Bone marrow-derived CD4 + T cells are depleted in SIV-infected macaques and contribute to the size of the replication competent reservoir on ART.

The bone marrow (BM) is the key anatomic site for hematopoiesis and plays a significant role in the homeostasis of mature T cells. However, very little is known on the phenotype of BM-derived CD4+ T cells, their fate during SIV infection, and their contribution to viral persistence during antiretroviral therapy (ART). Here, we characterized the immunologic and virologic status of BM-derived CD4+ T cells in rhesus macaques prior to SIV infection, during the early chronic phase of infection, and after ART. We found that BM memory CD4+ T cells are significantly depleted following SIV infection, at levels that are similar to those measured in PB. In addition, BM-derived memory CD4+ T cells include a high frequency of cells that express the co-inhibitory receptors CTLA-4 and PD-1, two subsets previously shown to be enriched in viral reservoir; these cells appear to have a more resting phenotype then the same cells in the blood (PB). Finally, when we analyzed SIV-infected RMs in which viral replication was effectively suppressed by 12-months of ART-treatment, we found that BM CD4+ T cells harbor SIV-DNA and SIV-RNA at levels comparable to those of PB CD4+ T cells, including replication competent SIV. Thus, BM is a largely understudied anatomic site of the latent reservoir which contributes to viral persistence during ART and needs to be further characterized and targeted when designing therapies for a functional or sterilizing cure to HIV. Importance The latent viral reservoir is one of the major obstacles in purging the immune system of HIV. It is paramount that we elucidate which anatomic compartments harbor replication competent virus, that upon ART-treatment interruption results in viral rebound and pathogenesis. Here, using the rhesus macaque model of SIV infection and ART treatment, we examined the immunologic status of the BM and its role as a potential sanctuary for latent virus. We found that the BM compartment undergoes a similar depletion of memory CD4+ T cells as PB, and during ART treatment the BM-derived memory CD4+ T cells contain high levels of cells expressing CTLA-4 and PD-1, as well as comparable amounts of cell-associated SIV-DNA, SIV-RNA, and replication competent virus as PB. These results enrich our understanding of which anatomic compartments harbor replication virus and suggests that BM-derived CD4+ T cells need to be targeted by therapeutic strategies aimed at achieving an HIV cure.