Microbial translocation, immune activation, and HIV disease

Abstract

The advent of combination antiretroviral therapy (cART) has significantly improved the prognosis of human immunodeficiency virus (HIV)-infected individuals. However, individuals treated long-term with cART still manifest increased mortality compared to HIV-uninfected individuals. This increased mortality is closely associated with inflammation, which persists in cART-treated HIV-infected individuals despite levels of plasma viremia below detection limits. Chronic, pathological immune activation is a key factor in progression to acquired immunodeficiency syndrome (AIDS) in untreated HIV-infected individuals. One contributor to immune activation is microbial translocation, which occurs when microbial products traverse the tight epithelial barrier of the gastrointestinal tract. Here we review the mechanisms underlying microbial translocation and its role in contributing to immune activation and disease progression in HIV infection.

Published by Elsevier Ltd.

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Figure 1

Mechanisms underlying damage to the tight epithelial barrier of the GI tract and microbial translocation during HIV infection. (a) In the absence of HIV infection, retinoic acid produced by CD103+ DCs helps to drive T cells and innate lymphoid cells (ILC) to produce IL-17 and IL-22, which contributes to a healthy epithelial barrier. B cells produce IgA in the lamina propria, which regulate microbial products in the lumen and prohibit microbes (purple rods) from interacting with and translocating across the epithelial barrier. Macrophages (Mφ) are capable of phagocytosing any bacterial products that translocate without a proinflammatory milieu. (b) However, during HIV infection, IL-17 and IL-22 producing lymphocytes are lost, both by direct infection of CD4+ T cells by HIV, and potentially by skewing of homeostatic responses to proinflammatory responses such as IFN-α production by plasmactyoid dendritic cells (pDCs). Further, hyperactivated macrophages no longer phagocytose bacterial products but respond with inflammatory cytokines such as TNF-α and IFN-α. In addition, decreased IgA may lead to decreased control of microbial products. Inflammation and loss of homeostatic cytokines such as IL-17 and IL-22 lead to damage to the tight epithelial barrier of the GI tract, allowing microbial products to translocate and furthering inflammation.