Candidate microbicide PPCM blocks human immunodeficiency virus type 1 infection in cell and tissue cultures and prevents genital herpes in a murine model.
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 microg/ml for ectocervix and 3.1 microg/ml for endocervix), and transfer of virus to target T cells via migratory cells was significantly impaired (IC(50) of 35.7 microg/ml for ectocervix and 54.6 microg/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.
Mesquita
Pedro M M
PM
Department of Cellular and Molecular Medicine, St. George's University of London, London, United Kingdom. pmesquit@aecom.yu.edu
Wilson
Sarah S
SS
Manlow
Philippe
P
Fischetti
Lucia
L
Keller
Marla J
MJ
Herold
Betsy C
BC
Shattock
Robin J
RJ
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D005782:Gels / Q000494:pharmacology; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006558:Herpes Genitalis / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D008156:Luciferases; D008333:Mandelic Acids / Q000737:chemistry; D051379:Mice; D018139:Simplexvirus / Q000187:drug effects*; D013464:Sulfuric Acids / Q000737:chemistry
D000890:Anti-Infective Agents; D005782:Gels; D008333:Mandelic Acids; D013464:Sulfuric Acids; D008156:Luciferases; C037938:mandelic acid; C033158:sulfuric acid