Innate Lymphoid Cells Are Depleted Irreversibly during Acute HIV-1 Infection in the Absence of Viral Suppression

Abstract

Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent immune dysfunction.

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Surprisingly, ILC3 can maintain their phenotype and function even in the absence of ROR γ t expression and persist for a significant length of time 53. Nonetheless, changes in dietary metabolites, chronic inflammation or infectious insult result in disruption of ILC3 effector functions or even irreversible depletion of ILC from the intestinal tissue altogether 54, 55. Further studies are required to understand how ILC3 numbers and functions are maintained and how they can be restored following damage or infection‐induced perturbation.…”

Orchestration of intestinal homeostasis and tolerance by group 3 innate lymphoid cells

“…HIV-1 infection in humans in particular is associated with impaired gut barrier and translocation of commensal bacteria which drive systemic inflammation [134]. While profound depletion of infected CD4 + T cells is the hallmark of HIV-1 infection, recent studies have demonstrated dysregulation of ILC3 in the blood, lymph, and/or intestinal tissues of HIV-1-infected humans or humanized mice and SIV-infected macaques [130–133]. Thus, in the setting of HIV or SIV infection, loss of tissue-protective ILC3 responses may lead to loss of mucosal tolerance towards gut commensals, propagating intestinal and systemic inflammation.…”

“…Thus, in the setting of HIV or SIV infection, loss of tissue-protective ILC3 responses may lead to loss of mucosal tolerance towards gut commensals, propagating intestinal and systemic inflammation. In support of this, loss of circulating ILC frequencies coincides with the elevation of markers associated with gut barrier breakdown and bacterial translocation [130, 135]. In addition, SIV-infected macaques have reduced frequencies of small intestinal IL-17-producing ILCs following initial and persisting infection [132].…”

“…In addition, SIV-infected macaques have reduced frequencies of small intestinal IL-17-producing ILCs following initial and persisting infection [132]. Notably, ILC3 depletion in HIV/SIV infection does not appear to be due to direct viral infection [130, 136]. Rather, mechanistic studies have suggested that ILC3 depletion is the result of apoptosis, possibly due to dysregulation of ILC survival signals [137].…”

“…Rather, mechanistic studies have suggested that ILC3 depletion is the result of apoptosis, possibly due to dysregulation of ILC survival signals [137]. As such, analysis of ILC3 from humans with HIV-1 viremia shows upregulation of genes linked to apoptosis and cell death, including CD95 (Fas) [130]. In humanized mice, CD95 expression on ILC3s can be induced by plasmacytoid DC-derived IFNα, which is also upregulated in the setting of HIV-1 infection [133].…”