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Perils at mucosal front lines for HIV and SIV and their hosts

Nature Reviews Immunology volume 5, pages 783–792 (2005)Cite this article

Key Points

  • In the current HIV/AIDS pandemic, most new infections are acquired by vaginal transmission.

  • Studies of this route of transmission in an animal model — monkeys infected intravaginally with simian immunodeficiency virus (SIV), a close relative of HIV-1 — have led to a new appreciation of the importance of events in the first weeks after exposure in determining the subsequent course of the slow infections that are caused by HIV-1 and SIV.

  • In their initial encounter at mucosal front lines, the virus and the host both face perils.

  • The host is vulnerable because it continuously renews cells at mucosal surfaces, and these cells — activated and recently activated but ostensibly resting CD4+ memory T cells — support viral replication.

  • The large population of 'resting' host CD4+ T cells at mucosal surfaces enables virus to establish a beachhead at the point of entry, and the huge number of these cells in gut-associated lymphoid tissue provides fuel for virus production, allowing the spread of infection throughout the lymphoid tissues.

  • The host is also vulnerable to massive depletion of CD4+ T cells in the gut and to blunting of immune responses by regulatory T cells.

  • Both vulnerabilities are associated with mechanisms that operate in the mucosal immune system to maintain a state of vigilance without causing immunopathological damage: CD95–CD95-ligand-mediated apoptosis of CD4+ effector memory T cells in the lamina propria, and an immunosuppressive response to immune activation.

  • Virus is most vulnerable at the point of entry for several days after exposure. At this stage, microbicides or a robust vaccine-induced mucosal immune response could prevent establishment of a self-propagating infection, both locally and systemically.

Abstract

HIV-1 and simian immunodeficiency virus (SIV), as well as their hosts, face perils at mucosal front lines in early infection. At these sites, 'resting' CD4+ memory T cells fuel infection (because they are hosts for virus), depleting CD4+ memory T cells throughout the lymphoid tissues, particularly in the gut, and eliciting an immunosuppressive regulatory T-cell response that impairs host defence. But HIV-1 and SIV also risk elimination at the earliest stage of infection, at the mucosal point of entry, if founder populations of infected cells do not expand sufficiently to establish a self-propagating infection. Microbicides and vaccines could increase these viral vulnerabilities at mucosal front lines.

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Figure 1: Schematic representation of vaginal transmission of HIV and SIV and the subsequent stages of infection.
Figure 2: Viral growth curve in cervicovaginal tissue in vivo
Figure 3: Roles of activated and 'resting' CD4+ T cells in transmission and acute infection.
Figure 4: Viral growth curve in lymphoid tissue in vivo
Figure 5: Massive depletion of CD4+ T cells in the gut lamina propria.

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Acknowledgements

The author thanks J. Carlis, Q. Li and J. Estes for helpful discussions, C. O'Neill and T. Leonard for help with the manuscript and figures, and the National Institutes of Health (United States) for research support.

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  1. Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street South East, Minneapolis, 55455, Minnesota, USA

    Ashley T. Haase

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DATABASES

Entrez Gene

CCR5

CD95

CD95 ligand

indoleamine 2,3-dioxygenase

interferon-γ

interleukin-10

transforming growth factor-β

tumour-necrosis factor

FURTHER INFORMATION

Ashley Haase's homepage

Glossary

LAMINA PROPRIA

The layer of mucosal tissue directly under the mucosal epithelial-cell surface, in which effector cells for mucosal immunity reside.

EFFECTOR MEMORY T CELL

A terminally differentiated T cell that lacks lymph-node-homing receptor but expresses receptors that enable it to home to inflamed tissues. Effector memory cells can exert immediate effector functions without the need for further differentiation.

IMMUNODOMINANT EPITOPE

An antigen within a complex mixture (such as a whole virus), or a region of an antigen, that is recognized preferentially during an immune response.

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Haase, A. Perils at mucosal front lines for HIV and SIV and their hosts. Nat Rev Immunol 5, 783–792 (2005). https://doi.org/10.1038/nri1706

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