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 4

IL-15 promotes replication of CCR5-tropic HIV-1.

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IL-15 promotes replication of CCR5-tropic HIV-1. (A and B) Activated blo...
(A and B) Activated blood CD4+ T cells were cultured in the presence of IL-7 or IL-15 for 6 days. Cells were infected with the single-round HIV-1 reporter virus NL4-3Δenv-EGFP pseudotyped with the Yu2 envelope. (A) GFP expression was measured 3 days post infection (dpi). n = 4. (B) Virus production per infected cell was determined by quantification of copies of HIV-1 RNA in supernatant, divided by the number of GFP+ cells in the culture. n = 3. (C and D) Survival of HIV-1–infected cells. Infection was performed as described in A. GFP+ cells were purified by cell sorting on 3 dpi and were cultured with IL-7 or IL-15 for 3 days. Cell viability was determined by flow cytometry. CD4+ T cells from 4 blood donors were included in this experiment. (E and F) Proliferation of HIV-1–infected cells. Infection was performed as described in A. Cells were stained with CellTrace Violet on 2 dpi. Proliferation of infected and uninfected cells was measured on 3 and 6 dpi. CD4+ T cells from 3 blood donors were included. (G and H) Quantification of HIV-1 replication. Activated blood CD4+ T cells were infected with HIVBa-L for 9 days in the presence of IL-7 or IL-15. (G) Culture supernatant was collected on day 3, 6, and 9 for p24 ELISA. CD4+ T cells from 10 blood donors were included. (H) Viable infected cells on day 9 were determined by flow cytometry. CD4+ T cells from four blood donors were included. P values were calculated using 1-way ANOVA with Tukey’s multiple-comparison test (A, D, and H), paired, 2-tailed t test (B), or 2-way ANOVA with Holm-Šidák multiple-comparison test (F and G). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.