Impact of Chronic HIV/SIV Infection on T Follicular Helper Cell Subsets and Germinal Center Homeostasis

Abstract

The discovery of broad and potent HIV-1 neutralizing antibodies (bNAbs) has renewed optimism for developing an effective vaccine against HIV-1. The generation of most bNAbs requires multiple rounds of B cell receptor affinity maturation, suggesting a crucial role of follicular helper T (Tfh) cells in their production. However, less than 1% of HIV-infected patients develop bNAbs that arise late in the course of infection, indicating probable Tfh and B cell dysfunctions in this context. Since the last few years, many studies have characterized Tfh cells from lymph nodes and spleen of HIV-infected individuals and SIV-infected macaques. Various lymphoid Tfh cell subsets have been identified, including precursor Tfh (pTfh), germinal center Tfh (GC Tfh), and the regulatory counterpart of Tfh cells, the follicular regulatory T cells. The latter have been reported to play a crucial role in the control of T and B cell crosstalk and GC reactions. More recently, circulating Tfh-like cells (cTfh) have been identified. Meanwhile, advances in single-cell technologies have made possible to analyze the transcriptional profiles of low abundant cells, such as Tfh populations. Using transcriptional signatures, we review here the impact of chronic SIV/HIV infection on Tfh, GC Tfh, pTfh, and cTfh differentiation and helper T cell functions with regard to their capacity to induce efficient B cell maturation. We will explore some hypothesis to explain the increased proportion of Tfh cells reported in chronically infected individuals and the impact on HIV pathogenesis.

Chronic simian immunodeficiency virus infection is associated with contrasting phenotypes of dysfunctional Bcl6+ germinal center B cells or Bcl6−Bcl2+ non‐germinal center B cells

“…B cell dysfunction is a hallmark of chronic HIV infection that has been shown to persist even during suppressive highly active anti‐retroviral therapy. Dysfunctional responses is thought to be driven by an expansion of Tfh cells that likely contribute to hyper‐reactive GC reactions characterized by an expansion of GC B cells that express Bcl6 and hypergammaglobulinemia . In contrast to hyper‐reactive B cell responses, B cell exhaustion associated with chronic immune activation has been reported during chronic HIV infection .…”

“…Dysfunctional responses is thought to be driven by an expansion of Tfh cells that likely contribute to hyper-reactive GC reactions characterized by an expansion of GC B cells that express Bcl6 and hypergammaglobulinemia. 1,3,4,[14][15][16] In contrast to hyperreactive B cell responses, B cell exhaustion associated with chronic immune activation has been reported during chronic HIV infection. 22 We observed similar contrasting phenotypes in chronically infected rhesus macaques with significantly higher frequencies of Bcl6 + IgG + 26,27 and elevated levels of IFNα have been reported in the LN during SIV and HIV infections.…”

“…Our results showed that IL- Both chronic HIV and SIV infections have been reported to exhibit an increase in Tfh cells that was found to be associated with hyperactive GC B cells and hypergammaglobulinemia. 1,3,4,[14][15][16] To assess if either the increased expression or lack of Bcl6 was accompanied by changes in the frequency of Tfh, we examined the frequency of Tfh in the LN from both SIV + Bcl6 hi and SIV + Bcl6 lo group of animals and compared them to uninfected animals. Tfh cells were discriminated based on the expression of PD-1, Bcl6 and ICOS ( Figure 2F) as reported previously.…”

Follicular Dendritic Cells of Lymph Nodes as Human Immunodeficiency Virus/Simian Immunodeficiency Virus Reservoirs and Insights on Cervical Lymph Node

“…In cART-naïve as well as treated individuals, T FH and GC B cells are elevated ( 94 ). In addition, there is a direct correlation of T FH and GC B cells with the activated T-cell population in the LNs ( 95 ).…”

Germinal centers B-cell reaction and T follicular helper cells in response to HIV-1 infection

“…By being highly permissive to HIV-1, Tfh cells are targeted early after infection (5,41). However, tissue-resident Tfh cells accumulate during the chronic phases of infection (38,39,42)…”