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12th International HIV Drug Resistance Workshop10–14 June 2003, Cabo del Sol, Los Cabos, Mexico |
BACKGROUND: Sexual transmission accounts for greater than 90% of worldwide HIV infection. Moreover, the incidence and prevalence of HIV infection in women has been increasing. Vaginal microbicides provide a female-controlled strategy to prevent HIV transmission in women. We have evaluated an HIV inactivating agent, 2-hydroxypropyl-betacyclodextrin (BCD), as a potential microbicide. Significantly, BCD recently has been proven as an effective microbicide in a mouse model for intravaginal HIV-1 transmission and is used extensively for other purposes in individuals.
METHODS: First, we evaluated the efficacy of virus neutralization in vitro, using a single cycle replication assay with HIV or SIV in the presence or absence of BCD. Based on encouraging in vitro data, we administered BCD intravaginally in rhesus macaques, followed by inoculation with large doses of highly pathogenic SIV. Control animals were treated with gel alone or nothing before inoculation with the same dose of SIV. The animals have been evaluated for infection by RTPCR of gag sequences in their plasma and nested PCR of gag sequences in their PBMC. These animals continue to be monitored for antiviral humoral and cellular immune responses. In addition, we selected different strains of HIV-1 in vitro in the presence of escalating doses of BCD.
RESULTS: BCD was successful in neutralizing infection of cells with both X4- and R5-tropic HIV as well as SIV in vitro. In fact, we could not see outgrowth of virus after 30 days post-exposure. Our in vivo data indicated that intravaginal pretreatment with BCD significantly reduced SIV mucosal transmission (1/6 animals infected) relative to untreated control animals (8/10 animals infected). Currently we are performing repeated challenges with BCD and SIV in the uninfected animals to assess whether they continue to be protected from infection. In addition, we are determining whether or not the uninfected BCD-treated animals have antiviral immune responses as compared to the controls. HIV that was selected with BCD in vitro was shown to be resistant to complete inactivation by BCD. Sequences of these viruses show mutations as compared to the same virus without BCD exposure.
CONCLUSIONS: Should BCD continue to prevent SIV transmission and not perturb mucosal tissues in this model, its current approved use in humans suggests it would be an important candidate for use as an anti-HIV microbicide. Nonetheless, the possibility of drug resistance against microbicides should be carefully evaluated before such drugs are administered to humans. Systemic antiviral therapy to manage HIV infection indicates that combinatorial approaches have significant benefits over monotherapy. Thus, we are also evaluating new models in which to examine the efficacy of BCD in combination with other potential microbicides.
PRESENTING AUTHOR: Z Ambrose
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2003-07-08
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