Germinal center T follicular helper cells are highly permissive to HIV-1 and alter their phenotype during virus replication

Stephanie L. Kohler, Michael N. Pham, Joy M. Folkvord, Tessa Arends, Shannon M. Miller, Brodie Miles, Amie L. Meditz, Martin McCarter, David N. Levy, Elizabeth Connick

Research output: Contribution to journalArticlepeer-review

Abstract

HIV-1 replication is concentrated within CD4+ T cells in B cell follicles of secondary lymphoid tissues during asymptomatic disease. Limited data suggest that a subset of T follicular helper cells (TFH) within germinal centers (GC) is highly permissive to HIV-1. Whether GC TFH are the major HIV-1 virus-producing cells in vivo has not been established. In this study, we investigated TFH permissivity to HIV-1 ex vivo by spinoculating and culturing tonsil cells with HIV-1 GFP reporter viruses. Using flow cytometry, higher percentages of GC TFH (CXCR5highPD-1high) and CXCR5+programmed cell death-1 (PD-1)low cells were GFP+ than non-GC TFH (CXCR5+PD-1intermediate) or extrafollicular (EF) (CXCR5-) cells. When sorted prior to spinoculation, however, GC TFH were substantially more permissive than CXCR5+PD-1low or EF cells, suggesting that many GC TFH transition to a CXCR5+PD-1low phenotype during productive infection. In situ hybridization on inguinal lymph node sections from untreated HIV-1-infected individuals without AIDS revealed higher frequencies of HIV-1 RNA+ cells in GC than non-GC regions of follicle or EF regions. Superinfection of HIV-1-infected individuals' lymph node cells with GFP reporter virus confirmed the permissivity of follicular cells ex vivo. Lymph node immunostaining revealed 96% of CXCR5+CD4+ cells were located in follicles. Within sorted lymph node cells from four HIV-infected individuals, CXCR5+ subsets harbored 11-66-fold more HIV-1 RNA than CXCR5- subsets, as determined by RT PCR. Thus, GC TFH are highly permissive to HIV-1, but downregulate PD-1 and, to a lesser extent, CXCR5 during HIV-1 replication. These data further implicate GC TFH as the major HIV-1-producing cells in chronic asymptomatic HIV-1 infection.

Original languageEnglish (US)
Pages (from-to)2711-2722
Number of pages12
JournalJournal of Immunology
Volume196
Issue number6
DOIs
StatePublished - Mar 15 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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