Quality and quantity of T _FH cells are critical for broad antibody development in SHIV _AD8 infection

Abstract

Broadly neutralizing antibodies (bNAbs) protect against HIV-1 infection, yet how they are generated during chronic infection remains unclear. It is known that T follicular helper (TFH) cells are needed to promote affinity maturation of B cells during an immune response; however, the role of TFH during HIV-1 infection is undefined within lymph node germinal centers (GCs). We use nonhuman primates to investigate the relationship in the early stage of chronic SHIVAD8 (simian-human immunodeficiency virus AD8) infection between envelope (Env)-specific TFH cells, Env-specific B cells, virus, and the generation of bNAbs during later infection. We found that both the frequency and quality of Env-specific TFH cells were associated with an expansion of Env-specific immunoglobulin G-positive GC B cells and broader neutralization across HIV clades. We also found a correlation between breadth of neutralization and the degree of somatic hypermutation in Env-specific memory B cells. Finally, we observed high viral loads and greater diversity of Env sequences in rhesus macaques that developed cross-reactive neutralization as compared to those that did not. These studies highlight the importance of boosting high-quality TFH populations as part of a robust vaccine regimen aimed at eliciting bNabs.

HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4 + T Cell Responses

“…Notably, none of these studies examined HIV-specific CD4 ϩ T cells. However, an eloquent study by Yamamoto et al recently reported that the quantity and quality of Env-specific germinal center (GC) Tfh cells were associated with broader antibody neutralization in SHIV-infected macaques (6). These authors found that IL-4-producing Env-specific GC Tfh cells were associated with an expansion of Env-specific immunoglobulin G-positive GC B cells, and using cluster analysis they identified 13 variables, including the percentage of Env-and Gagspecific CD154…”

“…Additionally, we calculated the antibody neutralization score to quantify the breadth and potency of plasma neutralization activity per patient. Points were assigned based on the ID 50 titers for each of the 11 tier 2/3 viruses: one point was awarded for titers up to 99, two points were given for titers of 100 to 999, and three points were awarded for titers greater than 1,000 ID 50 s, as described previously (6). The points were then summed to provide the overall neutralization score per patient.…”

“…The neutralization score is used to quantify both the breadth and potency of serum neutralization activity (6), where points are assigned and summed based on the 50% inhibitory dose (ID 50 ) titers for each of the 11 tier 2/3 viruses (one point for titers up to 99, two points for titers of 100 to 999, and three points for titers greater than 1,000). In this analysis, we observed that the breadth and magnitude of Gag-specific CD4 ϩ T cell responses were positively correlated with neutralization score, and a positive correlation was also observed for the breadth of Env-specific CD4 ϩ T cell targeting ( Fig.…”

“…The generation of broadly neutralizing antibodies likely requires functional germinal center formation and the provision of CD4 ϩ help to B cells. In nonhuman primates infected with simian-human immunodeficiency virus (SHIV), the quality and quantity of germinal center Env-specific CD4 ϩ T-follicular helper (Tfh) cells have been associated with the expansion of Envspecific B cells and broader antibody neutralization activity (6). In HIV-infected humans, studies have investigated the association between the frequencies of peripheral Tfh (pTfh) cells and the development of neutralizing antibodies (7)(8)(9).…”

Development of Broadly Neutralizing Antibodies and Their Mapping by Monomeric gp120 in Human Immunodeficiency Virus Type 1-Infected Humans and Simian-Human Immunodeficiency Virus SHIV SF162P3N -Infected Macaques

“…To date, bnAbs against HIV-1 tier 2 isolates have rarely been detected in SHIV-infected macaques (5)(6)(7)(8)(9). A previous screening of 40 macaques infected with uncloned SHIV AD8 or a molecular clone of SHIV AD8-CK15 identified a single animal, CE8J, that developed potent bnAbs directed to the N332 glycosylation site (5).…”