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  • Review Article
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Microbicides and other topical strategies to prevent vaginal transmission of HIV

Nature Reviews Immunology volume 6, pages 371–382 (2006)Cite this article

Key Points

  • There is an urgent need to prevent the spread of HIV infection, especially among women, who are increasingly vulnerable to infection.

  • Although the intact vaginal mucosa has features such as thickness, low pH, and hydrogen peroxide in secretions that resist HIV infection, trauma, infection, ulceration and inflammation can render this surface more susceptible to HIV.

  • Although numerous factors have been implicated in protecting persons from HIV infection, only factors that diminish access to the HIV co-receptor CC-chemokine receptor 5 (CCR5) have been clearly linked to protection. Nonetheless, among persons at highest risk for HIV infection but who remain uninfected, the factors protecting most people are unidentified.

  • Microbicides are topical agents that can be applied to mucosal surfaces to prevent acquisition of HIV. However, because many of these agents in development are not microbicidal, the term topical prevention strategies is often used.

  • The most promising topical prevention strategies include those that target HIV directly, blocking entry into target cells or post-entry events needed for HIV replication, and those strategies that target host elements used by HIV to enter and infect host cells.

  • Early hopes that a single topical prevention strategy might protect against HIV and other sexually transmissible pathogens might not be realized. Unfortunately, the necessary properties are shared only by membrane-disrupting agents that are often toxic to human cells from which the viral membrane is derived.

  • Animal and tissue explant studies have been used to explore the mechanisms of HIV transmission and to test the feasibility and safety of topical prevention strategies. More work must be done to understand better the relationships of these and other models to human infection and to explore the safety of the candidate agents.

  • In non-human primates, blocking the HIV co-receptor CCR5 provides high-level protection against vaginal challenge with chimeric simian–human immunodeficiency virus (SHIV).

  • Combination antiviral strategies have revolutionized HIV therapeutics and combinations of topically applied inhibitors of HIV–host-cell fusion have provided high level protection against vaginal challenge with SHIV in non-human primates.

  • The development of a successful topical prevention strategy will require coordination among basic scientists, formulation scientists, social scientists, clinicians and especially the pharmaceutical industry whose expertise in drug development and production are needed for timely implementation of these strategies.

Abstract

The HIV epidemic is, by many criteria, the worst outbreak of infectious disease in history. The rate of new infections is now ∼5 million per year, mainly in the developing world, and is increasing. Women are now substantially more at risk of infection with HIV than men. With no cure or effective vaccine in sight, a huge effort is required to develop topical agents (often called microbicides) that, applied to the vaginal mucosa, would prevent infection of these high-risk individuals. We discuss the targets for topical agents that have been identified by studies of the biology of HIV infection and provide an overview of the progress towards the development of a usable agent.

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Figure 1: Vaginal acquisition of HIV infection.
Figure 2: Factors that can increase or decrease risks for vaginal acquisition of HIV infection.
Figure 3: Topical strategies to prevent vaginal HIV transmission.

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Acknowledgements

This work was supported by the United States National Institutes of Health, the Swiss National Science Foundation, the James B. Pendleton Charitable Trust and the La Jolla Foundation for Microbicide Research. The authors acknowledge the Topical Strategies IP/CP team and in particular R. Kralik for collaboration and assistance.

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Authors and Affiliations

  1. Case Western Reserve University, 2061 Cornell Road, Cleveland, Ohio, USA

    Michael M. Lederman

  2. Mintaka Foundation for Medical Research, 14 chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland

    Robin E. Offord

  3. Department of Structural Biology and Bioinformatics Centre Médical Universitaire, 1 rue Michel Servet, Geneva, 4, 1211, Switzerland

    Oliver Hartley

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  1. Michael M. Lederman
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  3. Oliver Hartley
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Correspondence to Michael M. Lederman.

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Competing interests

R.O. was, until last year, a consultant for Gryphon Therapeutics, a company that funded part of the development of PSC-RANTES; however, the projects on which he consulted (including ones involving chemokines) did not involve microbicides.

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Glossary

Severe combined immunodeficienct mice

Mice with this defect in their immune system do not have B or T cells and can, therefore, accept cells from another species without rejection.

Squamous epithelial cell

A flattened epithelial cell that, in layers that are several cells thick, comprises the surface of the skin, vagina, penis, mouth and anus.

Transcytosis

The process of transport of material across an epithelium by uptake on one side of the cell into a coated vesicle, which can then be sorted through the trans-Golgi network and transported to the opposite side of the cell.

Progestins

Synthetic steroid hormones with progesterone-like activity. Progesterone is an ovarian hormone that prepares the endometrium (the lining of the uterus) to receive the fertilized egg and sustain pregnancy.

Endocervix

The internal canal and internal surfaces of the uterine cervix.

Discordant couple

Sexual partners in a long-term relationship wherein one is HIV infected and the other is not.

At-risk exposure

Any exposure, either through sex or through contact with blood or blood products that places an uninfected person at risk of acquiring HIV infection.

High-risk seronegative individual

A person who remains uninfected despite numerous at-risk exposures.

Cross-sectional study

A clinical study describing a group of people at a single time point or brief time period.

V3 region

The third variable (V3) region of the HIV envelope glycoprotein gp120. The amino-acid sequence in the V3 region determines whether the virus uses CXC-chemokine receptor 4 (CXCR4) or CC-chemokine receptor 5 (CCR5) as its co-receptor.

Six-helix bundle

A structure resulting from the interaction among three HIV envelope gp41 molecules, wherein two discontinuous repeating seven-residue sequences ('heptad repeats') on each gp41 molecule 'zip' together to form coiled coils with three molecules thereby forming a bundle of six helices. This coiling is thought to bring the virus membrane and cell membrane into close contact thereby facilitating fusion.

C-type lectin

Lectins are carbohydrate-binding molecules, and C-type lectins were named because their binding is dependent on the presence of calcium. C-type lectins on the surface of human cells have important roles in cellular adhesion and also in the uptake of microorganisms and microbial antigens.

Drug wash-out experiment

An experiment where exposure to drug is terminated by washing out free drug. This allows measurement of the duration of initial drug effect or binding.

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Lederman, M., Offord, R. & Hartley, O. Microbicides and other topical strategies to prevent vaginal transmission of HIV. Nat Rev Immunol 6, 371–382 (2006). https://doi.org/10.1038/nri1848

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