therapeutic interventions that limit expansion of SIV+ PD-1hi CD4 T cells at mucosal sites as a means to enhance viral control.

To evaluate antibody specificities induced by simian immunodeficiency virus (SIV) versus human immunodeficiency virus type 1 (HIV-1) envelope antigens in nonhuman primate (NHP), we profiled binding antibody responses to linear epitopes in NHP studies with HIV-1 or SIV immunogens. We found that, overall, HIV-1 Env IgG responses were dominated by V3, with the notable exception of the responses to the vaccine strain A244 Env that were dominated by V2, whereas the anti-SIVmac239 Env responses were dominated by V2 regardless of the vaccine regimen.

BackgroundIn early clinical studies, the live tuberculosis vaccine Mycobacterium bovis BCG exhibited 80% protective efficacy against pulmonary tuberculosis (TB). Although BCG still exhibits reliable protection against TB meningitis and miliary TB in early childhood it has become less reliable in protecting against pulmonary TB. During decades of in vitro cultivation BCG not only lost some genes due to deletions of regions of the chromosome but also underwent gene duplication and other mutations resulting in increased antioxidant production.Methodology/Principal FindingsTo determine whether microbial antioxidants influence vaccine immunogenicity, we eliminated duplicated alleles encoding the oxidative stress sigma factor SigH in BCG Tice and reduced the activity and secretion of iron co-factored superoxide dismutase. We then used assays of gene expression and flow cytometry with intracellular cytokine staining to compare BCG-specific immune responses in mice after vaccination with BCG Tice or the modified BCG vaccine. Compared to BCG, the modified vaccine induced greater IL-12p40, RANTES, and IL-21 mRNA in the spleens of mice at three days post-immunization, more cytokine-producing CD8+ lymphocytes at the peak of the primary immune response, and more IL-2-producing CD4+ lymphocytes during the memory phase. The modified vaccine also induced stronger secondary CD4+ lymphocyte responses and greater clearance of challenge bacilli.Conclusions/SignificanceWe conclude that antioxidants produced by BCG suppress host immune responses. These findings challenge the hypothesis that the failure of extensively cultivated BCG vaccines to prevent pulmonary tuberculosis is due to over-attenuation and suggest instead a new model in which BCG evolved to produce more immunity-suppressing antioxidants. By targeting these antioxidants it may be possible to restore BCG's ability to protect against pulmonary TB.

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HIV-epitope-specific T cell responses are often comprised of clonotypic expansions with distinct functional properties. In HIV+ individuals, we measured PD-1 and IL-7Rα expression, MHC-I tetramer binding, cytokine production, and proliferation profiles of dominant and sub-dominant T cell receptor clonotypes to evaluate the relationship between the composition of the HIV-specific T cell repertoire and clonotypic phenotype and function. Dominant clonotypes are characterized by higher PD-1 expression and lower C127 expression compared to sub-dominant clonotypes and TCR avidity positively correlates with PD-1 expression. At low peptide concentrations, dominant clonotypes fail to survive in culture. In response to stimulation with peptides representing variant epitopes, sub-dominant clonotypes produce higher relative levels of cytokines and display greater capacity for cross-recognition compared to dominant clonotypes. These data indicate that dominant clonotypes within HIV-specific T cell responses display a phenotype consistent with ongoing exposure to cognate viral epitopes and suggest that cross-reactive, sub-dominant clonotypes may retain greater capacity to suppress replication of viral variants as well as to survive in the absence of strong antigenic signaling.