This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term goal of this project is to develop and evaluate strategies for eradication of HIV-1 from infected individuals. These studies will be performed with an animal model that enables comprehensive analyses of viral reservoirs and replication dynamics during HAART. This model utilizes rhesus macaques infected by a chimeric virus of SIVmac239 containing the HIV-1 reverse transcriptase (RT) in place of the SIV RT (RT-SHIV). In this model a three-drug combination that is widely used in humans [efavirenz + (-)-FTC + PMPA] mimics HAART in HIV- 1-infected humans with respect to virus load (VL) suppression and rebound upon cessation of drug therapy. In order to study eradication strategies in the RT-SHIV/macaque model, we have developed a sensitive VL assay with a limit of detection of 1-2 copies of viral RNA (vRNA) per ml of plasma, and have also developed sensitive RT-PCR and PCR assays to measure vRNA and viral DNA (vDNA) in tissues. The goal of this project is to evaluate enhanced HAART in combinations that may more fully suppress plasma and tissue VLs to levels below detection with our sensitive PCR assays. Because a potential limitation of current antiretroviral therapy is access of drugs to key reservoir tissues, we will also determine levels of drugs in target tissues and use that information to optimize drug regimens. In addition to virological endpoints, the impact of these drug combinations will be evaluated in RT-SHIV-infected resting CD4+ lymphocyte populations. Importantly, the highly manipulatable RT-SHIV/macaque model enables assessment of potential clinical impact by determining effects on delay or reduction of viral rebound upon cessation of therapy. The drug combinations we propose are designed to evaluate: i) optimization of DNA chain termination with combinations of four potent nucleoside analogs (NRTI) in combination with efavirenz (NNRTI) or an integrase inhibitor, raltegravir;ii) combinations of the most effective NRTIs with both efavirenz and raltegravir;and iii) enhancement of the most potent drug combination with a protease inhibitor or a CCR5 antagonist. The overall Hypothesis of this project is that an intensified HAART regimen has the potential to eliminate RT-SHIV from infected macaques. These studies will provide insight on the requirements for complete suppression of virus replication in tissues and specific cell types as well as in plasma. Thus, this project aims to determine whether there is a limitation to suppression of residual viremia with antiviral drug combinations and whether eradication will also require """"""""induction"""""""" strategies for reactivation of latent virus.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Primate Research Center Grants (P51)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-CM-5 (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Veterinary Sciences
Schools of Veterinary Medicine
United States
Zip Code
Han, Pengcheng; Nielsen, Megan; Song, Melissa et al. (2017) The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques. Front Aging Neurosci 9:180
Pittet, Florent; Johnson, Crystal; Hinde, Katie (2017) Age at reproductive debut: Developmental predictors and consequences for lactation, infant mass, and subsequent reproduction in rhesus macaques (Macaca mulatta). Am J Phys Anthropol 164:457-476
Zhang, Xinjun; Kanthaswamy, Sree; Trask, Jessica S et al. (2017) Genetic Characterization of a Captive Colony of Pigtailed Macaques (Macaca nemestrina). J Am Assoc Lab Anim Sci 56:390-395
Jensen, Kara; Dela Pena-Ponce, Myra Grace; Piatak Jr, Michael et al. (2017) Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine. Clin Vaccine Immunol 24:
Rose, Destanie R; Careaga, Milo; Van de Water, Judy et al. (2017) Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav Immun 63:60-70
Hasan, M Kamrul; Feeroz, M Mostafa; Jones-Engel, Lisa et al. (2016) Performing monkeys of Bangladesh: characterizing their source and genetic variation. Primates 57:221-30
Austin, Christine; Smith, Tanya M; Farahani, Ramin M Z et al. (2016) Uncovering system-specific stress signatures in primate teeth with multimodal imaging. Sci Rep 6:18802
Scott, Julia A; Grayson, David; Fletcher, Evan et al. (2016) Longitudinal analysis of the developing rhesus monkey brain using magnetic resonance imaging: birth to adulthood. Brain Struct Funct 221:2847-71
Rueda, Cesar M; Presicce, Pietro; Jackson, Courtney M et al. (2016) Lipopolysaccharide-Induced Chorioamnionitis Promotes IL-1-Dependent Inflammatory FOXP3+ CD4+ T Cells in the Fetal Rhesus Macaque. J Immunol 196:3706-15
Bliss-Moreau, Eliza; Moadab, Gilda (2016) Variation in Behavioral Reactivity Is Associated with Cooperative Restraint Training Efficiency. J Am Assoc Lab Anim Sci 55:41-9

Showing the most recent 10 out of 393 publications