A new study reports the first evidence of simian-human immunodeficiency virus (SHIV) resistance to the protective vaginal microbicide, PSC-RANTES, in rhesus macaques. The researchers from Case Western Reserve University, Cleveland, Ohio; Tulane National Primate Research Center and Tulane University Health Sciences Center, Covington, Louisiana detail their findings in the May 2009 issue of the Journal of Virology.
Many recent failed attempts at developing a safe and effective vaccine against HIV-1 have led researchers to reexamine the potential of microbicides at preventing HIV-1 transmission. Along with cost and effectiveness, experts are now focusing on incorporating HIV-1 inhibitors, promising microbicide candidates capable of blocking virus replication. PSC-RANTES is one of the most potent entry inhibitors and a proven vaginal microbicide against SHIV in macaques when administered at high doses. However, further studies of PSC-RANTES suggest a dose-dependent decrease in protection in which case drug-resistant variants may emerge from the infecting SHIV or SIV population.
In this study researchers analyzed gene sequences from SHIV-infected rhesus macaques treated with varying doses of PSC-RANTES for drug-resistant variants. Results identified two distinct gene mutations present in the SHIV population, beginning at the earliest sample time and lasting throughout the 77 days of infection, in at least one macaque treated with a partially protective dose of PSC-RANTES.
"In conclusion, this PSC-RANTES-resistant variant in rhesus macaques is the first evidence for selection/infection by HIV or SHIV resistant to a vaginally applied microbiocide," say the researchers. "Due to the nature of microbicides, it is highly conceivable that after application, there will be a window of time when the drug is potent followed by a period when suboptimal doses of the drugs may provide the necessary conditions for emergence of drug resistance."
- Dudley et al. Selection of a Simian-Human Immunodeficiency Virus Strain Resistant to a Vaginal Microbicide in Macaques. Journal of Virology, 2009; 83 (10): 5067 DOI: 10.1128/JVI.00055-09
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