Laderman MM, Veazey RS, Offord R, et al. Science. 2004;306:485–487
Purpose of the Study.
Topical agents that prevent transmission of HIV across mucosae during sexual activity are urgently needed, because the vast majority of HIV infections are acquired through transmission across mucosal surfaces. However, the mechanisms of HIV entry at vaginal sites of infection are poorly understood. The chemokine receptor CCR5 serves as an essential coreceptor for HIV entry into target cells. Individuals who lack surface CCR5 expression are highly resistant to acquiring HIV infection through the mucosal route. Because viruses that use CCR5 predominate in the early stages of mucosal transmission, it is likely that such transmission selectively involves CCR5. This suggests a strategy by which vaginal transmission might be prevented.
The chemokine RANTES is a specific ligand for CCR5. The investigators generated an analog of RANTES, PSC-RANTES, that has an N-terminal modification. In vitro PSC-RANTES inhibited propagation of SHIV, a chimeric simian/human immunodeficiency virus. Thirty adult female rhesus macaques were pretreated with varying concentrations of PSC-RANTES intravaginally. The animals were subsequently challenged with high-multiplicity (300 median tissue culture infectious doses) SHIV intravaginally and monitored for up to 24 weeks.
All 5 animals treated with the highest dose of PSC-RANTES were protected from SHIV infection. Lower doses also proved protective to a lesser extent. Plasma levels of PSC-RANTES were not detectable, suggesting specific local protection against viral infection.
PSC-RANTES, a selective blocker of CCR5, protected rhesus macaques from intervaginal exposure to a highly infectious dose of SHIV, although the topical concentration of PSC-RANTES that was shown to be protective was many times higher than the concentration required to neutralize the same virus in vitro.
A safe, simple, and affordable topical microbicide that would effectively prevent vaginal transmission of HIV is desperately needed, particularly in the developing world. This study provides proof of the concept that targeting the coreceptor for HIV entry into target cells, CCR5, is a viable strategy for the prevention of vaginal transmission of HIV. Cost, however, would be a major obstacle to the implementation of this strategy, but it is now clear that HIV can be stopped before it infects the vaginal mucosa.