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.

Highlights

  • T-follicular helper cells (TFH) MemoryIt is well established in peripheral blood that CD4 central memory (CM) and transitional memory subsets contain the majority of proviral HIV DNA during antiretroviral therapy (ART) [34]

  • Specialty section: This article was submitted to HIV and AIDS, a section of the journal Frontiers in Immunology

  • The B cell follicle contains a large reservoir of extracellular HIV virions, which accumulate on the surface of follicular dendritic cells (FDCs) in germinal centers

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Summary

TFH Memory

It is well established in peripheral blood that CD4 central memory (CM) and transitional memory subsets contain the majority of proviral HIV DNA during ART [34]. It was reported in HIV infection that during ART, PD-1+ memory TFH are the major reservoir of cells harboring replication competent virus [36]. During SIV infection, ART results in the concentration of SIV DNA+ cells in PD1+ CTLA-4+ TFH in the B cell follicle. Replication competent virus was detected in PD-1+ CTLA-4+ memory CD4 T cells in seven of seven animals and in PD-1− CTLA-4+ memory CD4+ T cells in six of seven animals [37] Taken together, these data suggest that memory PD-1+ TFH contain a large reservoir of replication competent HIV and SIV during ART. A recent study demonstrated that peripheral blood TFH (pTFH) constitute the major reservoir for replication competent HIV from peripheral blood CM CD4+ T cells of patients on ART [38]. Some pTFH appear to traffic to GCs and appear similar to TFH post immunization, suggesting that cells may be able to transition between TFH and pTFH [40]

Impairments in Humoral Immunity Mediated by TFH Dysfunction
CTL CONTROL
FOLLICULAR DENDRITIC CELLS
NK CELLS
Likely ineffective because FDCs are not infected
Latency Reversal Agents
Clearing the HIV Reservoir on FDCs
CONCLUDING REMARKS
Full Text
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