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Zandrea Ambrose,
Sarah Palmer,
Valerie F Boltz,
Mary Kearney,
Kay Larsen,
Patricia Polacino,
Leon Flanary,
Kelli Oswald,
Michael Piatak,
Jeremy Smedley,
Wei Shao, Norbert Bischofberger,
Frank Maldarelli,
Jason T Kimata,
John W Mellors,
Shiu-Lok Hu,
John M Coffin,
Jeffrey D Lifson,
Vineet N KewalRamani
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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.
Journal of Virology 12/2007; 81(22):12145-55. · 5.40 Impact Factor
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Agneta S von Gegerfelt,
Margherita Rosati,
Candido Alicea,
Antonio Valentin,
Patricia Roth,
Jenifer Bear,
Genoveffa Franchini,
Paul S Albert, Norbert Bischofberger,
Jean D Boyer,
David B Weiner,
Phillip Markham,
Zimra R Israel,
John H Eldridge,
George N Pavlakis,
Barbara K Felber
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ABSTRACT: Rhesus macaques chronically infected with highly pathogenic simian immunodeficiency virus (SIV) SIVmac251 were treated with antiretroviral drugs and vaccinated with combinations of DNA vectors expressing SIV antigens. Vaccination during therapy increased cellular immune responses. After the animals were released from therapy, the virus levels of 12 immunized animals were significantly lower (P = 0.001) compared to those of 11 animals treated with only antiretroviral drugs. Vaccinated animals showed a persistent increase in immune responses, thus indicating both a virological and an immunological benefit following DNA therapeutic vaccination. Several animals show a long-lasting decrease in viremia, suggesting that therapeutic vaccination may provide an additional benefit to antiretroviral therapy.
Journal of Virology 03/2007; 81(4):1972-9. · 5.40 Impact Factor
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Kenneth Williams,
Susan Westmoreland,
Jane Greco,
Eva Ratai,
Margaret Lentz,
Woong-Ki Kim,
Robert A Fuller,
John P Kim,
Patrick Autissier,
Prahbat K Sehgal,
Raymond F Schinazi, Norbert Bischofberger,
Michael Piatak,
Jeffrey D Lifson,
Eliezer Masliah,
R Gilberto González
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ABSTRACT: Difficulties in understanding the mechanisms of HIV neuropathogenesis include the inability to study dynamic processes of infection, cumulative effects of the virus, and contributing host immune responses. We used H magnetic resonance spectroscopy and studied monocyte activation and progression of CNS neuronal injury in a CD8 lymphocyte depletion model of neuroAIDS in SIV-infected rhesus macaque monkeys. We found early, consistent neuronal injury coincident with viremia and SIV infection/activation of monocyte subsets and sought to define the role of plasma virus and monocytes in contributing to CNS disease. Antiretroviral therapy with essentially non-CNS-penetrating agents resulted in slightly decreased levels of plasma virus, a significant reduction in the number of activated and infected monocytes, and rapid, near-complete reversal of neuronal injury. Robust macrophage accumulation and productive virus replication were found in brains of infected and CD8 lymphocyte-depleted animals, but no detectable virus and few scattered infiltrating macrophages were observed in CD8 lymphocyte-depleted animals compared with animals not receiving antiretroviruses that were sacrificed at the same time after infection. These results underscore the role of activated monocytes and monocyte infection outside of the brain in driving CNS disease.
Journal of Clinical Investigation 10/2005; 115(9):2534-45. · 15.39 Impact Factor
