In the absence of an effective vaccine, blocking infection and transmission of HIV at mucosal surfaces might be our best chance of stemming the spread of HIV infection. Reporting in The Journal of Experimental Medicine, Qinxue Hu et al. explore the potential of HIV-1-specific antibodies and compounds that target HIV-1-binding cell-surface receptors to inhibit HIV-1 infection of and dissemination from human cervical tissue.

To infect cells, HIV-1 must interact with two receptors, CD4 and a co-receptor — CC-chemokine receptor 5 (CCR5) for R5 viruses and CXC-chemokine receptor 4 (CXCR4) for X4 viruses. Using a CD4-specific antibody or small molecule inhibitors of CCR5 and CXCR4, the authors could inhibit localized infection of mucosal tissue by R5 and X4 viruses, respectively. Although in vitro studies have identified viruses that can use other co-receptors, here, they show that infection of human cervical tissue using co-receptors other than CXCR4 or CCR5 is unlikely.

In addition to direct infection of mucosal tissue, HIV-1 can become attached to migratory cells, facilitating viral transmission and infection in lymphoid organs. Dendritic cells (DCs) that express the mannose-binding C-type lectin DC-SIGN are thought to be involved in this process. So, the authors collected migratory cells (which included both DC-SIGN− and DC-SIGN+ DCs) emigrating from cervical explants after HIV-1 inoculation in the presence or absence of inhibitors, and assayed for infection of indicator cells in co-cultures. In contrast to infection of cervical tissue, uptake of HIV-1 by migratory cells was not inhibited by a combination of CXCR4 and CCR5 inhibitors, but was inhibited when CD4-specific antibody and mannan were present. Presence of DC-SIGN-specific antibody also inhibited the capture of infectious virus by migratory cells, albeit to a lesser extent, indicating an important but not exclusive role for this receptor in virus capture and transmission.

Finally, by targeting HIV-1 directly with neutralizing gp120-specific antibody and a CD4–immunoglobulin fusion protein, both localized infection of cervical tissue and transfer of infectious virus by migratory cells were inhibited.

The design of novel microbicides that provide effective protection from sexual transmission of HIV relies on a detailed understanding of viral attachment and infection. This report indicates the main receptors involved in these processes in human cervical tissue and so might help towards the development of highly specific microbicides.