Jesse D Deere

University of California, Davis, Davis, CA, United States

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Publications (6)25.58 Total impact

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    ABSTRACT: Using an established non-human primate model, rhesus macaques were infected intravenously with a chimeric simian immunodeficiency virus consisting of SIVmac239 with the HIV-1 reverse transcriptase from clone HXBc2 (RT-SHIV). The impact of two enhanced (four and five drug) highly active antiretroviral therapies (HAART) on early viral decay and rebound were determined. The four-drug combination included an integrase inhibitor, L-870-812 (L-812), together with a three drug regimen including emtricitabine [(-)-FTC], tenofovir [TFV], and efavirenz [EFV]. The five-drug combination consisted of one analog for each of the four the DNA precursors (using TFV, (-)-FTC, (-)-β-D-(2R,4R)-1,3-dioxolane-2,6-diaminopurine [Amdoxovir®, DAPD], and zidovudine [AZT] together with EFV. A cohort treated with a three drug combination of (-)-FTC, TFV and EFV served as treated controls. Daily administration of three, four or five drug combination of antiretroviral agents was initiated (at week 6 or 8 after inoculation), continued up to week 50, and then followed by a rebound period. Plasma samples were collected routinely and drug levels monitored using LC-MS/MS. Viral loads were monitored with a standard TaqMan qRT-PCR assay. Comprehensive analyses of replication dynamics were performed. RT-SHIV infection in rhesus macaques produced typical viral infection kinetics with untreated controls establishing persistent viral loads of > 10(4) copies of RNA/mL. RT-SHIV viral loads at start of treatment (V0) were similar in all treated cohorts (p > 0.5). All antiretroviral drug levels were measureable in plasma. The four-drug and five-drug combination regimens (enhanced HAART) improved suppression of viral load (within one wk, p < 0.01) and had an overall greater potency (p < 0.02) than the three-drug regimen (HAART). Moreover, rebound viremia occurred rapidly following cessation of any treatment. The enhanced HAART (four- or five-drug combinations) had significant improvement in viral suppression compared to the three-drug combination, but no combination was sufficient to eliminate viral reservoirs.
    Antimicrobial Agents and Chemotherapy 04/2014; · 4.57 Impact Factor
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    ABSTRACT: RT-SHIV is a chimera of simian immunodeficiency virus (SIV) containing the reverse transcriptase (RT)-encoding region of human immunodeficiency virus type 1 (HIV-1) within the backbone of SIVmac239. It has been used in a non-human primate model for studies of non-nucleoside RT inhibitors (NNRTI) and highly active antiretroviral therapy (HAART). We and others have identified several mutations that arise in the "foreign" HIV-1 RT of RT-SHIV during in vivo replication. In this study we catalogued amino acid substitutions in the HIV-1 RT and in regions of the SIV backbone with which RT interacts that emerged 30 weeks post-infection from seven RT-SHIV-infected rhesus macaques. The virus set points varied from relatively high virus load, moderate virus load, to undetectable virus load. The G196R substitution in RT was detected from 6 of 7 animals at week 4 post-infection and remained in virus from 4 of 6 animals at week 30. Virus from four high virus load animals showed several common mutations within RT, including L74V or V75L, G196R, L214F, and K275R. The foreign RT from high virus load isolates exhibited as much variation as that of the highly variable envelope surface glycoprotein, and 10-fold higher than that of the native RT of SIVmac239. Isolates from moderate virus load animals showed much less variation in the foreign RT than the high virus load isolates. No variation was found in SIVmac239 genes known to interact with RT. Our results demonstrate substantial adaptation of the foreign HIV-1 RT in RT-SHIV-infected macaques, which most likely reflects selective pressure upon the foreign RT to attain optimal activity within the context of the chimeric RT-SHIV and the rhesus macaque host.
    PLoS ONE 01/2014; 9(1):e86997. · 3.73 Impact Factor
