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

Abstract

HIV-1 usually utilizes CCR5 as its co-receptor and rarely switches to CXCR4-tropic until the late stage of infection. CCR5 + CD4 + T cells are the major virus-producing cells in viremic individuals as well as SIV-infected non-human primates. The differentiation of CCR5 + CD4 + T cells is associated with the availability of IL15, which increases during acute HIV-1 infection. Here, we report that CCR5 is expressed by CD4 + T cells exhibiting effector or effector memory phenotypes with high expression levels of the IL2/IL15 receptor common beta and gamma chains. IL15 but not IL7 improves the survival of CCR5 + CD4 + T cells, drives their expansion, and facilitates HIV-1 infection in vitro and in humanized mice. Our study suggests that IL15 plays confounding roles in HIV-1 infection, and future studies on the IL15-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.

Proviral location affects cognate peptide–induced virus production and immune recognition of HIV-1–infected T cell clones

“…Whether rare proviruses are merely caught in between the evolutionary arms race against transposable elements or specifically targeted by repressive epigenetic mediators is yet to be determined ( 65 , 66 ). Moreover, our data also suggest that strategies that use agents like IL-15, which induce proliferation to augment effector responses, may paradoxically increase the size of the reservoir by causing expansion in the absence of viral expression of proviruses like ZNF721i that can partially evade the immune system ( 67 ). Finally, it should be noted that viral particle production does occur even from proviruses like ZNF721i, and thus immune recognition and elimination of productively infected cells would still be essential for elite control and for preventing viral rebound in most people on ART.…”

Immunomodulation with IL-7 and IL-15 in HIV-1 infection

“…There are two issues with the homeostatic cytokines that should be considered prior to any intervention. 1) The cytokine-induced CD4 + T cell expansion of the HIV-1 reservoir, 50 , 100 which might be overcome by making the interventional homeostatic cytokines CD8-targeted, but then the restoration of the CD4 + T cell compartment would be missed, or by simultaneously inhibiting cell-intrinsic anti-apoptosis pathways to diminish infected CD4 + T cells 101 , 102 ; and 2) The increased susceptibility to infection 103 , 104 by enhanced CCR5 expression on CD4 + T cells. 51 , 82 , 100 , 105 Importantly, a recent study found that IL-15 stimulation in vitro and in humanized mice promoted proliferation and survival of the HIV-1 target cell (CCR5 expressing CD4 + T cells), and furthermore the life span of infected CCR5-expressing CD4 + T cells was prolonged and their virus production was increased.…”

“… 51 , 82 , 100 , 105 Importantly, a recent study found that IL-15 stimulation in vitro and in humanized mice promoted proliferation and survival of the HIV-1 target cell (CCR5 expressing CD4 + T cells), and furthermore the life span of infected CCR5-expressing CD4 + T cells was prolonged and their virus production was increased. 100

Fig. 1 Effects of IL-7 and IL-15 therapies in vivo during suppressive antiretroviral threapy (ART).

…”