Spatial Alterations between CD4+ T Follicular Helper, B, and CD8+ T Cells during Simian Immunodeficiency Virus Infection: T/B Cell Homeostasis, Activation, and Potential Mechanism for Viral Escape

Abstract

HIV/SIV infections induce chronic immune activation with remodeling of lymphoid architecture and hypergammaglobulinemia, although the mechanisms leading to such symptoms remain to be fully elucidated. Moreover, lymph nodes have been highlighted as a predilection site for SIV escape in vivo. Following 20 rhesus macaques infected with SIVmac239, as they progress from pre to acute and chronic infection, we document for the first time the local dynamics T follicular helper (TFH) cells and B cells in situ. Progression of SIV infection was accompanied with increased numbers of well delineated follicles containing germinal centers (GCs) and TFH cells with a progressive increase in the density of PD-1 expression in lymph nodes. The rise in PD-1+ TFH cells was followed by a substantial accumulation of Ki67+ B cells within GCs. However, unlike in blood, major increases in the frequency of CD27+ memory B cells were observed in lymph nodes, indicating increased turnover of these cells, correlated with increases in total and SIV specific antibody levels. Of importance, compared to T cell zones, GCs seemed to exclude CD8+ T cells while harboring increasing numbers of CD4+ T cells, many of which are positive for SIVgag, providing an environment particularly beneficial for virus replication and reservoirs. Our data highlight for the first time important spatial interactions of GC cell subsets during SIV infection, the capacity of lymphoid tissues to maintain stable relative levels of circulating B cell subsets and a potential mechanism for viral reservoirs within GCs during SIV infection.

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

“…The dynamics of Tfh cell induction in acute HIV‐1 infection have not been precisely determined, but LN GCs containing proliferating Tfh cells are present in macaques by day 14 post‐SIV infection,168, 169 suggesting rapid induction of a Tfh cell response following infection.…”

“…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.…”

“…Despite the susceptibility of Tfh cells to infection with SIV/HIV, the frequency of GC Tfh cells begins to increase within a few months of infection188 and elevated Tfh cell numbers are routinely observed in LNs during chronic SIV and HIV infections,168, 173, 189, 190, 191 although Tfh cells are eventually depleted as progression to acquired immunodeficiency syndrome (AIDS) occurs 192. The expansion in Tfh cells is associated with an increase in GC B cells and plasma cells and elevated IgG production, suggesting that Tfh cells contribute to the dysregulation of B cells and antibody production that occurs during HIV‐1 infection 191.…”

“…The expansion in Tfh cells is associated with an increase in GC B cells and plasma cells and elevated IgG production, suggesting that Tfh cells contribute to the dysregulation of B cells and antibody production that occurs during HIV‐1 infection 191. The magnitude and duration of antigenic stimulation are known to be important determinants of the GC Tfh cell response,193 and although GC Tfh cell frequencies do not generally show a direct correlation with viral load, the increase in GC Tfh cells during chronic SIV/HIV infection is dependent on ongoing antigenic stimulation, as GC Tfh cell frequencies decline when viral replication is contained by antiretroviral therapy 168, 189, 191. Sustained LCMV replication in mice is also associated with expansion of GC Tfh cells, and here IL‐6 production has been shown to play a key role in driving Tfh cell differentiation during chronic infection 194, 195.…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…T FH cells are infected at higher frequencies in macaques and humans than in SMs [155]. In contrast to most other CD4þ T cells, this subset is expanded and accumulates in lymph node germinal centres during HIV and SIVmac infections [153,[156][157][158]. Whether T FH in HIV infection shows an altered function that could impact anti-HIV antibody development is unclear.…”