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J Virol. 2016 Sep 29;90(20):8954-67. doi: 10.1128/JVI.00612-16. Print 2016 Oct 15.

CD25+ FoxP3+ Memory CD4 T Cells Are Frequent Targets of HIV Infection In Vivo.

Author information

1
NIMR Mbeya Medical Research Centre, Mbeya, Tanzania mchachage@nimr-mmrc.org geldmacher@lrz.uni-muenchen.de.
2
Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
3
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Dusseldorf, Germany.
4
Department of Genome Oriented Bioinformatics, Technische Universität München, Freising, Germany.
5
NIMR Mbeya Medical Research Centre, Mbeya, Tanzania Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.
6
Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.
7
Institute for Medical Microbiology, Immunology and Hygiene, Helmholtz Center Munich, Technische Universität München, Munich, Germany Clinical Cooperation Groups Antigen-Specific Immunotherapy and Immune-Monitoring, Helmholtz Center Munich, Technische Universität München, Munich, Germany.
8
Institute for Medical Microbiology, Immunology and Hygiene, Helmholtz Center Munich, Technische Universität München, Munich, Germany.
9
Institute of Virology, Helmholtz Center Munich, Technische Universität München, Munich, Germany.
10
MRC Clinical Trials Unit at UCL, London, United Kingdom.
11
Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
12
NIMR Mbeya Medical Research Centre, Mbeya, Tanzania.
13
Kwame Nkrumah University of Science & Technology, Kumasi, Ghana.
14
Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
15
Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
16
Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany mchachage@nimr-mmrc.org geldmacher@lrz.uni-muenchen.de.

Abstract

Interleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replication in vitro and facilitates homeostatic proliferation of CD25(+) FoxP3(+) CD4(+) T cells. CD25(+) FoxP3(+) CD4(+) T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25(+) FoxP3(+) CD4(+) T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV(+) and HIV(-) study volunteers. Different memory CD4(+) T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV(+) subjects, 51% (median) of CD25(+) FoxP3(+) CD4(+) T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67(+) cells were detected in CD25(+) FoxP3(+) memory CD4(+) T cells (median, 27.6%) in comparison to CD25(-) FoxP3(-) memory CD4(+) T cells (median, 4.1%; P < 0.0001). HIV DNA content was 15-fold higher in CD25(+) FoxP3(+) memory CD4(+) T cells than in CD25(-) FoxP3(-) T cells (P = 0.003). EnvV1V3 sequences derived from CD25(+) FoxP3(+) memory CD4(+) T cells did not preferentially cluster with plasma-derived sequences. Quasi-identical cell-plasma sequence pairs were rare, and their proportion decreased with the estimated HIV infection duration. These data suggest that specific cellular characteristics of CD25(+) FoxP3(+) memory CD4(+) T cells might facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. The contribution of this cell population to plasma virion production remains unclear.

IMPORTANCE:

Despite recent advances in the understanding of AIDS virus pathogenesis, which cell subsets support HIV infection and replication in vivo is incompletely understood. In vitro, the IL-2 signaling pathway and IL-2-dependent cell cycle induction are essential for HIV infection of stimulated T cells. CD25(+) FoxP3(+) memory CD4 T cells, often referred to as regulatory CD4 T cells, depend on IL-2 signaling for homeostatic proliferation in vivo Our results show that CD25(+) FoxP3(+) memory CD4(+) T cells often express the HIV coreceptor CCR5, are significantly more proliferative, and contain more HIV DNA than CD25(-) FoxP3(-) memory CD4 T cell subsets. The specific cellular characteristics of CD25(+) FoxP3(+) memory CD4(+) T cells probably facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. However, the contribution of this cell subset to plasma viremia remains unclear.

PMID:
27384654
PMCID:
PMC5044822
DOI:
10.1128/JVI.00612-16
[Indexed for MEDLINE]
Free PMC Article

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