Wei-Shau Hu, Ph.D.
Dr. Hu is widely recognized as a key authority on retroviral recombination, RNA packaging, and virus assembly. Her innovations in combining molecular biology and biochemical approaches with state-of-the-art microscopy techniques for single-virion particle analysis have led to significant advancements in HIV molecular virology research. Under Dr. Hu’s direction, the Viral Recombination Section investigates multiple aspects of the retroviral life cycle that affect the transfer of viral genetic information. These studies have profound implications for questions that are fundamentally important to HIV replication, which can be used to generate new strategies to block the spread of HIV.
1) HIV pathogenesis, 2) retroviral replication, 3) RNA packaging and virus assembly,
4) virology, 5) molecular biology, 6) infectious diseases
Retroviral RNA Trafficking, RNA Packaging, Virus Assembly, and Replication
We study how retroviruses transfer genetic information to the next generation. HIV-1 packages two copies of full-length viral RNA into a particle. Upon infecting a new host cell, virion RNA is used as the template to generate viral DNA, which integrates into the host chromosome to form a provirus. We study several aspects of the viral replication cycles that affect the transfer of viral genetic information, including the transport and trafficking of the viral RNA, packaging of the viral RNA genome, virus assembly, and reverse transcription. We use molecular biology and biochemical approaches in combination with state-of-the-art microscopy techniques to study these topics.
Retroviral RNA packaging and virus assembly. In order to generate infectious viruses, HIV-1 must encapsidate full-length unspliced RNAs into its particle. To study HIV-1 RNA packaging, we have developed a novel assay to directly visualize viral RNA in the particles at single-RNA-molecule sensitivity. This assay reveals that most HIV-1 particles contain two copies of full-length viral RNA. Although it is known that retroviral RNAs that are packaged into particles are dimeric, standard biochemical assays cannot determine the number of RNA molecules in one particle; our results provide evidence to support the long-standing assumption that two RNA molecules (one dimer) are packaged into a particle. To better understand the mechanisms of RNA packaging, we have performed genetic, biochemical, and imaging analyses to show that HIV-1 RNA uses base-pairing of the dimerization initiation signal sequence to select its copackaged RNA partner, and this process occurs in the cytoplasm of the producer cell prior to RNA packaging into particles. We study the mechanisms that HIV-1 uses to regulate which and how many RNAs are packaged. Additionally, we study the interactions between viral Gag protein and full-length RNA that lead to the encapsidation of the viral genome during virus assembly.
Retroviral RNA trafficking. Full-length HIV-1 RNA needs to traffic to specific subcellular locations to carry out its functions, including serving as a template for Gag/Gag-Pol translation and as a genome in the newly assembled virion. The functions of the viral RNA and the translated proteins can be affected when RNA is targeted to incorrect locations in the cells. Using our newly developed imaging tools and live-cell imaging techniques, we study HIV-1 RNA transport and its relation to the function of viral RNAs. These experiments will provide an understanding of aspects of HIV-1 replication that we currently know very little about and will allow us to better understand how HIV-1 uses the cellular machinery to traffic its macromolecules.
Reverse transcription and recombination. Recombination plays an important role in HIV replication and evolution. For example, many of the primary isolates of HIV are recombinants, and recombination can assort mutations to generate variants that escape host immune responses or are resistant to multidrug treatment protocols. Recombination of HIV-1 occurs during reverse transcription, using information in the two RNAs to produce a hybrid DNA. Therefore, phenotypically different recombinants are generated from viruses containing two copies of different RNAs. Only cells that are doubly infected can produce virions containing two different RNAs. To better understand interactions in HIV-1 populations, we study the dynamics of double infection, the frequency of recombination, and the mechanism of reverse transcription.
Selected Key Publications
- Proc Natl Acad Sci U S A. 117: 6145-6155, 2020. [ Journal Article ]
Recombination is required for efficient HIV-1 replication and the maintenance of viral genome integrity.Nucleic Acids Res. 46: 10535-10545, 2018. [ Journal Article ]
- Proc Natl Acad Sci U S A. 113: E201-E208, 2016. [ Journal Article ]
- Proc Natl Acad Sci U S A. 111: E5205-E5213, 2014. [ Journal Article ]
- PLoS Pathog. 9(3): e1003249, 2013. [ Journal Article ]
Dr. Wei-Shau Hu received her Ph.D. in Genetics from the University of California, Davis, in 1987. She studied the mechanisms of DNA recombination that lead to human alpha-thalassemia in Dr. James Shen's laboratory. Under Dr. Howard Temin's guidance, she studied the mechanisms of retroviral recombination as a postdoctoral fellow at the University of Wisconsin. In 1991, Dr. Hu joined the faculty of West Virginia University as an Assistant Professor in the Department of Microbiology and Immunobiology and the Mary Babb Randolph Cancer Center. She was promoted to Associate Professor with tenure in 1998. In 1999, she joined the National Cancer Institute as Senior Investigator and Head of the Viral Recombination Section in the HIV Drug Resistance Program (renamed as the HIV Dynamics and Replication Program in 2015). Dr. Hu was an organizer of the 2009 Cold Spring Harbor Retroviruses conference. She served as the Frederick representative of Women Science Advisors for the National Cancer Institute from 2012 to 2016 and as a member of the AIDS Molecular and Cellular Biology Study Section of the National Institutes of Health extramural grant funding programs from 2010 to 2016. In 2012, she was the recipient of one of the five grants that the U.S.-Russia Joint Working Group on Biomedical Research Cooperation awarded to National Cancer Institute intramural investigators for their highly meritorious research applications; Dr. Hu's application was focused on understanding the impact of HIV-1 recombination and cell-to-cell transmission on vaccine development and chemoprevention strategy. She currently serves as a member of the National Cancer Institute Promotion Review Panel, the AIDS Molecular and Cellular Biology Study Section of the NIH extramural grant funding programs, and the NCI RNA Biology Initiative.
