A B cell follicle sanctuary permits persistent productive SIV infection in elite controllers

Chronic phase HIV/SIV replication is reduced by as much as 10,000-fold in elite controllers (EC) compared to typical progressors, but sufficient viral replication persists in EC tissues to allow viral sequence evolution and induce excess immune activation. Here, we show that productive SIV infection in rhesus monkey EC is strikingly restricted to follicular helper CD4(+) T cells (T(FH)), suggesting that while the potent SIV-specific CD8(+) T cells of these monkeys can effectively clear productive infection from extra-follicular sites, their relative exclusion from B cell follicles limits elimination of infected T(FH). Indeed, CD8(+) lymphocyte depletion of EC monkeys resulted in a dramatic re-distribution of productive SIV infection to non-T(FH), with T(FH) restriction resuming upon CD8(+) T cell recovery. Thus, B cell follicles constitute sanctuaries for persistent SIV replication in the presence of potent anti-viral CD8(+) T cell responses, potentially complicating efforts to cure HIV infection with therapeutic vaccination or T cell immunotherapy.