The B-cell follicle in HIV infection: Barrier to a cure

Matthew P. Bronnimann, Pamela J. Skinner, Elizabeth Connick

Research output: Contribution to journalReview articlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Article number20
JournalFrontiers in immunology
Volume9
Issue numberJAN
DOIs
StatePublished - Jan 25 2018

Bibliographical note

Funding Information:
This research was funded by R01 AI096966 and the Martin Delaney BELIEVE Collaboratory NIAID award UM1AI126617, co-funded by NIDA, NIMH, and NINDS.

Publisher Copyright:
© 2018 Bronnimann, Skinner and Connick.

Keywords

  • B cell follicle sanctuary
  • Cytotoxic T-cell (CTL)
  • Follicular dendritic cell
  • Gamma delta T cells
  • HIV cure research
  • NK cells
  • Regulatory T cells
  • T follicular helper cell subsets

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