Highly sensitive HIV RNA assays have demonstrated that viral replication persists in patients with clinically suppressed viral replication in their plasma. A number of anatomic sites have been proposed as the source of persistent viral production including the gastrointestinal tract, the central nervous system, lymphoid tissue, and the genitourinary system. Humanized mice and nonhuman primates are models for HIV infection, persistence, and eradication, yet no data currently exist to evaluate inter-species similarities or differences in drug distribution to these sites. This causes difficulty in applying research findings from one species to another, including extrapolating to humans. In addition, no information on intracellular drug distribution within the aforementioned anatomic tissues has been generated. Finally, there is limited information on factors responsible for drug distribution and activity at these sites, including protein binding, drug transporter activity, and (in the caseof nucleoside analogue reverse transcriptase inhibitors) intracellular endogenous nucleotide concentrations. The hypothesis for this project is: residual active viral reservoirs are a consequence of reduced antiretroviral penetration into target tissue cell subtypes, and a thorough understanding of tissue drug distribution between species must be conducted before rational intensification regimens can be designed.
Three specific aims are proposed: 1) In tissues implicated as active reservoirs, characterize distribution of 6 commonly used antiretrovirals from 5 drug classes in models of infected and uninfected humanized mice, nonhuman primates, and HIV+ subjects 2) Investigate important physiologic factors that may be responsible for antiretroviral activity and distribution, including protein binding, intracellular endogenous nucleotide concentrations, and drug transporter expression. 3) Develop a novel IR-MALDESI-MSI approach to visualize the dispersion of drugs across tissue reservoirs for all three species, and assess the role of this technology for future tissue studies in HIV infection and therapy. The goal of this work is to identify what species differences and pharmacologic barriers exist in extracellular and intracellular antiretroviral biodistribution and efficacy in eliminating active HIV reservoirs. Data generated from this proposal will enable the rational selection of antiretrovirals well suited to target active reservoirs, determine the pharmacologic advantages and limitations of animal models of HIV infection, and develop a novel strategy to measure cross-sectional drug dispersion in tissues.

Public Health Relevance

Despite antiretroviral therapy, HIV continues to replicate at low levels in tissues. This replication must be suppressed to help eradicate HIV from the body. Our data suggest that there are differences in how drugs concentrate in tissues both within and between people and animal models used for HIV infection. In order to rationally develop and select therapies that will suppress virus replication in all tissues, this application will identif which drugs get into tissues best, and what mechanisms they use to do so.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-ESB-A (J1))
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Zhang, Hao
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University of North Carolina Chapel Hill
Schools of Pharmacy
Chapel Hill
United States
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Rosen, Elias P; Thompson, Corbin G; Bokhart, Mark T et al. (2016) Analysis of Antiretrovirals in Single Hair Strands for Evaluation of Drug Adherence with Infrared-Matrix-Assisted Laser Desorption Electrospray Ionization Mass Spectrometry Imaging. Anal Chem 88:1336-44
Veselinovic, Milena; Charlins, Paige; Akkina, Ramesh (2016) Modeling HIV-1 Mucosal Transmission and Prevention in Humanized Mice. Methods Mol Biol 1354:203-20
Imaz, Arkaitz; Martinez-Picado, Javier; Niubó, Jordi et al. (2016) HIV-1-RNA Decay and Dolutegravir Concentrations in Semen of Patients Starting a First Antiretroviral Regimen. J Infect Dis 214:1512-1519
Bokhart, Mark T; Rosen, Elias; Thompson, Corbin et al. (2015) Quantitative mass spectrometry imaging of emtricitabine in cervical tissue model using infrared matrix-assisted laser desorption electrospray ionization. Anal Bioanal Chem 407:2073-84
Thompson, Corbin G; Bokhart, Mark T; Sykes, Craig et al. (2015) Mass spectrometry imaging reveals heterogeneous efavirenz distribution within putative HIV reservoirs. Antimicrob Agents Chemother 59:2944-8
Dumond, Julie B; Yang, Kuo H; Kendrick, Racheal et al. (2015) Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells. Antimicrob Agents Chemother 59:6395-401
Rosen, Elias P; Bokhart, Mark T; Ghashghaei, H Troy et al. (2015) Influence of Desorption Conditions on Analyte Sensitivity and Internal Energy in Discrete Tissue or Whole Body Imaging by IR-MALDESI. J Am Soc Mass Spectrom 26:899-910
Peterson, Christopher W; Haworth, Kevin G; Polacino, Patricia et al. (2015) Lack of viral control and development of combination antiretroviral therapy escape mutations in macaques after bone marrow transplantation. AIDS 29:1597-606
Rahangdale, Lisa; De Paris, Kristina; Kashuba, Angela D M et al. (2015) Immunologic, virologic, and pharmacologic characterization of the female upper genital tract in HIV-infected women. J Acquir Immune Defic Syndr 68:420-4
Rosen, Elias P; Bokhart, Mark T; Nazari, Milad et al. (2015) Influence of C-Trap Ion Accumulation Time on the Detectability of Analytes in IR-MALDESI MSI. Anal Chem 87:10483-90

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