Exposure to MIV-150 from a high-dose intravaginal ring results in limited emergence of drug resistance mutations in SHIV-RT infected rhesus macaques

• Published in: PloS one Vol. 9; no. 2; p. e89300
• Main Authors: Hsu, Mayla, Keele, Brandon F, Aravantinou, Meropi, Krawczyk, Noa, Seidor, Samantha, Abraham, Ciby J, Zhang, Shimin, Rodriguez, Aixa, Kizima, Larisa, Derby, Nina, Jean-Pierre, Ninochka, Mizenina, Olga, Gettie, Agegnehu, Grasperge, Brooke, Blanchard, James, Piatak, Jr, Michael J, Lifson, Jeffrey D, Fernández-Romero, José A, Zydowsky, Thomas M, Robbiani, Melissa
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.02.2014; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Administration, Intravaginal; AIDS; Analysis; Animals; Anti-Infective Agents, Local - administration & dosage; Antiretroviral agents; Antiretroviral drugs; Biology; Computational fluid dynamics; Disease resistance; DNA polymerases; Dosage; Dosage and administration; Drug resistance; Drug Resistance, Viral - genetics; Drug therapy; Drugs; Emergence; Exposure; Female; HIV; Human immunodeficiency virus; Impact resistance; Infection; Injections, Intramuscular; Lymph nodes; Macaca mulatta; Medicine; Microbial drug resistance; Microbicides; Mutation; Prevention; Pyridines - administration & dosage; Pyridines - pharmacology; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - pharmacology; RNA-directed DNA polymerase; Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - drug effects; Simian Immunodeficiency Virus - genetics; Time Factors; Tissues; Urea - administration & dosage; Urea - analogs & derivatives; Urea - pharmacology; Vagina; Viral Load; Viruses; Louisiana; New York; United States > US; Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0089300

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.