Initiation of ART during Early Acute HIV Infection Preserves Mucosal Th17 Function and Reverses HIV-Related Immune Activation

Abstract

Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation.

A Cytokine Pattern That Differentiates Preseroconversion From Postseroconversion Phases of Primary HIV Infection

“…7,[31][32][33] Recent studies also point out that ART initiated during early AHI either prevents loss of (at Fiebig stage I/II) or restores (at Fiebig stage III) mucosal Th17 cells. 34 Consequently, very early ART is associated with normalization of local and systemic immune activation, reversing a hallmark of HIV pathogenesis. 34 Although further analysis will be required to define whether there is a causal relationship between BAFF and MCP-1 expression and antibody generation, these cytokines might be potential targets to boost the humoral response in vaccination strategies or to accelerate the HIV-specific antibody response during PHI.…”

“…34 Consequently, very early ART is associated with normalization of local and systemic immune activation, reversing a hallmark of HIV pathogenesis. 34 Although further analysis will be required to define whether there is a causal relationship between BAFF and MCP-1 expression and antibody generation, these cytokines might be potential targets to boost the humoral response in vaccination strategies or to accelerate the HIV-specific antibody response during PHI. Modulation of these cytokines might promote an earlier development of autologous neutralizing antibodies that may contribute to faster and long-lasting control of HIV.…”

Preferential loss of gut-homing α4β7 CD4+ T cells and their circulating functional subsets in acute HIV-1 infection

“…35 Long-term HIV-1 nonprogressors (LTNPs) exhibit intact CD4 1 T-cell populations in the gut mucosa and a preserved balance of CD4 1 T-cell subsets in blood and mucosal sites. 36 Therefore, the protection mechanism of LTNPs may be similar to the effect of early treatment during acute HIV-1 infection, and gut-homing a4b7 CD4 1 T cells may be beneficial in the maintenance of normal CD4 1 Tcell levels in LTNPs and the reconstitution of gut CD4 1 T cells during the early initiation of ART in HIV-1-infected individuals.…”

An Immunological Perspective on Neonatal Sepsis

“…In humans, the clinical impact of IL-17 deficiency is more limited, highlighting another important difference across species [47]. Loss of Th17 cells in humans with chronic HIV infection results in a loss of gut-barrier function and subsequent microbial translocation [53]. Notably, adult humans lacking production of IL-17 appear specifically vulnerable to neonatal pathogens such as Candida and Staphylococcus aureus [54].…”