Education & Training
- B.A., Zoology and Pre-Medicine, Ohio Wesleyan University, 1994
- Ph.D., Pathobiology, University of Washington School of Public Health, 2001
- Post-doctoral and Research Fellow, National Cancer Institute, 2001-2007
Research Interest Summary
The Ambrose Lab studies diversity of HIV/SIV that develops in the blood and in tissues before, during, and after antiretroviral therapy to identify the nature and dynamic properties of persistent viral reservoirs at different anatomical sites. We showed that evolution and compartmentalization of drug-resistant viruses are unique in mucosal tissues, such as the gastrointestinal and female genital tracts that are sites of mucosal transmission, compared to the blood or lymphoid tissues. We also investigate the influence of M. tuberculosis infection and immunity on SIV replication during co-infection, focusing on the blood and lung using MiSeq deep sequencing.
We evaluate nanoparticle formulations of antiretroviral inhibitors as pre-exposure prophylaxis (PrEP) to prevent HIV transmission and as HIV treatment of infected individuals. A concern in using antiretroviral drugs for both treatment of HIV-infected individuals and for PrEP for uninfected individuals is the potential for transmission of or development of drug-resistant HIV during PrEP. The Ambrose Lab studies the efficacy of long-acting PrEP in preventing transmission of drug-resistant HIV. In addition, we evaluate whether long-acting PrEP can lead to development of drug-resistant mutations, using single-genome sequencing. If resistant HIV develops or is transmitted, we investigate how this impacts subsequent antiretroviral therapy (ART) and composition of viral tissue reservoirs.
The Ambrose Lab also investigates the post-entry events in HIV infection of different cell types. Specifically, we study HIV capsid uncoating, reverse transcription, and nuclear entry using molecular and cellular biology, including innovative imaging techniques. Understanding these cellular pathways and the host-pathogen interactions associated with them may provide potential novel therapeutic targets for virus inhibition. In addition, we study HIV resistance to novel capsid, reverse transcriptase, and integrase inhibitors to understand both the mechanisms of action of these drugs as well as understand basic HIV biology. Recently we began work studying SARS-CoV-2 post-entry biology research.
Zhong Z, Ning J, Boggs EA, Jang S, Wallace C, Telmer C, Bruchez MP, Ahn J, Engelman AN, Zhang P, Watkins SC, Ambrose Z. Cytoplasmic CPSF6 regulates HIV-1 capsid trafficking and infection in a cyclophilin A-dependent manner, mBio 2021, 12:e3142-20. PMCID: PMC8092277
Xu C, Fischer DK, Rankovic S, Li W, Dick R, Runge B, Ahn J, Aiken C, Polenova T, Engelman AN, Ambrose Z*, Rousso I*, Perilla JR*. Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis, PLoS Biol 2020, 18(12):e3001015. PMCID: PMC7775124
Melody K, Roy CN, Kline C, Cottrell ML, Evans D, Shutt K, Pennings PS, Keele BF, Bility M, Kashuba ADM, Ambrose Z. Long-acting rilpivirine (RPV LA) pre-exposure prophylaxis does not inhibit vaginal transmission of RPV-resistant HIV-1 nor select for high frequency drug resistance in humanized mice. J Virol 2020, 94(8):e01912-19. PMCID: PMC7108851
Boyer PL, Melody K, Smith SJ, Dunn LL, Kline C, Fischer DK, Dwivedi R, Clark PK, Hughes SH, Ambrose Z. Two coselected distal mutations in HIV-1 reverse transcriptase (RT) alter susceptibility to nonnucleoside RT inhibitors and nucleoside analogs. J Virol 2019, 93(11):e00224-19. PMCID: PMC6532099
Feder AF, Kline C, Polacino P, Cottrell M, Kashuba ADM, Keele BF, Hu SL, Petrov DA, Pennings PS, Ambrose Z. A spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host. PLoS Pathog 2017, 13(5):e1006358. PMCID: PMC5444849
Kearney MF, Anderson EM, Coomer C, Smith L, Shao W, Johnson N, Kline C, Spindler J, Mellors JW, Coffin JM, Ambrose Z. Well-mixed plasma and tissue viral populations in RT-SHIV-infected macaques implies a lack of viral replication in the tissues during antiretroviral therapy. Retrovirology 2015,12:93. PMCID: PMC4642622
Feder AF, Kline C, Polacino P, Cottrell M, Kashuba ADM, Keele BF, Hu SL, Petrov DA, Pennings PS, Ambrose Z. High resolution spatio-temporal assessment of simian/human immunodefiency virus (SHIV) evolution reveals a highly dynamic process within the host, bioRxiv 2017; http://biorxiv.org/content/early/2017/01/04/097980.
