Gut Microbiome Alterations During HIV/SIV Infection: Implications for HIV Cure

Abstract

Gut mucosal damage, associated with Human Immunodeficiency Virus-1 (HIV) infection, is characterized by depletion in CD4⁺ T cells and persistent immune activation as a result of early epithelial barrier disruption and systemic translocation of microbial products. Unique approaches in studying both HIV infection in human patients and Simian Immunodeficiency Virus (SIV) infection in rhesus macaques have provided critical evidence for the pathogenesis and treatment of HIV/AIDS. While there is vast resemblance between SIV and HIV infection, the development of gut dysbiosis attributed to HIV infection in chronically infected patients has not been consistently reported in SIV infection in the non-human primate model of AIDS, raising concerns for the translatability of gut microbiome studies in rhesus macaques. This review outlines our current understanding of gut microbial signatures across various stages of HIV versus SIV infection, with an emphasis on the impact of microbiome-based therapies in restoring gut mucosal immunity as well as their translational potential to supplement current HIV cure efforts.

Keywords: antiretroviral (ARV) therapy; gut microbiome; human immunodeficiency virus; mucosal immunity; simian immunodeficiency virus.

FIGURE 1

Pathologic manifestations of the small intestine in HIV or SIV infection in the gut. Depletion of CD4⁺ T cells occurs in early HIV infection (primary stage). Production of inflammatory cytokines in the primary stage leads to intestinal barrier disruption and microbial translocation, exacerbating the inflammatory milieu and increasing viral replication. Dysregulation in mucosal immunity and reduced anti-microbial peptide (AMP) production leads to bacterial overgrowth and altered pattern recognition receptor (PRR) expression in chronic HIV infection. Persistent gut inflammation in response to the cascade of mucosal events leads to enhanced viral replication and severe depletion of CD4⁺ T cells in the AIDS stage.

FIGURE 2

Current therapeutic modalities to repair mucosal damage during HIV and SIV infection. Strategies include (1) recovery of gut microbial communities, (2) prebiotic stimulation using butyrate, (3) addition of bacterial metabolites such as indoles, (4) enhancing host immune cell function through innate lymphoid cells (ILC), (5) combating cellular metabolism through mitochondrial targets such as ROS, and (6) anti-retroviral therapy (ART). Efforts made in regard to each strategy (Heise et al., 1993, 1994; Lim et al., 1993; Veazey et al., 1998; MacDonald and Monteleone, 2005; Lathrop et al., 2011) have led to modest increases in CD4⁺ T cell numbers, reduced inflammation, increased NK cell activity, enhanced IL-17/IL-22 production, and gut epithelial barrier repair.