Follicular T helper cells (Tfh), a subset of CD4 T lymphocytes, provide crucial help to B cells in the production of antigen-specific antibodies. Although several studies have analyzed the dynamics of Tfh cells in peripheral blood and lymph nodes (LNs) during Aids, none has yet addressed the impact of SIV infection on the dynamics of Tfh cells in the spleen, the primary organ of B cell activation. We show here a significant decrease in splenic Tfh cells in SIVmac251-infected rhesus macaques (RMs) during the acute phase of infection, which persists thereafter. This profound loss is associated with lack of sustained expression of the Tfh-defining transcription factors, Bcl-6 and c-Maf but with higher expression of the repressors KLF2 and Foxo1. In this context of Tfh abortive differentiation and loss, we found decreased percentages of memory B cell subsets and lower titers of SIV-specific IgG. We further demonstrate a drastic remodeling of the lymphoid architecture of the spleen and LNs, which disrupts the crucial cell-cell interactions necessary to maintain memory B cells and Tfh cells. Finally, our data demonstrated the early infection of Tfh cells. Paradoxically, the frequencies of SIV DNA were higher in splenic Tfh cells of RMs progressing more slowly suggesting sanctuaries for SIV in the spleen. Our findings provide important information regarding the impact of HIV/SIV infection on Tfh cells, and provide new clues for future vaccine strategies.

Whereas antiretroviral therapy (ART) suppresses viral replication, ART discontinuation results in viral rebound, indicating the presence of viral reservoirs (VRs) established within lymphoid tissues. Herein, by sorting CD4 T-cell subsets from the spleen, mesenteric and peripheral lymph nodes (LNs) of SIVmac251-infected rhesus macaques (RMs), we demonstrate that effector memory (TEM) and follicular helper (TFH) CD4 + T cells harbor the highest frequency of viral DNA and RNA, as well of early R-U5 transcripts in ART-naïve RMs. Furthermore, our results highlight that these two CD4 T cells subsets harbor viral DNA and early R-U5 transcripts in the spleen and mesenteric LNs (but not in peripheral LN) of RMs treated with ART at day 4 post infection suggesting that these two anatomical sites are important for viral persistence. Finally, after ART interruption, we demonstrate the rapid and, compared to peripheral LNs, earlier seeding of SIV in spleen and mesenteric LNs, thereby emphasizing the importance of these two anatomical sites for viral replication dynamics. Altogether our results advance understanding of early viral seeding in which visceral lymphoid tissues are crucial in maintaining TEM and TFH VRs.