In:
Journal of Virology, American Society for Microbiology, Vol. 90, No. 17 ( 2016-09), p. 7833-7847
Abstract:
Human immunodeficiency virus (HIV) infects and depletes CD4 + T cells, but subsets of CD4 + T cells vary in their susceptibility and permissiveness to infection. For example, HIV preferentially depletes interleukin-17 (IL-17)-producing T helper 17 (T h 17) cells and T follicular helper (T fh ) cells. The preferential loss of T h 17 cells during the acute phase of infection impairs the integrity of the gut mucosal barrier, which drives chronic immune activation—a key determinant of disease progression. The preferential loss of T h 17 cells has been attributed to high CD4, CCR5, and CXCR4 expression. Here, we show that T h 17 cells also exhibit heightened permissiveness to productive HIV infection. Primary human CD4 + T cells were sorted, activated under T h 17- or T h 0-polarizing conditions and infected, and then analyzed by flow cytometry. T h 17-polarizing cytokines increased HIV infection, and HIV infection was disproportionately higher among T h 17 cells than among IL-17 − or gamma interferon-positive (IFN-γ + ) cells, even upon infection with a replication-defective HIV vector with a pseudotype envelope. Further, T h 17-polarized cells produced more viral capsid protein. Our data also reveal that T h 17-polarized cells have diminished expression of RNase A superfamily proteins, and we report for the first time that RNase 6 inhibits HIV. Thus, our findings link T h 17 polarization to increased HIV replication. IMPORTANCE Our study compares the intracellular replicative capacities of several different HIV isolates among different T cell subsets, providing a link between the differentiation of T h 17 cells and HIV replication. T h 17 cells are of key importance in mucosal integrity and in the immune response to certain pathogens. Based on our findings and the work of others, we propose a model in which HIV replication is favored by the intracellular environment of two CD4 + T cell subsets that share several requirements for their differentiation: T h 17 and T fh cells. Characterizing cells that support high levels of viral replication (rather than becoming latently infected or undergoing cell death) informs the search for new therapeutics aimed at manipulating intracellular signaling pathways and/or transcriptional factors that affect HIV replication.
Type of Medium:
Online Resource
ISSN:
0022-538X
,
1098-5514
DOI:
10.1128/JVI.02869-15
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2016
detail.hit.zdb_id:
1495529-5
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