|Jianbo Chen, Ph.D.||Staff Scientist|
|Alice Duchon Ph.D.||Postdoctoral Fellow (CRTA)|
|Olga A. Nikolaitchik Ph.D.||Research Biologist|
|Jonathan Rawson Ph.D.||Postdoctoral Fellow (CRTA)|
|Jennifer Yoo||Postbaccalaureate Fellow (CRTA)|
Intramural AIDS Research Fellowship
Jonathan Rawson received 2018 and 2017 Intramural AIDS Research Fellowship (IARF) awards from the Office of AIDS Research, Office of Intramural Research, and Office of Intramural Research & Training in the National Institutes of Health to support his proposed research project on "Understanding the Pseudodiploid Nature of HIV-1." IARF awards include full stipend support to successful candidates who demonstrate outstanding scientific potential through both an imaginative and thoughtful research plan and a well thought out career development plan.
Young Investigator Awards, Conference on Retroviruses and Opportunistic Infections
Yang Liu won a Young Investigator Award in 2017 to present his research findings at the Conference on Retroviruses and Opportunistic Infections (CROI). In 2015, Luca Sardo also received this highly selective CROI travel scholarship.
NIH Fellows Award for Research Excellence
Sheikh Abdul Rahman received a 2016 NIH Fellows Award for Research Excellence (FARE) for travel to attend and present his work at a scientific meeting in the U.S. This award, which acknowledges outstanding scientific research performed by intramural postdoctoral fellows, is sponsored by the NIH Fellows Committee, Scientific Directors, and Office of Intramural Training and Education and is funded by the Scientific Directors. FARE awards are based on scientific merit, originality, experimental design, and overall quality/presentation of the abstracts.
Members of the Hu Lab who were FARE awardees in previous years include Luca Sardo (2015), Kari Dilley (2012), Michael Moore (2009), Mario P.-S. Chin (2006 and 2007), Kazushi Motomura (2007), and Olga Nikolaitchik (2006).
Travel Award, HIV DRP Think Tank Meeting
Yang Liu received a travel award for one of the two best presentations by NCI fellows at the 2015 HIV DRP Think Tank Meeting. The $1000 travel award was provided by the HIV DRP, Center for Cancer Research, NCI.
Award from U.S.-Russia Joint Working Group on Biomedical Research Cooperation
In 2012, Wei-Shau Hu was the recipient of one of the five grants that the U.S.-Russia Joint Working Group on Biomedical Research Cooperation awarded to National Cancer Institute intramural investigators for their highly meritorious research applications. Dr. Hu is the Principal Investigator on a project focused on understanding the impact of HIV-1 recombination and cell-to-cell transmission on vaccine development and chemoprevention strategy.
Marie Curie Postdoctoral Fellowship
Andrea Galli was awarded a Marie Curie Postdoctoral Fellowship in 2011 by Copenhagen University. He is currently completing his postdoctoral training in the Hepatitis C Program at Hvidovre Hospital, Copenhagen, Denmark.
Howard Temin Pathway to Independence Award (K99/R00)
In 2008, Mario P.-S. Chin successfully competed for a Howard Temin Pathway to Independence (PI) Award (K99/R00) from the National Institutes of Health. The PI Award Program establishes and maintains a strong cohort of new and talented NIH-supported independent investigators. Subsequent to receiving this award, Dr. Chin accepted a position at the Aaron Diamond AIDS Research Center (ADARC) in New York as the first ADARC Scholar. At the ADARC, he has established an independent research program that is focused on the evolution and adaption of HIV-1 in response to antiviral drug and host immune selection pressures.
Kitazato Shibasaburo Award
In 2008, Kazushi Motomura won the Kitazato Shibasaburo Award in recognition of the important findings from a study on HIV-1 and HIV-2 recombination that he reported with Jianbo Chen and Wei-Shau Hu (J. Virol. 82: 1923-1933, 2008). This award is one of the most prestigious prizes in the infectious disease field in Japan.
Scholarship Award, Keystone Symposia on HIV Pathogenesis
Michael Moore was awarded a travel scholarship to present his research findings at the 2008 Keystone Symposia on HIV Pathogenesis.
Scholarship Award, International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention
Mario P.-S. Chin was awarded a scholarship to present his findings at the 2007 IAS Conference on HIV Pathogenesis, Treatment and Prevention in Sydney, Australia.
Poster Awards, Spring Research Festival at NCI-Frederick
Michael Moore and Olga Nikolaitchik won poster awards for their presentations at the NCI-Frederick Spring Research Festival in 2007 and 2006, respectively.