Incomplete Protection against Simian Immunodeficiency Virus Vaginal Transmission in Rhesus Macaques by a Topical Antiviral Agent Revealed by Repeat Challenges

Abstract

The rising prevalence of human immunodeficiency virus type 1 (HIV-1) infection in women, especially in resource-limited settings, accentuates the need for accessible, inexpensive, and female-controlled preexposure prophylaxis strategies to prevent mucosal transmission of the virus. While many compounds can inactivate HIV-1 in vitro, evaluation in animal models for mucosal transmission of virus may help identify which approaches will be effective in vivo. Macaques challenged intravaginally with pathogenic simian immunodeficiency virus (SIV mac251 ) provide a model to preclinically evaluate candidate microbicides. 2-Hydroxypropyl-␤-cyclodextrin (BCD) prevents HIV-1 and SIV infection of target cells at subtoxic doses in vitro. Consistent with these findings, intravaginal challenge of macaques with SIV mac251 preincubated with BCD prevented mucosal transmission, as measured by plasma viremia and antiviral antibodies, through 10 weeks postchallenge. In an initial challenge, BCD applied topically prior to SIV mac251 prevented intravaginal transmission of virus compared to controls (P < 0.0001). However, upon a second virus challenge following BCD pretreatment, the majority of the previously protected animals became infected. The mechanism through which animals become infected at a frequency similar to that of controls after prior exposure to BCD and SIV mac251 in subsequent intravaginal virus challenges (P ‫؍‬ 0.63), despite the potent antiviral properties of BCD, remains to be determined. These results highlight the unpredictability of antiviral compounds as topical microbicides and suggest that repeated exposures to candidate treatments should be considered for in vivo evaluation.

Implications for lipids during replication of enveloped viruses

“…Nef contains cholesterol binding sequence in its C terminus which allows transport to and association with lipid rafts HIV (Zheng et al, 2003) Cholesterol depletion enhances virus budding Influenza virus (Barman and Nayak, 2007) Cholesterol depletion inhibits virus production HIV (Ono and Freed, 2001;Pickl et al, 2001) "Lipid-raft" dependent viruses do not co-localize on the plasma membrane HIV, Influenza virus, EBOV (Khurana et al, 2007;Leung et al, 2008 (Graham et al, 2003), influenza virus (Barman and Nayak, 2007;Ambrose et al, 2008)…”

“…(3) The hydroxyl group of cholesterol hydrogen bonds with the ceramide group of sphingolipids, while its planar sterol ring interacts with the saturated acyl chain (Xu and London, 2000;Ramstedt and Slotte, 2006). As a proof of concept, it has been shown that the removal of virion-associated cholesterol using ␤-cyclodextrin permeabilized the viral membrane of HIV, SIV and influenza virus and the enveloped viruses became inactivated due to a loss in their protein core and genome integrity (Graham et al, 2003;Barman and Nayak, 2007;Ambrose et al, 2008).…”

Early HIV‐1 Target Cells in Human Vaginal and Ectocervical Mucosa

“…To be effective, such measures must interrupt one or more of the early events in HIV-1 mucosal transmission and infection, including HIV-1 translocation across the epithelial barrier, entry into subepithelial target mononuclear cells, and mucosal and systemic dissemination. Although some antibodies and topically applied microbicides are reportedly capable of preventing HIV-1 infection in model systems, [5][6][7][8][9] including simian immunodeficiency virus (SIV) infection in macaques, [10][11][12][13][14][15][16] suc-After translocation through the pleuristratified epithelium of the lower female genital tract, HIV-1 encounters potential target mononuclear cells in the lamina propria of the vagina and ectocervix. Here we show that each major type of genital mononuclear cells, including dendritic cells (DCs), macrophages and lymphocytes, are susceptible to HIV-1 in vitro.…”

Cyclodextrins: Emerging Medicines of the New Millennium

“…The animals were treated with HPβCD by intravaginal administration and then subjected to SIV contact, with HPβCD protecting them from infection upon first contact with the virus. However, repeating the viral inoculation 11 or 47 weeks later, also under treatment with HPβCD, led to large-scale infection [37]. This means that HPβCD, at the tested doses, is unsuited as a vaccine for repeated exposure to the virus.…”