HIV Infection and Gut Mucosal Immune Function: Updates on Pathogenesis with Implications for Management and Intervention

Abstract

HIV is primarily a sexually transmitted infection. However, given that the gastrointestinal tract (GIT) houses most of the body's lymphocytes, including activated memory CD4(+) T cells that are preferential targets for HIV, recent research has focused on the role of the GIT in transmission and pathogenesis. In health, the GIT maintains a balance between immune tolerance and rapid responsiveness. A complex network of innate and adaptive responses maintains this balance, which is severely perturbed in HIV infection. Recent studies have focused on mechanisms of GIT CD4(+) T-cell depletion and epithelial disruption in HIV infection, the role of inflammation in accelerating viral dissemination, the kinetics of the adaptive response following transmission, and the extent of T-cell reconstitution following antiretroviral therapy. This review summarizes the results of recent investigations that may have important implications for the development of vaccines, microbicides, and therapeutic interventions for HIV and other mucosal pathogens.

Fig. 1

Intestinal inductive and effector sites in HIV infection: an idealized intestinal mucosa, lined with simple columnar epithelium. Inductive sites are organized structures such as Peyer’s patches (most abundant in terminal ileum) and lymphoid aggregates. These structures contain defined B- and T-cell zones in which antigen presentation occurs. Peyer’s patches are overlaid by epithelium containing M cells, which nonspecifically take up particulate antigens and transfer them to lymphocytes and antigen-presenting cells harbored in basolateral pockets. Once antigen presentation occurs, newly primed T and B cells move through efferent lymphatics to the draining lymph nodes, and eventually enter peripheral circulation via the thoracic duct. They then selectively home to mucosal effector sites, taking up residence as intraepithelial lymphocytes (IEL) or lamina propria lymphocytes (LPL). The lamina propria in an uninfected individual contains mainly CD4⁺ T cells, whereas IEL are mainly CD8⁺ T cells. Macrophages and plasma cells also reside in the lamina propria. HIV may cross the epithelium and initiate infection (1) by transcytosis across intact epithelial cells or M cells; (2) by adhering to dendrites of mucosal dendritic cells; or (3) by direct passage through epithelial breaches. Intestinal CD4⁺ T cells (in both inductive and effector sites) are rapidly infected and depleted during acute HIV infection. The figure also illustrates some consequences of HIV infection on mucosal integrity (4). Tight junctions in the intestinal epithelium are compromised. The lamina propria loses most of its CD4⁺ T cells but gathers an influx of CD8⁺ T cells. Collagen deposition occurs and may hinder reconstitution of CD4⁺ T cells. Inductive sites lose their distinctive architecture and contain many apoptotic T and B cells, with few CD4⁺ T cells (not pictured)