Mucosal immunology of HIV infection

Abstract

Recent advances in the immunology, pathogenesis, and prevention of human immunodeficiency virus (HIV) infection continue to reveal clues to the mechanisms involved in the progressive immunodeficiency attributed to infection, but more importantly have shed light on the correlates of immunity to infection and disease progression. HIV selectively infects, eliminates, and/or dysregulates several key cells of the human immune system, thwarting multiple arms of the host immune response, and inflicting severe damage to mucosal barriers, resulting in tissue infiltration of 'symbiotic' intestinal bacteria and viruses that essentially become opportunistic infections promoting systemic immune activation. This leads to activation and recruitment or more target cells for perpetuating HIV infection, resulting in persistent, high-level viral replication in lymphoid tissues, rapid evolution of resistant strains, and continued evasion of immune responses. However, vaccine studies and studies of spontaneous controllers are finally providing correlates of immunity from protection and disease progression, including virus-specific CD4(+) T-cell responses, binding anti-bodies, innate immune responses, and generation of antibodies with potent antibody-dependent cell-mediated cytotoxicity activity. Emerging correlates of immunity indicate that prevention of HIV infection may be possible through effective vaccine strategies that protect and stimulate key regulatory cells and immune responses in susceptible hosts. Furthermore, immune therapies specifically directed toward boosting specific aspects of the immune system may eventually lead to a cure for HIV-infected patients.

Fig. 1. Langerhans cells in the vaginal epithelium distinguished by co-expression of HLA-DR and CD1a (LC appear yellow – see arrows)

Other DCs are evident in the deeper lamina propria as HLA-DR⁺ (green), yet HLA-DR alone is not specific for DCs.

Fig. 2. Lymphoid follicles within organized lymphoid tissue

Follicles are within the intestine (A) and lymph node (B) showing distribution of B cells (red) and T-cell zones (blue). Note IgA (green) is readily detected in cells in the intestinal lamina propria but not detectable in peripheral lymph nodes.

Fig. 3. T-cell proliferation (Ki-67⁺, red) and activation (CD69⁺, green) in the intestinal lamina propria (A) and lymph node (B) of a normal macaque

Abundant activated (CD69⁺; green) KI-67⁺ T cells are constitutively present in intestinal tissues, but activated cells are rare in normal lymph nodes. Note intestinal crypt epithelial cells are also highly Ki-67⁺ due to intrinsic rapid rate of turnover.

Fig. 4. T-regulatory (Treg) cells in the intestinal lamina propria of a normal macaque distinguished by intracellular FoxP3 (red nuclei) and surface CD25 (green) expression

Fig. 5. Comparison of T cells in the intestine and lymph node of macaques

Tissues are stained for CD3 (blue), CD4 (red) and CD8 (green) so CD3⁺CD4⁺ T cells appear ‘purple’ and CD8⁺ T cells appear ‘yellow’). Note both gut (A) and lymph node (C) contain CD4⁺ and CD8⁺ T cells. However, the intestine contains small ‘cryptopatches’ containing CD3⁻CD4⁺ cells (red;B) consistent with Lti cells, and CD3⁻CD8⁺ ILC (green), which are not detected in lymph nodes (C).