IL-15 enhances HIV-1 infection by promoting survival and proliferation of CCR5+CD4+ T cells
Yuhao Li, Hongbo Gao, Kolin M. Clark, Liang Shan
Yuhao Li, Hongbo Gao, Kolin M. Clark, Liang Shan
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Research Article AIDS/HIV Immunology

IL-15 enhances HIV-1 infection by promoting survival and proliferation of CCR5+CD4+ T cells

Abstract

HIV-1 usually utilizes CCR5 as its coreceptor and rarely switches to a CXCR4-tropic virus until the late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in viremic individuals as well as SIV-infected nonhuman primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 was expressed by CD4+ T cells exhibiting effector or effector memory phenotypes with high expression levels of the IL-2/IL-15 receptor common β and γ chains. IL-15, but not IL-7, improved the survival of CCR5+CD4+ T cells, drove their expansion, and facilitated HIV-1 infection in vitro and in humanized mice. Our study suggests that IL-15 plays confounding roles in HIV-1 infection, and future studies on the IL-15–based boosting of anti–HIV-1 immunity should carefully examine the potential effects on the expansion of HIV-1 reservoirs in CCR5+CD4+ T cells.

Authors

Yuhao Li, Hongbo Gao, Kolin M. Clark, Liang Shan

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Figure 2

IL-15 drives proliferation of CCR5+CD4+ T cells.

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IL-15 drives proliferation of CCR5+CD4+ T cells. (A) The distribution of...
(A) The distribution of memory T cell subsets among total, CCR5–, and CCR5+ CD4+ T cells. Blood samples were collected from 5 heathy donors without stimulation. Tn, naive T cells (CD45RA+CCR7+); Tem, effector memory T cells (CD45RA–CCR7–CD27–); Ttm, transitional memory T cells (CD45RA–CCR7–CD27+); Tcm, central memory T cells (CD45RA–CCR7+CD27+); Temra, RA+ effector memory T cells (CD45RA+CCR7–). (B–D) Differentiation of CCR5+CD4+ T cells following T cell activation. CD4+ T cells from blood, tonsils, or lymph nodes were costimulated with anti-CD3 and anti-CD28 antibodies for 3 days and then cultured in the presence of IL-7 or IL-15 for 6 days. Frequency of CCR5+ cells was determined by flow cytometry. Circles indicate blood (n = 20), squares indicate tonsils (n = 2), and triangles lymph nodes (n = 2). (E–H) Expansion of CCR5+CD4+ T cells by IL-15. Total CD4+ cells from blood were costimulated with anti-CD3 and anti-CD28 antibodies for 3 days. Activated cells were then stained with CFSE and cultured in the presence of IL-7 or IL-15. Mean CFSE intensity and number of CCR5+ cells were determined by flow cytometry. In F, CD4+ T cells from 6 blood donors were included. In G, fold increase was calculated on day 12. CD4+ T cells from 5 blood donors were included. (I and J) CD122 and CD132 expression in CCR5+ and CCR5– CD4+ T cells. CCR5+ and CCR5– cells were purified by sorting for RNA extraction and cDNA synthesis. CD122 and CD132 expression levels were normalized to POLR2A. CD4+ T cells from 5 blood donors were included. P values were calculated using a paired, 2-tailed t test (C, D, F, G, I, and J) or 2-way ANOVA with Tukey’s multiple-comparison test (H). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.