The roles of FRCs in HIV-1 spread and establishment of latency

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Secondary lymphoid organs including lymph nodes (LNs) are a major site for HIV-1 spread. Furthermore, secondary lymphoid organs harbor viral reservoirs, which are a barrier to curing AIDS. Follicular helper T cells and follicular dendritic cells in B cell follicles are well studied as viral reservoirs in LNs. Notably, in addition to B cell follicles, T cell zones (TCZs) within LNs contain bona fide latent and persistent viral reservoirs in antiretroviral therapy-suppressed HIV-1 patients. However, despite the potential of TCZs as a source of viral reservoirs, how HIV-1 disseminates and how viral reservoirs are generated in TCZs are poorly understood. In this application, we propose to determine the effect of TCZ fibroblastic reticular cells (TRCs) on HIV-1 and SIV spread and latency establishment. We previously demonstrated that TRCs isolated from human LNs mediate trans-infection of HIV- 1 and that the interaction between hyaluronan (a polysaccharide) and CD44 plays a key role in this process. Additionally, our preliminary experiments showed that TRCs render resting CD4+ T cells, the most abundant cell group in TCZs, permissive to both productive and latent infection when the T cells are cocultured with TRCs prior to infection. Therefore, it is possible that the interactions between resting CD4+ T cells and TRCs promote HIV- 1 spread by two mechanisms, i.e., enhancing of permissiveness to HIV-1 infection and mediating trans-infection. However, it is unknown whether TRCs mediate trans-infection of HIV-1 through CD44-hyaluronan interactions in vivo and how TRCs enhance the permissiveness of resting CD4+ T cells to productive and latent infection. We will investigate whether TRCs isolated from rhesus macaque LNs mediate trans-infection of SIV via CD44- hyaluronan interactions ex vivo. This investigation allows us to determine the extent of conservation of the trans- infection mechanism described above and the usefulness of an in vivo SIV/rhesus macaque model for studies of TRC-dependent HIV-1 spread in secondary lymphoid organs. Additionally, we will identify the TRC factors that render resting CD4+ T cells permissive to HIV-1 infection and define the roles of TRCs in latency establishment in TCZs. Completion of the proposed research establishes the basis for a mechanistic understanding of the roles of TRCs in HIV dissemination and latency and could contribute to the development of a strategy inhibiting latency establishment.