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    ABSTRACT: Highly active antiretroviral therapy (HAART) can reduce levels of human immunodeficiency virus type 1 (HIV-1) to undetectable levels in infected individuals, but the virus is not eradicated. The mechanisms of viral persistence during HAART are poorly defined, but some reservoirs have been identified, such as latently infected resting memory CD4(+) T cells. During latency, in addition to blocks at the initiation and elongation steps of viral transcription, there is a block in the export of viral RNA (vRNA), leading to the accumulation of multiply-spliced transcripts in the nucleus. Two of the genes encoded by the multiply-spliced transcripts are Tat and Rev, which are essential early in the viral replication cycle and might indicate the state of infection in a given population of cells. Here, the levels of multiply-spliced transcripts were compared to the levels of gag-containing RNA in tissue samples from RT-SHIV-infected rhesus macaques treated with HAART. Splice site sequence variation was identified during development of a TaqMan PCR assay. Multiply-spliced transcripts were detected in gastrointestinal and lymphatic tissues, but not the thymus. Levels of multiply-spliced transcripts were lower than levels of gag RNA, and both correlated with plasma virus loads. The ratio of multiply-spliced to gag RNA was greatest in the gastrointestinal samples from macaques with plasma virus loads <50 vRNA copies per mL at necropsy. Levels of gag RNA and multiply-spliced mRNA in tissues from RT-SHIV-infected macaques correlate with plasma virus load.
    PLoS ONE 01/2014; 9(2):e87914. · 3.73 Impact Factor
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    ABSTRACT: This review will focus on recent developments in several nonhuman primate models of AIDS. These models are being used to address viral latency and persistence during antiretroviral therapy in studies that are not feasible in humans. Further characterization of the various macaque models of AIDS has demonstrated that several aspects of viral persistence during antiretroviral therapy model HIV-1 infection in humans, including viral decay kinetics. Widespread distribution of viral RNA and viral DNA has been detected in many tissue organs. In addition, the brain has been identified as a site of persistent viral DNA. The macaque models of AIDS are well suited for addressing viral persistence during antiretroviral therapy, including viral latency, residual replication, and tissue organ distribution.
    Current opinion in HIV and AIDS 01/2011; 6(1):57-61. · 4.75 Impact Factor
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    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, preamplification, 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 to 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 the spleen, lymph nodes, and gastrointestinal tract tissues. This study is the first comprehensive analysis of the tissue and organ distribution of a primate AIDS virus during HAART. These data demonstrate widespread persistence of residual virus in tissues during HAART.
    Journal of Virology 03/2010; 84(6):2913-22. · 5.08 Impact Factor
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    ABSTRACT: To prevent progression to AIDS, persons infected with human immunodeficiency virus type 1 (HIV-1) must remain on highly active antiretroviral therapy (HAART) indefinitely since this modality does not eradicate the virus. The mechanisms involved in viral persistence during HAART are poorly understood, but an animal model of HAART could help elucidate these mechanisms and enable studies of HIV-1 eradication strategies. Due to the specificity of non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for HIV-1, we have used RT-SHIV, a chimeric virus of simian immunodeficiency virus with RT from HIV-1. This virus is susceptible to NNRTIs and causes an AIDS-like disease in rhesus macaques. In this study, two groups of HAART-treated, RT-SHIV-infected macaques were analyzed to determine viral decay kinetics. In the first group, viral loads were monitored with a standard TaqMan RT-PCR assay with a limit of detection of 50 viral RNA copies per mL. Upon initiation of HAART, viremia decayed in a bi-phasic manner with half-lives of 1.7 and 8.5 days, respectively. A third phase was observed with little further decay. In the second group, the macaques were followed longitudinally with a more sensitive assay utilizing ultracentrifugation to concentrate virus from plasma. Bi-phasic decay of viral RNA was also observed in these animals with half-lives of 1.8 and 5.8 days. Viral loads in these animals during a third phase ranged from 2-58 RNA copies/mL, with little decay over time. The viral decay kinetics observed in these macaques are similar to those reported for HIV-1 infected humans. These results demonstrate that low-level viremia persists in RT-SHIV-infected macaques despite a HAART regimen commonly used in humans.
    PLoS ONE 01/2010; 5(7):e11640. · 3.73 Impact Factor