Reversing Gut Damage in HIV Infection: Using Non-Human Primate Models to Instruct Clinical Research

Abstract

Antiretroviral therapy (ART) has led to dramatic improvements in the lives of HIV-infected persons. However, residual immune activation, which persists despite ART, is associated with increased risk of non-AIDS morbidities. Accumulating evidence shows that disruption of the gut mucosal epithelium during SIV/HIV infections allows translocation of microbial products into the circulation, triggering immune activation. This disruption is due to immune, structural and microbial alterations. In this review, we highlighted the key findings of gut mucosa studies of SIV-infected macaques and HIV-infected humans that have revealed virus-induced changes of intestinal CD4, CD8 T cells, innate lymphoid cells, myeloid cells, and of the local cytokine/chemokine network in addition to epithelial injuries. We review the interplay between the host immune response and the intestinal microbiota, which also impacts disease progression. Collectively, these studies have instructed clinical research on early ART initiation, modifiers of microbiota composition, and recombinant cytokines for restoring gut barrier integrity.

Keywords: Gut barrier integrity; HIV; Interleukin-21; Interleukin-7; Microbial translocation; SIV.

Fig. 1

Schematic representation of the multiple mechanisms that induce gut damage following SIV/HIV infections and strategies to reduce mucosal inflammation. Gut damage includes alterations to the microbiota, injuries to the gut epithelium, and changes to the immune mucosal landscape, all of which lead to persistent inflammation and systemic immune activation. Lymphoid cellular damage, which occurs in early infection, consists of CD4 T cell depletion, an altered Th17/Treg ratio, the loss of IL-17 producing innate lymphoid cells (ILCs), accumulation of CD8 T cells, and monocyte activation. These changes, which persist during disease progression, are accompanied by myeloid changes such as macrophage accumulation and defective phagocytosis, neutrophil and pDC infiltration, and the loss of CD103⁺ DCs. The loss of IL-17-producing CD8 T cells (Tc17 cells) also characterizes the chronic phase of infection. Overproduction of kynurenine (Kyn) metabolites from dietary tryptophan (Trp) by the immunosuppresive enzyme indoleamine 2,3-dioxygenase (IDO) contributes to an altered Th17/Treg ratio. Strategies to reduce mucosal inflammation are depicted in red.