To successfully infect a target host-cell HIV has to perform the early-steps of infection to integrate into the host chromatin. After integration, HIV completes the late-steps of infection where new particles assemble. These virions contain viral host proteins and the RNA viral genome. Recently, the early steps of HIV infection have been under intense scrutiny. Multiple approaches utilized by a number of laboratories have begun to advance our understanding of the kinetics, dynamics, and intracellular location of the different steps of the early events including viral interaction with cellular co-factors, or cellular innate/intrinsic immune factors. Although insightful, each of these systems have strengths and weaknesses leading to conflicting data due to different cellular models, techniques, and analysis of populations of viruses that do not infect a cell. A question under debate is whether the HIV capsid shields the reverse transcribed genome from innate sensors before nuclear translocation, e.g. cGAS. To date, it is not clear how the innate sensing machinery targets viral particles and whether these particles are degraded, accumulate in specific cellular compartments, or infect a cell. Throughout my research career, I have optimized methods that study the early-steps of HIV-1, primary isolates from HIV-2, and various circulating SIVs. My long-term career plan is to elucidate the various viral mechanisms and their interactions with the cell by utilizing techniques that I previously developed. These methods monitor the behavior of individual viral particles and directly connect particle behavior to successful cellular infection. The main goal of this proposal is the clarification of key aspects of the early-steps of HIV infection and to definitively connect viral behavior to productive cell infection of primary cells. This research project aims to clarify if the actors in innate sensing have a direct impact on infectious particles, or lead to an abortive infection during the activation of innate sensing pathways. The study of these cellular and viral mechanisms will shed new light into cellular mechanisms that could be utilized to have a positive outcome and application on the HIV/AIDS epidemic.

Public Health Relevance

The Human Immunodeficiency Virus (HIV) is the etiological agent of the AIDS pandemic. To infect a target cell, HIV has to complete a series of tasks initiating with fusion, followed by reverse transcription in the cytoplasm, nuclear translocation, and integration into the host DNA. These proposed studies aim to give unprecedented insights into the early-steps of HIV-1 infectious particles and its interaction with the infected host-cell, opening up new paths to therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Career Transition Award (K22)
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Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
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Mcdonald, David Joseph
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Rush University Medical Center
Schools of Medicine
United States
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