In the online-ahead-of-print section of the Journal of Virology, a group of researchers led by Thomas North describe a new macaque model of viral persistence during antiretroviral therapy. Because non-nucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral drugs are not active against the reverse transcriptase (RT) of simian immunodeficiency virus (SIV), the study employs a SIV-HIV hybrid encoding the RT from HIV (RT-SHIV). A group of nine macaques were treated with a combination of the NNRTI efavirenz (Sustiva) and the nucleotide RT inhibitors emtricitabine and tenofovir (Truvada), while three served as untreated controls. All treated animals showed peripheral blood viral load levels of less than 50 copies/mL after 18 weeks of treatment. After a total of 26 weeks of ART, five treated animals and the three untreated controls were euthanized and comprehensive analyses of different tissues were conducted to assess for the presence of viral DNA and RNA.
The results showed that, as expected, viral DNA and RNA levels were much higher in untreated versus treated macaques. The highest levels of DNA and RNA in the treated group were in lymphoid tissues, particularly spleen and lymph nodes, while lower levels were found in GI tract tissues. All the treated animals had detectable levels of viral RNA in their spleen and all lymph nodes. Some also showed RNA in thymus (3 of 5) and tonsils (4 of 5), but none had detectable viral RNA in bone marrow. All lymphoid tissues from the treated macaques had detectable viral DNA except bone marrow from two of the animals. The authors of the study state: “these findings are consistent with a widespread distribution of latent viral reservoirs in RT-SHIV-infected macaques.” They go on to explain that the goal of developing this model is to explore strategies for eradicating viral reservoirs, in the hopes of eventually discovering effective interventions that can be evaluated in humans.
JVI Accepts, published online ahead of print on 23 December 2009
J. Virol. doi:10.1128/JVI.02356-09
VIRAL SANCTUARIES DURING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY IN A NONHUMAN PRIMATE MODEL FOR AIDS
Thomas W. North*, Joanne Higgins, Jesse D. Deere, Timothy L. Hayes,Andradi Villalobos, Lourdes A. Adamson, Barbara L. Shacklett,Raymond F. Schinazi, and Paul A. Luciw
Center for Comparative Medicine, Department of Veterinary Molecular Biosciences, Department of Medical Microbiology and Immunology, and Department of Pathology, School of Medicine, University of California, Davis, CA 95616; and Emory University School of Medicine, Veterans Affairs Medical Center, Decatur, GA 30033
Abstract
Highly active antiretroviral therapy (HAART) enables long-term suppression of plasma HIV-1 loads in infected persons, but low level virus persists and rebounds following cessation of therapy. During HAART, this virus resides in latently-infected cells, such as resting CD4+ T cells, and in other cell types that may support residual virus replication. Therapeutic eradication will require elimination of virus from all reservoirs. We report here a comprehensive analysis of these reservoirs in fluids, cells and tissues in a rhesus macaque model that mimics HAART in HIV-infected humans. This nonhuman primate model uses RT-SHIV, a chimera of simian immunodeficiency virus containing the HIV-1 reverse transcriptase (RT). Methods were developed for extraction, pre-amplification and real-time PCR analyses of viral DNA (vDNA) and viral RNA (vRNA) in tissues from RT-SHIV-infected macaques. These methods were used to identify viral reservoirs in RT-SHIV-infected macaques treated with a potent HAART regimen consisting of efavirenz, emtricitabine and tenofovir. Plasma virus loads at necropsy ranged from 11-28 copies of vRNA per ml. Viral RNA and DNA were detected during HAART in tissues from numerous anatomical locations. Additional analysis provided evidence for full-length viral RNA in tissues of animals with virus suppressed by HAART. The highest levels of vDNA and vRNA in HAART-treated macaques were in lymphoid tissues, particularly spleen, lymph nodes, and gastrointestinal tract tissues. This study is the first comprehensive analysis of tissue and organ distribution of a primate AIDS virus during HAART. These data demonstrate widespread persistence of residual virus in tissues during HAART.
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