Abstract
To extend our observations that single or repeated application of a gel containing the NNRTI MIV-150 (M) and zinc acetate dihydrate (ZA) in carrageenan (CG) (MZC) inhibits vaginal transmission of simian/human immunodeficiency virus (SHIV)-RT in macaques, we evaluated safety and anti-SHIV-RT activity of MZC and related gel formulations ex vivo in macaque mucosal explants. In addition, safety was further evaluated in human ectocervical explants. The gels did not induce mucosal toxicity. A single ex vivo exposure to diluted MZC (1∶30, 1∶100) and MC (1∶30, the only dilution tested), but not to ZC gel, up to 4 days prior to viral challenge, significantly inhibited SHIV-RT infection in macaque vaginal mucosa. MZC's activity was not affected by seminal plasma. The antiviral activity of unformulated MIV-150 was not enhanced in the presence of ZA, suggesting that the antiviral activity of MZC was mediated predominantly by MIV-150. In vivo administration of MZC and CG significantly inhibited ex vivo SHIV-RT infection (51–62% inhibition relative to baselines) of vaginal (but not cervical) mucosa collected 24 h post last gel exposure, indicating barrier effect of CG. Although the inhibitory effect of MZC (65–74%) did not significantly differ from CG (32–45%), it was within the range of protection (∼75%) against vaginal SHIV-RT challenge 24 h after gel dosing. Overall, the data suggest that evaluation of candidate microbicides in macaque explants can inform macaque efficacy and clinical studies design. The data support advancing MZC gel for clinical evaluation.
Highlights
Considering that sexual intercourse is the main route of HIV acquisition, products that block sexual HIV-1 transmission are urgently needed
The Population Council’s (PC’s) lead microbicide gel (MZC) containing 50 mM of the NNRTI MIV-150 and 14 mM zinc acetate dihydrate (ZA) in carrageenan (CG) protects DepoProvera-treated macaques against a single vaginal simian/human immunodeficiency virus (SHIV)-reverse transcriptase (RT) challenge completely for up to 8 h and protects,75% of macaques when challenged 24 h after gel dosing [2,3,4]
ZA could contribute to the antiviral activity of MZC through zinc targeting the reverse transcriptase (RT), involving sites not targeted by traditional RTIs (Mizenina et al, in preparation) [6] and induction of immune changes [7,8,9,10] that can influence infection
Summary
Considering that sexual intercourse is the main route of HIV acquisition, products that block sexual HIV-1 transmission are urgently needed. The success of the CAPRISA 004 clinical trial, in which vaginal application of a 1% tenofovir gel reduced HIV-1 acquisition by 39% overall and by 54% in high adherers [1], emphasizes the promise for anti-HIV microbicide development. The Population Council’s (PC’s) lead microbicide gel (MZC) containing 50 mM of the NNRTI MIV-150 and 14 mM zinc acetate dihydrate (ZA) in carrageenan (CG) protects DepoProvera-treated macaques against a single vaginal simian/human immunodeficiency virus (SHIV)-RT challenge completely for up to 8 h and protects ,75% of macaques when challenged 24 h after gel dosing (original and modified gels optimized for use in human) [2,3,4]. ZA could contribute to the antiviral activity of MZC through zinc targeting the reverse transcriptase (RT), involving sites not targeted by traditional RTIs (Mizenina et al, in preparation) [6] and induction of immune changes (e.g., cytokines/chemokines/other innate factors) [7,8,9,10] that can influence infection
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