Warner Greene, MD, PhD
Director and Senior Investigator, Center for HIV Cure Research

Other Professional Titles

Nick and Sue Hellmann Distinguished
Professor, University of California, San Francisco, Department of Medicine, Microbiology and Immunology;
Co-Director, University of California, San Francisco-GIVI, Center for AIDS Research

Phone

(415) 734-4805

Fax

(415) 355-0855

Assistant

Robin Givens
(415) 734-4805

On The Web

Areas of Investigation

My laboratory seeks to better understand the pathological interplay of human retroviruses like human immunodeficiency virus (HIV) and human T-cell lymphotropic virus (HTLV) with their cellular hosts with the goal of providing new approaches for prophylaxis and therapy. A major focus of the lab is understanding how HIV promotes CD4 T-cell death. We have shown that most CD4 T cells die as a result of an innate immune response launched against cytoplasmic viral DNA accumulating as a result of abortive infection in these “bystander” CD4 T cells. Other studies in the laboratory focus on the molecular mechanisms underlying HIV latency, including a role for host proteins and miRNAs that reinforce the latent state as well as the action of host proteins such as NF-kB that antagonize latency. Ultimately, we hope to contribute to efforts to develop a combination of inducing agents that can effectively purge virus from the latent reservoir. A third area of investigation examines host and viral determinants that are associated with heightened transmission at mucosal surfaces. Finally, we are delineating the innate immune signaling pathways governing the antiviral restriction activities of the protein SAMHD1.

Lab Focus

What are the mechanisms occurring during cell-to-cell transmission of HIV that are required to elicit CD4 T-cell death?
How does abortive HIV infection of bystander CD4 T lymphocytes promote their death?
Is this abortive infection and pyroptotic cell death not operating in non-pathogenic lentiviral infections of natural hosts?
Why are circulating peripheral blood CD4 T cells resistant to this form of HIV-induced cell death?
What is the effect of the HIV-2 accessory protein Vpx on HIV infectivity and the cell death pathway in lymphoid CD4 T cells?
Does the inflammation associated with CD4 T-cell death contribute to the accelerated appearance of aging diseases in HIV-infected subjects?
Do the semen-derived amyloid fibrils enhance HIV transmission in vivo?
What viral and host factors affect HIV transmission in the genital mucosa?
How do long-range chromatin interactions affect the establishment and maintenance of HIV latency?
Which cellular microRNAs are involved in reinforcing HIV latency?
How is the antiviral activity of SAMHD1 regulated?
What are the mechanisms by which the host factor SAMHD1 restricts HIV reverse transcription?

Achievements

Demonstrated that unsuccessful HIV infection of “bystander” CD4 T cells results in an accumulation of abortive HIV reverse transcripts that elicit innate antiviral and inflammatory responses and cell death in non-permissive cells.
Demonstrated that abortively infected cells activate caspase-1 to produce a fiery cell death known as pyroptosis, causing significant inflammation as they release their entire cytoplasmic contents, including inflammatory cytokines, into the extracellular space.
Identified interferon-gamma–inducible protein 16 (IFI16) as a host DNA sensor required for CD4 T-cell death due to abortive HIV infection.
Showed that semen contains at least two distinct amyloid fibrils that greatly increase HIV infection in vitro.
Established a Jurkat cell model of HIV latency (5A8 cells) that is inducible by T-cell receptor cross-linking and displays drug reactivation profiles resembling that from resting CD4 T cells from aviremic patients. These cells could be conveniently used for high-throughput screening for novel HIV anti-latency compounds.
Demonstrated that Vif subverts the antiviral activity of APOBEC3G by promoting its degradation in the 26S proteasome and by impairing its synthesis.
Demonstrated that ABOBEC3G, in conjunction with RNA granules, functions to regulate endogenous mobile genetic elements (e.g., Alu RNAs), whose mobility contributes to a variety of human diseases including cancers and leukemias.
Discovered that APOBEC3 encodes Rfv3, a gene influencing production of neutralizing antibody responses in retrovirus infection.
Discovered that HIV-1 virions transmitted in trans from dendritic cells to T cells principally involves virions located on the surface of DCs instead of internalized virions.
Demonstrated that laboratory-adapted CCR5-tropic 81A virions fuse rapidly and efficiently to immature MDDCs, whereas NL4-3, the isogenic CXCR4-tropic counterpart of 81A, fuse slowly and inefficiently to both immature and mature MDDCs.
Identified NF-κB as a modulator of inhibitory tone in the brain by regulating expression of GAD65 in inhibitory GABAergic interneurons.
Discovered NF-κB p50/HDAC1 as a transcriptionally repressive complex promoting HIV-1 latency.
Showed that Vpr can disrupt nuclear envelope architecture and integrity.
Cloned first cytokine receptor (alpha chain of IL-2 receptor).
Demonstrated that IκBα undergoes stimulus coupled degradation and that the activation of NF-κB in turn induces de novo IκBα synthesis.
Showed that acetylation/deacetylation of RelA subunit of NF-κB functions as an intranuclear switch controlling both the magnitude and duration of its transcriptional response.
Demonstrated that HIV Nef inhibits ASK-1 dependent death signaling providing a mechanism for protecting infected cells from premature death.
Described deregulated expression of IL-2 receptors on HTLV-I induced adult T cell leukemia lymphocytes.
Described how p50 subunit of NF-κB is generated by a cotranslational action of the proteasome.

