Candidate Microbicide PPCM Blocks Human Immunodeficiency Virus Type 1 Infection in Cell and Tissue Cultures and Prevents Genital Herpes in a Murine Model

Abstract

A structurally novel candidate microbicide, PPCM, which is formed from the reaction of D,L-mandelic acid with sulfuric acid, provides activity against human immunodeficiency virus (HIV) and herpes simplex virus (HSV) and is not cytotoxic. The objectives of the current studies were to comprehensively evaluate the activity of PPCM in cell and explant cultures, explore the possibility of combining PPCM with HIV-specific reverse transcriptase inhibitors, and evaluate the efficacy of a formulated gel against genital herpes in a murine model. PPCM inhibited infection by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture. Ectocervical and endocervical tissue explants exposed to HIV-1 BaL in the presence of PPCM were protected (50% inhibitory concentrations [IC 50 ] of 3.9 g/ml for ectocervix and 3.1 g/ml for endocervix), and transfer of virus to target T cells via migratory cells was significantly impaired (IC 50 of 35.7 g/ml for ectocervix and 54.6 g/ml for endocervix). The drug also blocked infection by cell-associated virus. Combinations of PPCM with UC-781 or PMPA in vitro exhibited additive anti-HIV activity. PPCM was incorporated into stable, low-pH gel formulations at concentrations of 0.4% and 4%. Both gels prevented genital herpesvirus infection in mice, even when virus was introduced in human seminal plasma. The abilities of PPCM to inhibit primary HIV isolates, reduce infection by cell-associated virus, and transfer of HIV from migratory to T cells, combined with the complete protection provided by formulated gel against genital herpes, indicate that this drug is an excellent candidate for inclusion in a combination microbicide and would provide protection against both HIV and HSV.

Multipurpose prevention technologies: the future of HIV and STI protection

“…Poly-[1,4-phenylene-(1-carboxy) methylene] (PPCM), another candidate microbicide that targets the viral envelope, is currently being evaluated for its anti-HSV and contraceptive activity, and is a potential candidate for MPT [24, 25]. Thus, both GRFT and PPCM are candidate drugs for coformulation with TDF/TFV or dapivirine.…”

Use of Human Mucosal Tissue to Study HIV-1 Pathogenesis and Evaluate HIV-1 Prevention Modalities

“…Consequently, many tissue replicates are possible for each treatment condition. Using this model system, drug entities known as active pharmaceutical ingredients (APIs) have been tested to determine safety in tissue and ability to prevent HIV-1 and dissemination [13, 59, 62–66, 67••, 68–72] as well as HSV-2 infection [73•, 74] (Table 1). Non-polarized tissue is pre-treated with the API for a short period of time, typically 15 to 30 minutes, and then virus is added to the cultures.…”

Cox-2 inhibitors induce early c-Myc downregulation and lead to expression of differentiation markers in leukemia cells

“…70 Importantly, the re-activation of c-Myc protein expression is per se sufficient to reactivate the malignant phenotype. 71 We do not know yet what exactly maintains the cells so longer in dormancy. Conceivably, cells may cycle very much slower rather than completely stopping in G 0 , to be maintained so long times.…”