Key Points
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The sexual transmission of HIV-1 is mediated by exposure to HIV-1-infected cells and/or infectious virus in mucosal secretions or semen.
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The stratified mucosal epithelium and the endocervical epithelium form effective barriers against HIV-1 or HIV-1-infected cells; however, breaches in the integrity of these barriers are frequent, increasing susceptibility to infection. Once the epithelial barriers have been breached, HIV-1 can target cells in the underlying epithelial layers, including T cells, dendritic cells and macrophages.
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Fundamental research into the mechanisms of HIV-1 binding and entry into host cells has facilitated the logical identification of suitable and logical targets for microbicides that are aimed at inhibiting the sexual transmission of HIV-1.
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The development of topical microbicides that inhibit HIV-1 attachment to, and fusion with, host cells is being investigated as a strategy to prevent infection of mucosal tissue. Such microbicides can target either the virus itself, or the host cells that the virus infects.
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Effective microbicide candidates that target the virus must target conserved features. Some microbicides, such as nonoxynol-9, target the viral membrane; however, these compounds can also damage the host cell membrane, and in fact nonoxynol-9 has been shown to increase the risk of HIV-1 transmission. The viral membrane is therefore problematic as a target.
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More specific microbicide candidates include those that target the viral envelope glycoprotein (Env). Compounds being investigated include monoclonal antibodies (mAbs; for example, b12, 2G12 and 2F5); proteins (for example, PRO-542) and peptides (for example, T-20, licensed as Enfuvirtide, and T-1249, now in Phase 1 trials) that specifically target the gp120 or gp41 moieties of the Env protein; long-chain anionic polymers, such as dextrin-2-sulphate and cellulose acetate phlatate, that target positively charged regions of gp120, mainly around the V3 loop; and compounds such as cyanovirin-N that target the glycan residues that are associated with gp120.
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Research into microbicidal agents that target the cell have focused mainly on targeting the cellular receptors for HIV-1, that is, the mannose C-type lectin receptors, such as (but not exclusively) DC-SIGN; CD4; and the CCR5 and CXCR4 co-receptors, using mAbs, modified chemokines and small-molecule inhibitors. Microbicides aimed at inhibiting HIV-1 binding to cellular receptors must reach the target cells with at least the same efficiency as HIV-1 and be maintained at a concentration high enough to provide protection. As entry inhibitors target specific regions of the Env protein, which shows a high degree of sequence divergence, combinations of inhibitors could be used to achieve breadth of coverage.
Abstract
The worldwide infection rate for HIV-1 is estimated to be 14,000 per day, but only now, more than 20 years into the epidemic, are the immediate events between exposure to infectious virus and the establishment of infection becoming clear. Defining the mechanisms of HIV-1 transmission, the target cells involved and how the virus attaches to and fuses with these cells, could reveal ways to block the sexual spread of the virus. In this review, we will discuss how our increasing knowledge of the ways in which HIV-1 is transmitted is shaping the development of new, more sophisticated intervention strategies based on the application of vaginal or rectal microbicides.
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The authors gratefully acknowledge the help of P. Greenhead and R. Moss for electron microscopy.
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Glossary
- DISCORDANT COUPLES
-
Two sexual partners in, usually, a stable monogamous relationship, in which one person is HIV-infected and the other is not.
- ACUTE INFECTION
-
An initial infection that is associated with a high viral load — often resolving with seroconversion, 3–6 months after infection.
- X4 VIRUSES
-
HIV-1 strains that use the CXCR4 chemokine receptor as a co-receptor to enter target cells.
- R5 VIRUSES
-
HIV-1 strains that use the CCR5 chemokine receptor as a co-receptor to enter target cells
- STRATIFIED SQUAMOUS EPITHELIUM
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An epithelium consisting of several layers of keratin-containing cells, in which the surface cells are flattened and scale-like and the deeper cells are polyhedral in form.
- DESMOSOME
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A junction between the cell membranes of neighbouring cells, which consists of associated intracellular microfilaments and intercellular mucopolysaccharides and are important in cell-to-cell adhesion.
- COLUMNAR EPITHELIUM
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An epithelium that is formed of a single layer of cells, which are taller than they are wide.
- TIGHT JUNCTION
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A specialized intercellular junction in which the two plasma membranes are separated by only 1–2 nm. They are found near the apical surface of cells in simple epithelia and prevents fluid moving through the intercellular gap.
- CERVICAL OS
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The 'mouth' or 'opening' of the endocervical canal into the vaginal vault.
- CERVICAL ECTOPY
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An outgrowth of endocervical columnar epithelium—that is usually restricted to the endocervical canal — onto the exocervical surface at the top of the vaginal vault.
- M CELLS
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Specialized epithelial cells that deliver samples of luminal material from the lumen into organized lymphoid tissue by transepithelial vesicular transport. They are classically found in the gastrointestinal tract, but absent from the genital epithelia.
- LANGERHANS CELLS
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Dendritic, antigen-presenting cells that contains characteristic racket-shaped granules, known as birbeck granules, and which expressing the CD1a antigen. Principally found in the stratified squamous epithelium.
- PYKNOTIC NUCLEI
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Nuclei that have contracted contents — a feature that is visible with deep staining and is a sign of cell death.
- DC-SIGN
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DC-specific intercellular adhesion molecule (ICAM)-grabbing non-integrin.
- RANTES
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A CC-chemokine that binds to and activates signal transduction by several chemokine receptors, including CCR5, and that has modest inhibitory activity against HIV-1 entry through the same receptor.
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Shattock, R., Moore, J. Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 1, 25–34 (2003). https://doi.org/10.1038/nrmicro729
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DOI: https://doi.org/10.1038/nrmicro729
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