Affiliations

  • American Federation for Clinical Research
  • American Association of Immunologists
  • Association of American Physicians
  • American College of Physicians
  • American Rheumatism Association
  • American Society for Microbiology
  • American Society for Cell Biology
  • American Society for Clinical Investigation
  • California Academy of Medicine
  • Academic Alliance Foundation
  • American Association for the Advancement of Science
  • Global Virus Network
  • Center for AIDS Research, University of Alabama at Birmingham
  • The New Biologist (Editorial Board)
  • Cytokine (Editorial Board)
  • AIDS Research and Human Retroviruses (Editorial Board)
  • Molecular Biology of the Cell (Editorial Board)
  • Academic Press “InScight” Internet News Service (Editorial Board)
  • Journal of Acquired Immune Deficiency Syndrome (Editorial Board)
  • Retrovirology (Editorial Board)
  • Cell Host & Microbe (Editorial Board)

Professional titles

Nick and Sue Hellmann Distinguished
Professor, University of California, San Francisco, Department of Medicine, Microbiology and Immunology;
Co-Director, University of California, San Francisco-GIVI, Center for AIDS Research

Education

1971
BA
  • Stanford University
1977
MD
  • Washington University
1977
PhD
  • Washington University

Honors and Awards

2014 American Academy of Arts and Sciences (Elected)
2014 Tim Gill Distinguished Lecturer, University of Colorado, Denver
2013 Francis Gilman Blake Award, Association of American Physicians
2013 Avant-Garde Award, National Institutes of Health
2012 Alumni Achievement Award, Washington University in St. Louis
2012 President, Association of American Physicians
2011 President-Elect, Association of American Physicians
2011 Center Director, Global Viruses Network
2010 Invited Speaker, MSTP 40th Anniversary Symposium, Washington University
2009 Distinguished Leader in Medicine Lecture, Dalhousie University
2009 Interview Panelist, NIH Director's Pioneer Award
2008 Lecturer, Royal Society, Cytidine Deaminases
2008 Co-Chair, NIAID Summit on HIV Vaccine Research and Development, Bethesda, MD
2006 Nick and Sue Hellman Distinguished Professor of Translational Medicine
2006 Review Committee, NIH Director's Pioneer Award Program
2005 Elected to the National Academy of Medicine
2005 Counsilor, Association of American Physicians
2004 Elected Fellow, American Association for the Advancement of Science
2003 Honorary Co-Chair, AIDS Memorial Advisory Board
2003 Board of Directors, Academic Alliance Foundation
2001 Selected as Original Member, ISI Highly Cited Researchers
1999 Executive Committee Member, Scientific Advisory Board of the Institute of Human Virology
1993 California Academy of Medicine (Elected)
1990 Association of American Physicians (Elected)
1988 Young Investigator Award, American Rheumatism Association
1987 Outstanding Investigator Award, American Federation for Clinical Research
1985 American Society for Clinical Investigation (Elected)
1984 Washington Academy of Sciences Award in the Biological Sciences
1977 St. Louis Internists Prize in Medicine
1976 Sigma Xi Research Honorary
1970 California Heart Association Research Fellowship Award