Feasibility of Repurposing the Polyanionic Microbicide, PPCM, for Prophylaxis against HIV Transmission during ART

Abstract

HIV-serodiscordant couples wishing to conceive often seek assisted reproduction, during which spermatozoa from infected men are washed to minimize the risk of HIV transmission to partner and fetus. We sought to improve this method by adding a microbicide, PPCM, as an HIV prophylactic. HIV-1 (BaL) inhibition by PPCM appears irreversible and independent of added Ca2+. Without added Ca2+, PPCM (≤10 mg/mL, ≤90 min), a stimulus of Ca2+-dependent acrosomal loss, has no effect on sperm motility, forward progression, or acrosomal status. PPCM-treated (10 mg/mL) sperm retain their ability to acrosome react when Ca2+ is added. Sperm DNA integrity/function is unaffected by PPCM (≤10 mg/mL). Adding PPCM (5 mg/mL, 30 min) to washing media reduces infectivity (viral antigen p24 and RNA) of ex-vivo HIV-infected semen by 3-4 Logs compared with washing alone. Sperm washing with appropriate extracellular Ca2+ levels and PPCM is significantly more effective than washing alone at reducing HIV infectivity.

Evaluation of the novel vaginal contraceptive agent PPCM in preclinical studies using sperm hyaluronan binding and acrosome status assays

“…Spermatozoa exposed to PPCM in the vagina retain motility and may move into the upper reproductive tract, but are unlikely to bind to hyaluronan surrounding the ovum and fertilize the egg due to premature acrosome reaction. This is consistent with PPCM's presumptive mechanism of action of inhibiting normal acrosome function rather than a general cytotoxic effect 43,52 …”

“…This is consistent with multiple in vitro studies confirming the safety of PPCM. [42][43][44][45][46][47][48][49][50][51][52] Our studies also support the use of the HBA in vitro to evaluate con-…”

Development of multipurpose technologies products for pregnancy and STI prevention: update on polyphenylene carboxymethylene MPT gel development†

“…Polyphenylene carboxymethylene (PPCM sodium salt) was originally developed as a potential MPT by the TOPCAD research group at Rush University. PPCM is an anionic mandelic acid condensation polymer that may provide excellent MPT protection [ 87–92 ]. It differs from other polyanion candidate products in several important ways.…”

“…PPCM causes a premature loss of the sperm acrosome (PAL), a critical organelle required for successful sperm–oocyte interaction. This contraceptive activity may be caused by induction of PAL through dysregulation of Ca 2+ signaling [ 87 , 88 , 110 ]. The same mechanism may be partly responsible for the multiple activities of this contraceptive microbicide.…”

Guidelines for risk reduction when handling gametes from infectious patients seeking assisted reproductive technologies

“…Adding PPCM to sperm washing medium reduced the viral titre of HIV-positive semen by 3-4 logs or 99.94% compared with 1-2 logs or 92% for washing alone under research laboratory conditions. This irreversible inhibition of HIV-1 had no adverse effect on sperm motility, forward progression or acrosome reaction (Anderson et al, 2011). The use of microbicides against transmission of HIV-1, however, has not completed phase III clinical trials for HIV prevention.…”