Immune responses to HIV and SIV in mucosal tissues: 'location, location, location'

Abstract

Purpose of review: This review summarizes research literature regarding mucosal immunity to HIV and simian immunodeficiency virus (SIV), with an emphasis on work published within the past 18 months.

Recent findings: Notable recent studies have focused on the pivotal events occurring within mucosal tissues during acute HIV/SIV infection that serve to establish a balance between detrimental immune activation and beneficial adaptive responses. In cervicovaginal mucosa, an early inflammatory response leads to recruitment of susceptible target cells. At this acute stage, the in-vivo ratio between CD8 effector cells and infected CD4 T-cells may be critical for limiting viral dissemination. Acute infection is also accompanied by loss of germinal center architecture and T/B cell apoptosis in Peyer's patches of the gastrointestinal tract. During chronic infection, mucosal CD8 T-cells may play a role in immune control, as suggested by studies of elite controllers.

Summary: Mucosal tissues serve as the major portal of entry for HIV, and house a majority of the body's lymphocytes, including CD4 T-cells that are targets for infection. Recent studies have focused renewed attention on events occurring immediately after transmission, and underscore the concept that the balance between inflammation and protective immunity is established by host responses in mucosal tissues.

Figure 1. Immune defenses in the gastrointestinal mucosa

(A) Idealized mucosal defenses. Virus may enter the gut through transcytosis, direct entry via epithelial breaches, or by binding to dendritic cells. Immune defenses in the lamina propria are shown from left to right: (1) Mucosal antibodies are secreted by plasma cells in the lamina propria. IgA dimers are taken up by epithelial cells and secreted into the GI lumen. Mucosal IgA may block infection by binding and neutralizing free virus, infected cells, and/or by blocking transcytosis of virus by epithelial cells. (2) Virus-specific CTL can kill infected cells by granule exocytosis. “Polyfunctional” CTL also secrete multiple cytokines and chemokines. In order to adequately control infection, a high in vivo E:T ratio is required. (3) Uninfected CD4+ T-cells are abundant in the intestinal lamina propria, and are exquisitely sensitive to HIV infection. Th17 cells may be preferentially infected and depleted. (B) Mucosal immune defenses are impaired in HIV infection. From left to right: (1) Mucosal B-cell function is affected by disruption of Peyer’s patches, induction of T/B-cell apoptosis, and by direct effects of Nef on class switching. (2) Mucosal CTL express low levels of perforin and high levels of PD-1. Free E-cadherin may ligate KLRG-1, inhibiting CTL function. (3) Lamina propria CD4+ T-cells, including Th17 cells, are rapidly infected and depleted. Collagen fibrosis impairs their reconstitution following antiretroviral therapy. (4) Local production of proinflammatory cytokines and loss of the Th17/Treg balance leads to increased epithelial permeability to microbial products. This may contribute to systemic immune activation.

Figure 1. Immune defenses in the gastrointestinal mucosa

(A) Idealized mucosal defenses. Virus may enter the gut through transcytosis, direct entry via epithelial breaches, or by binding to dendritic cells. Immune defenses in the lamina propria are shown from left to right: (1) Mucosal antibodies are secreted by plasma cells in the lamina propria. IgA dimers are taken up by epithelial cells and secreted into the GI lumen. Mucosal IgA may block infection by binding and neutralizing free virus, infected cells, and/or by blocking transcytosis of virus by epithelial cells. (2) Virus-specific CTL can kill infected cells by granule exocytosis. “Polyfunctional” CTL also secrete multiple cytokines and chemokines. In order to adequately control infection, a high in vivo E:T ratio is required. (3) Uninfected CD4+ T-cells are abundant in the intestinal lamina propria, and are exquisitely sensitive to HIV infection. Th17 cells may be preferentially infected and depleted. (B) Mucosal immune defenses are impaired in HIV infection. From left to right: (1) Mucosal B-cell function is affected by disruption of Peyer’s patches, induction of T/B-cell apoptosis, and by direct effects of Nef on class switching. (2) Mucosal CTL express low levels of perforin and high levels of PD-1. Free E-cadherin may ligate KLRG-1, inhibiting CTL function. (3) Lamina propria CD4+ T-cells, including Th17 cells, are rapidly infected and depleted. Collagen fibrosis impairs their reconstitution following antiretroviral therapy. (4) Local production of proinflammatory cytokines and loss of the Th17/Treg balance leads to increased epithelial permeability to microbial products. This may contribute to systemic immune activation.