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
Daily oral pre-exposure prophylaxis (PrEP) using two antiretroviral drugs is effective at preventing HIV transmission in high-risk populations. 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 isolates during PrEP. The Ambrose laboratory is studying the efficacy of long-acting PrEP in preventing transmission of HIV, including against drug-resistant isolates. In addition, we are interested in whether long-acting PrEP can lead to development of drug-resistant mutations, using state of the art single-genome sequencing methods. In turn, if resistant HIV develops or is transmitted, we are interested in understanding how this impacts subsequent antiretroviral therapy (ART). We are currently evaluating long-acting non-nucleoside reverse transcriptase inhibitors as PrEP.
In addition, we study diversity of HIV or SIV that develops in the blood and in different tissues before, during, and after antiretroviral therapy to identify the nature and dynamic properties of persistent viral reservoirs at different anatomical sites. Viral evolution can be measured over time in the blood and tissues using single-genome sequencing. We have shown that viral evolution and compartmentalization is 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. For example, the composition of the viral DNA population in the blood and lymph nodes is mostly wild type (WT) over time. However, the viral DNA population in the gastrointestinal tract becomes dominated by mutant viruses, suggesting higher turnover of infected cells in the gut compared to the blood. More recently we have started looking at the influence of Mycobacterium tuberculosis infection and immunity on SIV replication during co-infection, focusing on the blood and lung and using MiSeq deep sequencing.
To identify new therapeutic targets for HIV, we are investigating the early post-entry events in HIV infection of different cell types. Specifically we are studying HIV capsid uncoating, reverse transcription, and nuclear entry by molecular and cellular biology, including innovative imaging techniques. Understanding these cellular pathways and the host-pathogen interactions associated with them will help us to understand HIV infection better and may provide potential novel therapeutic targets for virus inhibition. Previously we identified a capsid mutation, N74D, that disrupts HIV interaction with the host protein CPSF6 and uses a different nuclear import pathway for viral DNA. CPSF6 binds to the karyopherin-b protein TNPO3 for nuclear import through the nuclear pore complex, which contains two proteins, Nup358 and Nup153, required for HIV infection. We continue to study the processes of HIV capsid uncoating and its influence on reverse transcription, trafficking and entry into the nucleus, and use of host cell factors.
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.