MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model

Abstract

The transmission of both cell-free and cell-associated immunodeficiency viruses has been demonstrated directly in multiple animal species and possibly occurs in humans, as suggested by genotyping of the infecting human immunodeficiency virus (HIV) in acutely infected women and in semen from their partners. Therefore, a microbicide may need to block both mechanisms of HIV transmission to achieve maximum efficacy. To date, most of the preclinical evaluation of candidate microbicides has been performed using cell-free HIV. New models of mucosal transmission of cell-associated HIV are needed to evaluate candidate microbicide performance. The MIV-150/zinc acetate/carrageenan (MZC) gel protects Depo-Provera-treated macaques against cell-free simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection when applied vaginally up to 8 h before challenge. We recently demonstrated the potent activity of MZC gel against cell-free SHIV-RT in macaque vaginal explants. In the current study, we established a cell-associated SHIV-RT infection model of macaque vaginal tissues and tested the activity of MZC gel in this model. MZC gel protected tissues against cell-associated SHIV-RT infection when present at the time of viral exposure or when applied up to 4 days prior to viral challenge. These data support clinical testing of the MZC gel. Overall, our ex vivo model of cell-associated SHIV-RT infection in macaque vaginal mucosa complements the cell-free infection models, providing tools for prioritization of products that block both modes of HIV transmission. Women account for about half of human immunodeficiency virus type 1 (HIV-1) infections, with the majority of infections transmitted via sexual intercourse (1). A longitudinal study reported that the genotype of the infecting HIV-1 in acutely infected women closely matches the virus in the seminal plasma and seminal cells from their chronically infected sexual partners (2), suggesting that transmission of both cell-free and cell-associated HIV-1 occurs in vivo. Furthermore, transmitter/founder donor variants were identified in peripheral blood mononuclear cells (PBMCs) and blood plasma, also suggesting that both cell-free transmission and cell-associated HIV transmission occur in vivo (3, 4). Which mode of transmission has a primary role in the establishment of mucosal infection is yet to be determined (5).Cell-to-cell HIV transmission is associated with efficient in vitro viral transfer through virological synapses (6-9). Cell-associated HIV was shown to pass the epithelial monolayer and infect the underlying target cells in vitro (10, 11). In agreement with this information, seminal cells (12) and macrophages (13) were shown to penetrate the epithelium in cervical explant tissues and thus could potentially deliver HIV to target cells. Recent studies mimicking HIV transmission in the intestinal tract in a rectal explant model revealed that ex vivo transmission of cell-associated simian immunodeficiency virus (SIV mac251 ) is more efficient than transmission o...

MZC Gel Inhibits SHIV-RT and HSV-2 in Macaque Vaginal Mucosa and SHIV-RT in Rectal Mucosa

“…Primers for SIV were 5′-GGTTGCACCCCCTATGACAT-3′ (SIV667 gag Fwd) and 5′-TGCATAGCCGCTTGATGGT-3′ (SIV731 gag Rev). Results were analyzed by the standard curve method, using SIV mac1A11 DNA obtained from Dr. Paul Luciw through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH 52 as the standard ( 37,65 . Primers for HSV-2 pol were 5′-GCTCGAGTGCGAAAAAACGTTC-3′ (HSV-2 pol Fwd) and 5′-TGCGGTTGATAAACGCGCAGT-3′ (HSV-2 pol Rev) 13,53 .…”

“…Analysis of gel activity against SHIV-RT and HSV-2 was performed as described in 36,37,39,40,54 using a log-normal generalized linear mixed model with SOFT or CUM as the response and gel treatment as the predictor. For the experiments using rectal biopsies, a random intercept for each animal was included.…”

“…The Population Council (PC) gel containing 50μM of the NNRTI M IV-150 and 14mM zinc acetate dihydrate ( Z A) in carrageenan ( C G) demonstrated activity against vaginal SHIV-RT (RM), vaginal HSV-2 (RM, mice), anorectal HSV-2 (mice), vaginal and anorectal HPV (mice) 29–35 . MZC protects against SHIV-RT in RM vaginal explants 36,37 and against HIV and HSV-2 in human cervical explants 64 . A recently completed Phase I clinical trial demonstrated a favorable vaginal safety profile of MZC 38,66 .…”

On-demand microbicide products: design matters

“…Of these, gels incorporating macromolecules such as proteins, multipurpose technology (MPT) products that combine HIV and other STI prevention, and dual compartment products, represent some of the most recent activities within this class. A combination microbicide gel containing MIV-150 and zinc acetate formulated in a carrageenan gel showed efficacy against HIV-1, HSV-2, and HPV in macaques after vaginal and rectal challenges [91]. A phase-1 study showed that this product is safe, and the cervicovaginal lavages (CVLs) show in vitro activity against HIV-1 and HPV [16].…”

First-in-Human Trial of MIV-150 and Zinc Acetate Coformulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence, and Pharmacodynamics

“…CG is the most potent inhibitor of HPV known, 26 potentiates the anti-HSV-2 activity of ZA, 27,28 and has been found safe for vaginal use in multiple studies. 29–34 PC-1005 is active in vivo against vaginal or rectal challenge with HIV, simian-human immunodeficiency virus-reverse transcriptase, HSV-2, and HPV 24,35,36 ; ex vivo against simian-human immunodeficiency virus-reverse transcriptase in explants 37,38 and remains active in the presence of semen. 27,28 …”