Cyanovirin-N Inhibits AIDS Virus Infections in Vaginal Transmission Models

Abstract

The cyanobacterial protein cyanovirin-N (CV-N) potently inactivates diverse strains of HIV-1 and other lentiviruses due to irreversible binding of CV-N to the viral envelope glycoprotein gp120. In this study, we show that recombinant CV-N effectively blocks HIV-1(Ba-L) infection of human ectocervical explants. Furthermore, we demonstrate the in vivo efficacy of CV-N gel in a vaginal challenge model by exposing CV-N-treated female macaques (Macaca fascicularis) to a pathogenic chimeric SIV/HIV-1 virus, SHIV89.6P. All of the placebo-treated and untreated control macaques (8 of 8) became infected. In contrast, 15 of 18 CV-N-treated macaques showed no evidence of SHIV infection. Further, CV-N produced no cytotoxic or clinical adverse effects in either the in vitro or in vivo model systems. Together these studies suggest that CV-N is a good candidate for testing in humans as an anti-HIV topical microbicide.

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

“…An example of the successful use of an NHP model in HIV prevention is the study of Parikh, et al, which used SHIV SF162P3 and pig-tailed macaques to predict that tenofovir gel could block vaginal HIV transmission as was subsequently determined in the CAPRISA 004 clinical trial (1,38). Yet because many new-generation microbicides being considered contain antiretrovirals that often exhibit exquisite specificity for HIV, multiple SIV/SHIV macaque models need to be developed for efficacy testing in vivo (20,27,28,38,46,50,52). Furthermore, within different NHP models there are differences in viral (i.e., HIV versus SHIV envelope variable region 3) and host (i.e., human versus macaque CCR5) sequences, resulting in distinctions that preclude the use of certain HIV-specific inhibitors and can confound the interpretation of the data obtained (4,33,42,49).…”

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

“…Another group of four macaques were not pretreated with DMPA prior to virus challenge. Two macaques in each group were inoculated intravaginally with 500 TCID 50 of RT-SHIV; the remaining two macaques in each group received 1,000 TCID 50 as previously described [13,14]. Briefly, 0.5 ml of virus preparation was atraumatically introduced to the vaginal mucosa using a stainless steel animal feeding tube.…”

“…SIVmac239 gag -specific primers were used to amplify virus DNA by PCR as described previously [13,14,46]. …”

Cyanovirin-N potently inhibits human immunodeficiency virus type 1 infection in cellular and cervical explant models

“…This binding then inhibits the conformational change required for virus-target cell attachment and subsequent fusion. Previous in vivo studies, with CV-N formulated as a gel, have shown promising efficacy when the compound was used topically as a rectal or vaginal microbicide in macaques challenged with the highly pathogenic SHIV89.6P virus (Tsai et al, 2003(Tsai et al, , 2004.…”

“…These studies expand and build on our early demonstration of compound efficacy in tissue and animal models (Tsai et al, 2004). In this study, we have evaluated multiple aspects of CV-N activity including: the ability to block cell-free and cell-to-cell HIV-1 transmission; its activity in the presence of semen; efficacy in the presence of Candida albicans; and activity in human cervical explant cultures (Fletcher et al, 2005;Greenhead et al, 2000;Hu et al, 2004).…”