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Ambrose Lab



Principal Investigator

Zandrea Ambrose, PhD
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Location

541 Bridgeside Point 2
450 Technology Drive
Pittsburgh, PA 15219

Research Description

The Ambrose laboratory studies antiretroviral therapeutics used for HIV prevention and suppression, including the characterization of new drug targets against early steps of the virus life cycle, and the impact of drug resistance on HIV transmission, prevention, and treatment.

Understanding early HIV infection steps 

We investigate the early post-entry events in HIV infection of different cell types as part of the Pittsburgh Center for HIV Protein Interactions. 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. 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 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.

 

Transmission and prevention of drug-resistant HIV 

Daily oral pre-exposure prophylaxis (PrEP) using two antiretroviral drugs is effective at preventing HIV transmission in high-risk populations. We are currently evaluating long-acting non-nucleoside reverse transcriptase inhibitors as PrEP. 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 methods. If resistant HIV develops or is transmitted, we investigate how this impacts subsequent antiretroviral therapy (ART).

 

Establishment and persistence of HIV reservoirs 

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 viral evolution and compart- mentalization 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 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. Recently we started investigating the influence of M. tuberculosis infection and immunity on SIV replication during co-infection, focusing on the blood and lung and using MiSeq deep sequencing.

Lab Members

Douglas Fischer, MS - Graduate Student

Chandra Nath Roy, PhD - Postdoctoral Fellow

Austin Souryavong - Undergraduate Researcher

Youya Wang - Undergraduate Researcher

Zhou Zhong - Graduate Student

Members

Christopher Kline -Lab Manager
Richa Dwivedi -Postdoctoral Fellow