The B-Cell Follicle in HIV Infection: Barrier to a Cure

Abstract

The majority of HIV replication occurs in secondary lymphoid organs (SLOs) such as the spleen, lymph nodes, and gut-associated lymphoid tissue. Within SLOs, HIV RNA + cells are concentrated in the B-cell follicle during chronic untreated infection, and emerging data suggest that they are a major source of replication in treated disease as well. The concentration of HIV RNA + cells in the B-cell follicle is mediated by several factors. Follicular CD4 + T-cell subsets including T-follicular helper cells and T-follicular regulatory cells are significantly more permissive to HIV than extrafollicular subsets. The B cell follicle also contains a large reservoir of extracellular HIV virions, which accumulate on the surface of follicular dendritic cells (FDCs) in germinal centers. FDC-bound HIV virions remain infectious even in the presence of neutralizing antibodies and can persist for months or even years. Moreover, the B-cell follicle is semi-immune privileged from CTL control. Frequencies of HIV- and SIV-specific CTL are lower in B-cell follicles compared to extrafollicular regions as the majority of CTL do not express the follicular homing receptor CXCR5. Additionally, CTL in the B-cell follicle may be less functional than extrafollicular CTL as many exhibit the recently described CD8 T follicular regulatory phenotype. Other factors may also contribute to the follicular concentration of HIV RNA + cells. Notably, the contribution of NK cells and γδ T cells to control and/or persistence of HIV RNA + cells in secondary lymphoid tissue remains poorly characterized. As HIV research moves increasingly toward the development of cure strategies, a greater understanding of the barriers to control of HIV infection in B-cell follicles is critical. Although no strategy has as of yet proven to be effective, a range of novel therapies to address these barriers are currently being investigated including genetically engineered CTL or chimeric antigen receptor T cells that express the follicular homing molecule CXCR5, treatment with IL-15 or an IL-15 superagonist, use of bispecific antibodies to harness the killing power of the follicular CD8 + T cell population, and disruption of the follicle through treatments such as rituximab.

CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

“…In addition, in the analyzed six HIV-infected patients, a high percentage of HIV-expressing cells localized within the B cell follicle also coexpressed the CD32a transcripts (median, 94%) compared to 4% of cells that were single CD32a + and 2% of cells that only expressed HIV RNA. The B cell follicle has been identified as an immune-privileged sanctuary site for HIV persistence (39). No differences were observed between viremic and aviremic donors (Fig.…”

Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

“…In order to determine the immunological effects of VDZ on the GI tract, we examined both immune inductive sites (represented by lymphoid aggregates, concentrated in the TI) and Moreover, B cell follicles may be semi-immune privileged sites due to the inability of cytotoxic T cells lacking follicular homing molecule CXCR5 (54) from entering them (55). In accordance with this concept, it has been hypothesized that overcoming the immune privilege of lymphoid follicles may be key to HIV-cure efforts (56). Among the strategies being considered are the development CXCR5-expressing chimeric antigen receptor (CAR) T cells (57), the use of bispecific antibodies (58) or treatment with latency reversal agents (LRA) (59).…”

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

“…It is well established that macrophages can serve as a reservoir for HIV [106][107][108]; thus, the BLTS-humanized mouse model provides a system for investigating human splenic macrophage-HIV interactions [5]. Additionally, the spleen is a major lymphoid tissue reservoir, with B cell follicles in the white-pulp serving as an immune privilege site for anti-HIV T-cells [109]. The human spleen in BLTShumanized mice provides a model for investigating anti-HIV immune response within the white-pulp and the role of B cell follicle in mediating HIV persistence.…”