About HIV
Infection of Cells
HIV infects CD4+ cells by hijacking cellular proteins and processes, leading to viral genome nuclear entry and integration into host chromosomes
Transmission
The majority of HIV transmission occurs via mucosal tissues, leading to viral evolution and dissemination throughout the body
Therapeutics
Antiretroviral treatments reduce HIV-related morbidity and mortality, restore/preserve immunologic function, and prevent transmission
Drug Resistance
HIV drug resistance can be transmitted or acquired and leads to reduced treatment options and increased disease progression and virus transmission
Lab Projects
Virus-Host Protein Interactions
The Ambrose Lab investigates the 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. We have characterized capsid mutations (i.e. N74D, N57A, etc.) that disrupt HIV interactions with host proteins, impacting infection and leading to the approval of the antiretroviral drug lenacapavir. 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 in different cell types. Understanding mechanisms of HIV infection may lead to novel therapeutics to inhibit virus replication. 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. We also study SARS-CoV-2 replication in cells as part of the Pittsburgh Center for Vaccine Research.
HIV Therapeutics & Drug Resistance
Daily oral pre-exposure prophylaxis (PrEP) using two antiretroviral drugs is effective at preventing HIV transmission in high-risk populations. The Ambrose Lab evaluates nanoparticle formulations of antiretroviral inhibitors as HIV PrEP as prevention and treatment of people living with HIV (PLWH). A concern in using antiretroviral drugs for both treatment of PLWH and for PrEP to prevent HIV 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), virus replication, and composition of viral tissue reservoirs. With the Gummuluru and Reinhard Labs, we are evaluating novel antiretroviral nanoparticle formulations for improved delivery of antiretrovirals into lymphoid and mucosal tissues where most HIV-infected cells reside.
Establishment of HIV Reservoirs
As part of the Pittsburgh Center for Evolutionary Biology and Medicine (CEBaM), 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. In addition, we are studying compartmentalization and latency of HIV-1 in the central nervous system, particularly in microglial cells in the brain, with the Ayyavoo Lab. In a collaboration with the Lin Lab and as part of the Pittsburgh Center for Vaccine Research (CVR), we are also investigating the influence of M. tuberculosis infection and immunity on SIV replication during co-infection, focusing on the blood, lymph nodes, and lung.