HIV-1 infection is initiated by fusion of virus and target cell membranes, resulting in delivery of the ribonucleoprotein core into the host cell cytoplasm. The ensuing events that immediately follow fusion are poorly understood for all retroviruses. It is generally assumed that the viral core undergoes an uncoating process involving dissolution of the viral capsid. Studies in our laboratory have shown that relatively subtle perturbations in HIV-1 capsid stability result in poorly infectious virions that are impaired for viral DNA synthesis in target cells, suggesting that uncoating is a finely tuned process and is crucial for efficient reverse transcription. The high sensitivity of HIV-1 infection to alterations in capsid stability, and the ability of the restriction factor TRIM51 to block HIV-1 infection by targeting CA, suggest that uncoating may be an attractive target for antiviral therapy. Besides CA, other viral and cellular molecules are likely to participate in the regulation of HIV-1 uncoating in vivo. In this application, we propose to use biochemical and cell-based assays to better understand the mechanism of HIV-1 uncoating and to identify relevant virus-host cell interactions suitable for therapeutic targeting. The work will be planned according to five Specific Aims: 1. To analyze the uncoating of poorly infectious HIV-1 CA mutants in target cells. 2. To identify novel pseudorevertants of HIV-1 uncoating mutants. 3. To identify structural intermediates in HIV-1 uncoating. 4. To identify host cell factors which regulate HIV-1 uncoating. 5. To determine the effect of TRIM51 on HIV-1 uncoating in vitro. Collectively, these studies will elucidate an obscure stage of the HIV-1 life cycle and reveal new possibilities for HIV/AIDS therapy.

Public Health Relevance

HIV-1 infection is critically dependent on the poorly understood process of uncoating of the viral core. We will perform biochemical and molecular genetic studies to identify viral and cellular determinants of uncoating and to define stages in the process. Ultimately, these studies will help determine whether uncoating can be a useful target in the development of new antiretroviral therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Salzwedel, Karl D
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Vanderbilt University Medical Center
Schools of Medicine
United States
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Carnes, Stephanie K; Zhou, Jing; Aiken, Christopher (2018) HIV-1 Engages a Dynein-Dynactin-BICD2 Complex for Infection and Transport to the Nucleus. J Virol :
Rankovic, Sanela; Varadarajan, Janani; Ramalho, Ruben et al. (2017) Reverse Transcription Mechanically Initiates HIV-1 Capsid Disassembly. J Virol 91:
Burse, Mallori; Shi, Jiong; Aiken, Christopher (2017) Cyclophilin A potentiates TRIM5? inhibition of HIV-1 nuclear import without promoting TRIM5? binding to the viral capsid. PLoS One 12:e0182298
Henning, Matthew S; Dubose, Brittany N; Burse, Mallori J et al. (2014) In vivo functions of CPSF6 for HIV-1 as revealed by HIV-1 capsid evolution in HLA-B27-positive subjects. PLoS Pathog 10:e1003868
Mathew, Sheeba; Nguyen, Minh; Wu, Xuhong et al. (2013) INI1/hSNF5-interaction defective HIV-1 IN mutants exhibit impaired particle morphology, reverse transcription and integration in vivo. Retrovirology 10:66
Shah, Vaibhav B; Shi, Jiong; Hout, David R et al. (2013) The host proteins transportin SR2/TNPO3 and cyclophilin A exert opposing effects on HIV-1 uncoating. J Virol 87:422-32
Shah, Vaibhav B; Aiken, Christopher (2013) Cell Fractionation and Quantitative Analysis of HIV-1 Reverse Transcription in Target Cells. Bio Protoc 3:
Shi, Jiong; Friedman, David B; Aiken, Christopher (2013) Retrovirus restriction by TRIM5 proteins requires recognition of only a small fraction of viral capsid subunits. J Virol 87:9271-8
Yufenyuy, Ernest L; Aiken, Christopher (2013) The NTD-CTD intersubunit interface plays a critical role in assembly and stabilization of the HIV-1 capsid. Retrovirology 10:29
Yu, Zhiheng; Dobro, Megan J; Woodward, Cora L et al. (2013) Unclosed HIV-1 capsids suggest a curled sheet model of assembly. J Mol Biol 425:112-23

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