Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy.
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.
Ambrose
Zandrea
Z
HIV Drug Resistance Program, National Cancer Institute, Building 535, Room 123, Frederick, MD 21702, USA.
Palmer
Sarah
S
Boltz
Valerie F
VF
Kearney
Mary
M
Larsen
Kay
K
Polacino
Patricia
P
Flanary
Leon
L
Oswald
Kelli
K
Piatak
Michael
M
Smedley
Jeremy
J
Shao
Wei
W
Bischofberger
Norbert
N
Maldarelli
Frank
F
Kimata
Jason T
JT
Mellors
John W
JW
Hu
Shiu-Lok
SL
Coffin
John M
JM
Lifson
Jeffrey D
JD
KewalRamani
Vineet N
VN
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*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase