Abstract
Prevalent infection with human herpes simplex 2 (HSV-2) or human papillomavirus (HPV) is associated with increased human immunodeficiency virus (HIV) acquisition. Microbicides that target HIV as well as these sexually transmitted infections (STIs) may more effectively limit HIV incidence. Previously, we showed that a microbicide gel (MZC) containing MIV-150, zinc acetate (ZA) and carrageenan (CG) protected macaques against simian-human immunodeficiency virus (SHIV-RT) infection and that a ZC gel protected mice against HSV-2 infection. Here we evaluated a modified MZC gel (containing different buffers, co-solvents, and preservatives suitable for clinical testing) against both vaginal and rectal challenge of animals with SHIV-RT, HSV-2 or HPV. MZC was stable and safe in vitro (cell viability and monolayer integrity) and in vivo (histology). MZC protected macaques against vaginal (p<0.0001) SHIV-RT infection when applied up to 8 hours (h) prior to challenge. When used close to the time of challenge, MZC prevented rectal SHIV-RT infection of macaques similar to the CG control. MZC significantly reduced vaginal (p<0.0001) and anorectal (p = 0.0187) infection of mice when 106 pfu HSV-2 were applied immediately after vaginal challenge and also when 5×103 pfu were applied between 8 h before and 4 h after vaginal challenge (p<0.0248). Protection of mice against 8×106 HPV16 pseudovirus particles (HPV16 PsV) was significant for MZC applied up to 24 h before and 2 h after vaginal challenge (p<0.0001) and also if applied 2 h before or after anorectal challenge (p<0.0006). MZC provides a durable window of protection against vaginal infection with these three viruses and, against HSV-2 and HPV making it an excellent candidate microbicide for clinical use.
Highlights
human immunodeficiency virus (HIV), human papillomavirus (HPV) and HSV-2 constitute the three major viral sexually transmitted infections (STIs), and infection with HPV [1] or HSV-2 [2] increases HIV susceptibility
Preemptive and post-procedural anesthetics and analgesics are required by the Tulane National Primate Research Center (TNPRC) division of veterinary medicine for procedures that would likely cause more than momentary pain or distress in humans undergoing the same procedure
Magnetic resonance imaging (MRI) performed 2 h after vaginal MZC administration in macaques showed distribution of the gel throughout the vaginal vault; gel was no longer detected by 24 h post-gel application (Fig. S1)
Summary
HIV, HPV and HSV-2 constitute the three major viral STIs, and infection with HPV [1] or HSV-2 [2] increases HIV susceptibility. Like HIV, these viruses have no cure. Quadrivalent (targeting genotypes 6, 11, 16 and 18) and divalent (targeting genotypes 16 and 18) preventive vaccines against HPV are commercially available, HPV vaccination rates are currently low due to many challenges, including parental autonomy and cost [3]. Other important HPV types are not targeted, and the vaccine requires a cold supply chain, which limits its use in developing countries [3] and confirms the need for other preventive modalities, such as microbicides with anti-HPV activity. The Phase 2b CAPRISA 004 trial demonstrated reduced vaginal acquisition of both viruses in the presence of 1% tenofovir (TFV) gel and set the stage for advancing microbicide development against HIV and broadening the target to include co-pathogens [4]
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