Melody K, McBeth S, Kline C, Kashuba ADM, Mellors JW, Ambrose Z. Low frequency of drug-resistant variants selected by long-acting rilpivirine (RPV LA) in macaques infected with RT-SHIV. Antimicrob Agents Chemother 2015; 59:7762-7770. PMCID: PMC4649225
Kearney MF, Anderson EM, Coomer C, Smith L, Shao W, Johnson N, Kline C, Spindler J, Mellors JW, Coffin JM, Ambrose Z. Well-mixed plasma and tissue viral populations in RT-SHIV-infected macaques implies a lack of viral replication in the tissues during antiretroviral therapy. Retrovirology 2015, 12:93. PMC4642622
Xu H, Franks T, Gibson G, Huber K, Rahm N, Strambio De Castillia C, Luban J, Aiken C, Watkins S, Sluis-Cremer N, Ambrose Z. Evidence for biphasic uncoating during HIV-1 infection from a novel imaging assay. Retrovirology 2013; 10:70. PMC3716918
Kline C, Ndjomou J, Franks T, Kiser R, Coalter V, Smedley J, Piatak M, Mellors JW, Lifson JD, Ambrose Z. Persistence of viral reservoirs in multiple tissues after ART suppression in a macaque RT-SHIV model. PLoS One 2013; 8(12):e84275. PMC3867492
Ambrose Z, Lee K, Ndjomou J, Xu H, Oztop I, Matous J, Takemura T, Unutmaz D, Engelman A, Hughes SH, KewalRamani VN. Human immunodeficiency virus type 1 (HIV-1) capsid mutation N74D alters cyclophilin A dependence and impairs macrophage infection. J Virol 2012; 86:4708-14. PMC3318671
Kearney M, Spindler J, Shao W, Maldarelli F, Palmer S, Hu SL, Lifson JD, KewalRamani VN, Mellors JW, Coffin JM, Ambrose Z. Genetic diversity of simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT-SHIVmne) persists in macaques despite antiretroviral therapy. J Virol 2011; 85:1067-76. PMC3019993
Jun S, Ke D, Debiec K, Zhao G, Meng X, Ambrose Z, Gibson GA, Watkins SC, and Zhang, P. Direct visualization of HIV-1 infection using correlative live-cell microscopy and cryo-electron microscopy. Structure, 2011; 19:1573-81. PMC3217200
Lee K, Ambrose Z, Martin TD, Oztop I, Mulky A, Julias JG, Vandegraaff N, Baumann JG, Wang R, Yuen W, Takemura T, Shelton K, Taniuchi I, Li Y, Sodroski J, Littman DR, Coffin JM, Hughes SH, Unutmaz D, Engelman A, KewalRamani VN. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe 2010; 7:221-33. PMC2841689
Ambrose Z, Palmer S, Boltz VF, Kearney M, Larsen K, Polacino P, Flanary L, Oswald K, Piatak M, Smedley J, Shao W, Bischofberger N, Maldarelli F, Kimata JT, Mellors JW, Hu SL, Coffin JM, Lifson JD, KewalRamani VN. Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance.