Inhibiting sexual transmission of HIV-1 infection

The sexual transmission of HIV-1 is mediated by exposure to HIV-1-infected cells and/or infectious virus in mucosal secretions or semen.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.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.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.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.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.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.