B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers

Abstract

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 (TFH), 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 TFH. Indeed, CD8+ lymphocyte depletion of EC monkeys resulted in a dramatic re-distribution of productive SIV infection to non-TFH, with TFH 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.

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Furthermore, Tfh cell populations in both LNs and blood constitute a major (although not the only) site of SIV/HIV latency in macaques/humans receiving antiretroviral therapy 171, 176, 177, 178, 179. GC Tfh cells are not only highly activated cells that are good targets for HIV‐1 infection but are also located in close proximity to FDCs, which are an important reservoir of infectious virus and can readily transmit infection to Tfh cells 180, 181, 182, 183.…”

“…GC Tfh cells are not only highly activated cells that are good targets for HIV‐1 infection but are also located in close proximity to FDCs, which are an important reservoir of infectious virus and can readily transmit infection to Tfh cells 180, 181, 182, 183. Virus replication in GC Tfh cells may also be facilitated by the limited ability of antiviral CD8 + T cells to enter B‐cell follicles,168, 171, 175, 179, 184 although recent studies in the lymphocytic choriomeningitis virus (LCMV) mouse model show that persisting virus can be cleared from Tfh cells and B cells by a CXCR5 +  CD8 + T‐cell population that is able to enter B‐cell follicles,185, 186, 187 raising the intriguing prospect that if an analogous antiviral CD8 + T‐cell population expressing sufficiently high levels of CXCR5 could be induced in humans, this may enable targeting of Tfh cells that harbor persistent HIV‐1 such as the latent pool.…”

HIV-1 Reservoirs in Elite Controllers: Clues for Developing a Functional Cure?

“…A recent study in the monkey model of elite control showed that viral replication was mostly restricted to CD4 + follicular helper T (TFH) cells in B-cell follicles in lymph nodes [24]. CD8 + T cells are mostly excluded from this compartment and the low frequency of these effector cells could potentially explain why there is ongoing viral replication.…”

The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles

“…In HIV elite controllers and antiretroviral therapy (ART)-treated patients, T FH cells are the major source of persistent HIV. 5,6 Accordingly, the development of therapeutic strategies that induce virus-specific CD8 1 T cells capable of infiltrating into the B-cell follicle to eliminate reactivated latently HIV-infected T FH is a major unmet goal of shock-and-kill approaches for achieving an immune-mediated HIV cure.…”