title: The nonnucleoside reverse transcriptase inhibitor MIV-150 in carrageenan gel prevents rectal transmission of simian/human immunodeficiency virus infection in macaques.
abstract: Development of a microbicide that prevents rectal transmission of human immunodeficiency virus (HIV) is a vital component in reducing HIV spread. We recently demonstrated that a formulation of the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 in carrageenan reduced vaginal infection of macaques with simian immunodeficiency virus SIVmac239 with HIV-1(HxB2) reverse transcriptase (SHIV-RT). Herein, we performed the first testing of MIV-150-carrageenan against rectal infection. Rhesus macaques were treated rectally with MIV-150-carrageenan or methyl cellulose (MC) placebo gel up to 4 h prior to rectal challenge with 10³ or 10(4) 50% tissue culture infective doses (TCID₅₀) of SHIV-RT. Infection was assessed by measuring plasma virus RNA as well as T and B cell responses. MIV-150-carrageenan protected all animals challenged with 10³ TCID(₅₀ when gel was applied either 30 min or 4 h prior to challenge, while 100% of the MC-treated animals became infected (n = 4 each; P < 0.03). Partial protection (2 of 4 animals) by MIV-150-carrageenan was observed for rectal challenge with 10-fold more virus applied 4 h after the gel. Sequencing of the RT gene from plasma virus RNA isolated at peak viremia confirmed that both of these animals (like infected MC controls) were infected with wild-type virus. Infection correlated with the development of SIV-specific T and B cell responses. MIV-150 was detected in the rectal fluids and tissues 4 h after gel application but was not detected in the blood at any time (0.5 to 24 h). These data are promising for the development of NNRTI-containing gels to prevent rectal HIV transmission.
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, USA.
authors.forename: R
authors.initials: R
authors.lastname: Singer
authors.forename: N
authors.initials: N
authors.lastname: Derby
authors.forename: A
authors.initials: A
authors.lastname: Rodriguez
authors.forename: L
authors.initials: L
authors.lastname: Kizima
authors.forename: J
authors.initials: J
authors.lastname: Kenney
authors.forename: M
authors.initials: M
authors.lastname: Aravantinou
authors.forename: A
authors.initials: A
authors.lastname: Chudolij
authors.forename: A
authors.initials: A
authors.lastname: Gettie
authors.forename: J
authors.initials: J
authors.lastname: Blanchard
authors.forename: J D
authors.initials: JD
authors.lastname: Lifson
authors.forename: M
authors.initials: M
authors.lastname: Piatak
authors.forename: J A
authors.initials: JA
authors.lastname: Fernández-Romero
authors.forename: T M
authors.initials: TM
authors.lastname: Zydowsky
authors.forename: M
authors.initials: M
authors.lastname: Robbiani
mesh_terms: D000285:Administration, Rectal; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage* / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology; D002351:Carrageenan / Q000008:administration & dosage* / Q000494:pharmacology; D005782:Gels / Q000008:administration & dosage* / Q000494:pharmacology; D008253:Macaca mulatta; D010919:Placebos / Q000008:administration & dosage; D010949:Plasma / Q000821:virology; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D012367:RNA, Viral / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000635:transmission; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000891:Anti-Infective Agents, Local; D005782:Gels; C510296:MIV 150; D010919:Placebos; D011725:Pyridines; D012367:RNA, Viral; D014508:Urea; D002351:Carrageenan