An antiretroviral/zinc combination gel provides 24 hours of complete protection against vaginal SHIV infection in macaques

Abstract

Background: Repeated use, coitus-independent microbicide gels that do not contain antiretroviral agents also used as first line HIV therapy are urgently needed to curb HIV spread. Current formulations require high doses (millimolar range) of antiretroviral drugs and typically only provide short-term protection in macaques. We used the macaque model to test the efficacy of a novel combination microbicide gel containing zinc acetate and micromolar doses of the novel non-nucleoside reverse transcriptase inhibitor MIV-150 for up to 24 h after repeated gel application.

Methods and findings: Rhesus macaques were vaginally challenged with SHIV-RT up to 24 h after repeated administration of microbicide versus placebo gels. Infection status was determined by measuring virologic and immunologic parameters. Combination microbicide gels containing 14 mM zinc acetate dihydrate and 50 µM MIV-150 afforded full protection (21 of 21 animals) for up to 24 h after 2 weeks of daily application. Partial protection was achieved with the MIV-150 gel (56% of control at 8 h after last application, 11% at 24 h), while the zinc acetate gel afforded more pronounced protection (67% at 8-24 h). Marked protection persisted when the zinc acetate or MIV-150/zinc acetate gels were applied every other day for 4 weeks prior to challenge 24 h after the last gel was administered (11 of 14 protected). More MIV-150 was associated with cervical tissue 8 h after daily dosing of MIV-150/zinc acetate versus MIV-150, while comparable MIV-150 levels were associated with vaginal tissues and at 24 h.

Conclusions: A combination MIV-150/zinc acetate gel and a zinc acetate gel provide significant protection against SHIV-RT infection for up to 24 h. This represents a novel advancement, identifying microbicides that do not contain anti-viral agents used to treat HIV infection and which can be used repeatedly and independently of coitus, and underscores the need for future clinical testing of their safety and ability to prevent HIV transmission in humans.

Figure 1. A single dose of 500 µM MIV-150 partially protects against vaginal SHIV-RT infection.

A. 500 µM MIV-150 in carrageenan (PC-817) or MC placebo were administered 24 or 4 h prior to (Pre) or 1 h or 4 h after (Post) challenge with 10³ TCID₅₀ SHIV-RT. The number of animals in each treatment group is indicated and animals treated with MC at any time are pooled into one dataset. Plasma viral loads (SIV RNA copies/ml of plasma) were measured over time and each symbol denotes an individual animal. B. The percentages of animals infected in each group are summarized.

Figure 2. Repeated daily application of 50 µM MIV-150/zinc acetate protects fully for at least 24 h.

A. Animals were treated daily for 2 weeks with either MC placebo, carrageenan vehicle (PC-515), or carrageenan gel containing 50 µM MIV-150 (PC-815), 14 mM zinc acetate dihydrate (PC-707), or 50 µM MIV-150/14 mM zinc acetate dihydrate (PC-1005). SHIV-RT was then applied vaginally 8 or 24 h after the last gel. The data within the MC and carrageenan controls both represent pooled datasets from different time points (see Table S2). Plasma viral loads were measured over time, and the data for each animal are shown. The numbers of animals in each treatment group are noted. B. Animals were treated every other day for 4 weeks with carrageenan gel containing either 14 mM zinc acetate dihydrate or 50 µM MIV-150/14 mM zinc acetate dihydrate, before challenge with SHIV-RT 24 h later. Viral RNA copies/ml are shown.

Figure 3. MIV-150 does not accumulate systemically after repeated application.

Animals were treated with 50 µM MIV-150 (PC-815) or 50 µM MIV-150/14 mM zinc acetate dihydrate (PC-1005) daily for 2 weeks (daily) or with 50 µM MIV-150/14 mM zinc acetate dihydrate every other day for 4 weeks (EOD). (A) Plasma and vaginal swabs and (B) cervical and vaginal tissues were collected 8 or 24 h after the last gel and the levels of MIV-150 measured by RIA. The mean concentrations (±SEM, n = 6) of MIV-150 for each treatment group are shown.