title: Exposure to MIV-150 from a high-dose intravaginal ring results in limited emergence of drug resistance mutations in SHIV-RT infected rhesus macaques.
abstract: When microbicides used for HIV prevention contain antiretroviral drugs, there is concern for the potential emergence of drug-resistant HIV following use in infected individuals who are either unaware of their HIV infection status or who are aware but still choose to use the microbicide. Resistant virus could ultimately impact their responsiveness to treatment and/or result in subsequent transmission of drug-resistant virus. We tested whether drug resistance mutations (DRMs) would emerge in macaques infected with simian immunodeficiency virus expressing HIV reverse transcriptase (SHIV-RT) after sustained exposure to the potent non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 delivered via an intravaginal ring (IVR). We first treated 4 SHIV-RT-infected animals with daily intramuscular injections of MIV-150 over two 21 day (d) intervals separated by a 7 d drug hiatus. In all 4 animals, NNRTI DRMs (single and combinations) were detected within 14 d and expanded in proportion and diversity with time. Knowing that we could detect in vivo emergence of NNRTI DRMs in response to MIV-150, we then tested whether a high-dose MIV-150 IVR (loaded with >10 times the amount being used in a combination microbicide IVR in development) would select for resistance in 6 infected animals, modeling use of this prevention method by an HIV-infected woman. We previously demonstrated that this MIV-150 IVR provides significant protection against vaginal SHIV-RT challenge. Wearing the MIV-150 IVR for 56 d led to only 2 single DRMs in 2 of 6 animals (430 RT sequences analyzed total, 0.46%) from plasma and lymph nodes despite MIV-150 persisting in the plasma, vaginal fluids, and genital tissues. Only wild type virus sequences were detected in the genital tissues. These findings indicate a low probability for the emergence of DRMs after topical MIV-150 exposure and support the advancement of MIV-150-containing microbicides.
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Mayla
authors.initials: M
authors.lastname: Hsu
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc. (formerly SAIC-Frederick, Inc.), Frederick National Laboratory, Frederick, Maryland, United States of America.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Meropi
authors.initials: M
authors.lastname: Aravantinou
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Noa
authors.initials: N
authors.lastname: Krawczyk
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Samantha
authors.initials: S
authors.lastname: Seidor
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Ciby J
authors.initials: CJ
authors.lastname: Abraham
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Aixa
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Larisa
authors.initials: L
authors.lastname: Kizima
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Nina
authors.initials: N
authors.lastname: Derby
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Ninochka
authors.initials: N
authors.lastname: Jean-Pierre
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Mizenina
authors.affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, United States of America.
authors.forename: Brooke
authors.initials: B
authors.lastname: Grasperge
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Blanchard
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc. (formerly SAIC-Frederick, Inc.), Frederick National Laboratory, Frederick, Maryland, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Piatak
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc. (formerly SAIC-Frederick, Inc.), Frederick National Laboratory, Frederick, Maryland, United States of America.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández-Romero
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Zydowsky
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Robbiani
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D009154:Mutation; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics*; D013997:Time Factors; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019562:Viral Load
chemical_list: D000891:Anti-Infective Agents, Local; C510296:MIV 150; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D014508:Urea