Candidate microbicide PPCM blocks human immunodeficiency virus type 1 infection in cell and tissue cultures and prevents genital herpes in a murine model

Pedro M M Mesquita, Sarah S. Wilson, Philippe Manlow, Lucia Fischetti, Marla J. Keller, Betsy Herold, Robin J. Shattock

Research output: Contribution to journalArticle

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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 expiant 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-1BaL in the presence of PPCM were protected (50% inhibitory concentrations [IC50] of 3.9 μg/ml for ectocervix and 3.1 μg/ml for endocervix), and transfer of virus to target T cells via migratory cells was significantly impaired (IC 50 of 35.7 μg/ml for ectocervix and 54.6 μg/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.

Original languageEnglish (US)
Pages (from-to)6576-6584
Number of pages9
JournalJournal of Virology
Volume82
Issue number13
DOIs
StatePublished - Jul 2008

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Herpes Genitalis
Human immunodeficiency virus
Virus Diseases
Anti-Infective Agents
Human immunodeficiency virus 1
genitalia
tissue culture
HIV-1
cell culture
Cell Culture Techniques
anti-infective agents
animal models
HIV
infection
viruses
Gels
Satellite Viruses
gels
inhibitory concentration 50
herpes simplex

ASJC Scopus subject areas

  • Immunology

Cite this

Candidate microbicide PPCM blocks human immunodeficiency virus type 1 infection in cell and tissue cultures and prevents genital herpes in a murine model. / Mesquita, Pedro M M; Wilson, Sarah S.; Manlow, Philippe; Fischetti, Lucia; Keller, Marla J.; Herold, Betsy; Shattock, Robin J.

In: Journal of Virology, Vol. 82, No. 13, 07.2008, p. 6576-6584.

Research output: Contribution to journalArticle

Mesquita, Pedro M M ; Wilson, Sarah S. ; Manlow, Philippe ; Fischetti, Lucia ; Keller, Marla J. ; Herold, Betsy ; Shattock, Robin J. / Candidate microbicide PPCM blocks human immunodeficiency virus type 1 infection in cell and tissue cultures and prevents genital herpes in a murine model. In: Journal of Virology. 2008 ; Vol. 82, No. 13. pp. 6576-6584.
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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 expiant 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-1BaL in the presence of PPCM were protected (50{\%} inhibitory concentrations [IC50] of 3.9 μg/ml for ectocervix and 3.1 μg/ml for endocervix), and transfer of virus to target T cells via migratory cells was significantly impaired (IC 50 of 35.7 μg/ml for ectocervix and 54.6 μg/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.",
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