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Background: The germinal center (GC) resident T follicular helper cells (Tfh) represent a significant fraction of total pool of HIV/SIV infected cells during chronic infection and HAART. The GC are generally thought to exclude CD8 T cells and antiviral CD8 T cells with potential to migrate to GC (follicular CD8) may enhance HIV/SIV control and reduce viral reservoirs. Here we studied the follicular CD8 in a cohort of DNA/MVA vaccinated rhesus macaques (RM) that controlled or did not control a pathogenic SIV infection. Methods: RM were vaccinated with a DNA/MVA SIV vaccine and challenged intrarectally with SIVmac251. Animals with viral load below 1,000 copies at set point were defined as controllers. All controller RM (n = 19) were vaccinated and noncontroller RM (n = 18) consisted of both vaccinated and unvaccinated. Results: Post challenge, we observed an aberrant enrichment of SIV + PD-1 CD4 T cells in the LN and rectum of non-controllers but not controllers. The enhanced viral control was associated with higher frequency of Gag CM9 Tet + CD8 T cells in the LN of controller RM compared to non-controller RM. This was not evident in blood. Interestingly, a significant fraction of anti-viral CD8 T cells in the controller RM co-expressed CXCR5 (required for homing to B cell follicles/GC). The frequency of Tet + CXCR5 + granzyme B + cells was also higher in the LN of controller RM and higher frequencies correlated with lower Tfh and enhanced viral control. Immunofluorescence staining revealed co-localization of CD8 T cells with PD-1 cells in IgDGC, a phenomena not observed in the non-controller RM. Impressively, the CXCR5 + CD8 T cells from the controller RM restricted the anti-CD3 driven expansion of CM9 peptide pulsed Tfh cells in vitro suggesting their killing potential. Conclusions: Our results reveal a novel subset of anti-viral CD8 T cells that may contribute to enhanced control of pathogenic SIV infection by infiltrating to GC of lymphoid sites and limiting SIV replication in Tfh in a vaccine setting.

A Novel T-cell Vaccine Eliciting T-cell Specificities Associated with Control of HIV-1 In Humans Is Highly Immunogenic in Mice and Macaques