title: Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy.
abstract: Antiretroviral therapy (ART) in human immunodeficiency virus type 1 (HIV-1)-infected patients does not clear the infection and can select for drug resistance over time. Not only is drug-resistant HIV-1 a concern for infected individuals on continual therapy, but it is an emerging problem in resource-limited settings where, in efforts to stem mother-to-child-transmission of HIV-1, transient nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy given during labor can select for NNRTI resistance in both mother and child. Questions of HIV-1 persistence and drug resistance are highly amenable to exploration within animals models, where therapy manipulation is less constrained. We examined a pigtail macaque infection model responsive to anti-HIV-1 therapy to study the development of resistance. Pigtail macaques were infected with a pathogenic simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT-SHIV) to examine the impact of prior exposure to a NNRTI on subsequent ART comprised of a NNRTI and two nucleoside RT inhibitors. K103N resistance-conferring mutations in RT rapidly accumulated in 2/3 infected animals after NNRTI monotherapy and contributed to virologic failure during ART in 1/3 animals. By contrast, ART effectively suppressed RT-SHIV in 5/6 animals. These data indicate that suboptimal therapy facilitates HIV-1 drug resistance and suggest that this model can be used to investigate persisting viral reservoirs.
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, Building 535, Room 123, Frederick, MD 21702, USA.
authors.forename: Zandrea
authors.initials: Z
authors.lastname: Ambrose
authors.forename: Sarah
authors.initials: S
authors.lastname: Palmer
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Boltz
authors.forename: Mary
authors.initials: M
authors.lastname: Kearney
authors.forename: Kay
authors.initials: K
authors.lastname: Larsen
authors.forename: Patricia
authors.initials: P
authors.lastname: Polacino
authors.forename: Leon
authors.initials: L
authors.lastname: Flanary
authors.forename: Kelli
authors.initials: K
authors.lastname: Oswald
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.forename: Jeremy
authors.initials: J
authors.lastname: Smedley
authors.forename: Wei
authors.initials: W
authors.lastname: Shao
authors.forename: Norbert
authors.initials: N
authors.lastname: Bischofberger
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.forename: Jason T
authors.initials: JT
authors.lastname: Kimata
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.forename: Shiu-Lok
authors.initials: SL
authors.lastname: Hu
authors.forename: John M
authors.initials: JM
authors.lastname: Coffin
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Vineet N
authors.initials: VN
authors.lastname: KewalRamani
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral / Q000235:genetics; D019143:Evolution, Molecular; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008251:Macaca; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D014766:Viremia / Q000188:drug therapy*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase