University of California, San Francisco  |  About UCSF  |  Search UCSF  |  UCSF Medical Center  |  Log In

Warner C. Greene, MD, PhD

Warner C. Greene, MD, PhD
Professor, Medicine, Microbiology and Immunology
Nick and Sue Hellman Distinguished Professor of Translational Medicine
Director and Senior Investigator, Gladstone Institute of Virology and Immunology
Co-Director, UCSF-GIVI Center for AIDS Research
Research Summary:
Molecular Analysis of HIV Pathogenesis

My laboratory seeks to better understand the pathological interplay of human retroviruses like HIV and HTLV with their cellular hosts with the goal of providing new approaches for therapy. Currently, we are exploring 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 are focusing 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 various host proteins like NF-kappaB 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. Additional studies are examining how two different amyloid fibrils found in human semen propel HIV infection by promoting virion attachment to target cells. We seek to better understand the role of these factors in HIV transmission and to design novel inhibitors against these fibrils that could be coupled with antiviral drugs to create a new class of more effective combination microbicides.

In a related area of investigation, we are attempting to identify viral determinants that are associated with heightened transmission at mucosal surfaces. Finally, we are examining the role of the APOBEC3 family of cytidine deaminases in both the restriction of exogenous retroviruses like HIV and the inhibition of endogenous retroelements like LINE1 in human embryonic stem cells and induced pluripotent stem cells (iPSCs) where LINE-1 expression is greatly increased.

Due to the broad scope of experimental questions, we employ a wide range of molecular, biochemical, cell biological and immunological techniques to study HIV and HTLV-I pathogenesis. Individuals completing training in the laboratory routinely acquire expertise in all of these areas. Increasingly, we are utilizing transgenesis and gene disruption approaches to study the function of specific genes in vivo. Our studies often take advantage of the outstanding core services offered at the Gladstone Institutes, including cores in Virology, Immunology, Genomics, Flow Cytometry, Microscopy, Histology, Transgenesis and Gene Disruption.

Selected Publications

Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC. HIV-1 Nef inhibits ASK1-dependent death signaling providing a potential mechanism for protecting the infected host cell. Nature 410:834–838, 2001.

Chen L-f, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-κB action regulated by reversible acetylation. Science 293:1653–1657, 2001.

de Noronha CMC, Sherman MP, Lin HW, Cavrois M, Moir RD, Goldman RD, Greene WC. Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr. Science 294:1105–1108, 2001.

Cavrois M, de Noronha C, Greene WC. A sensitive and specific enzyme-based assay detecting HIV-1 virion fusion in primary T lymphocytes. Nat. Biotech. 20:1151–1154, 2002.

Stopak K, de Noronha C, Yonemoto W, Greene WC. HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Mol. Cell. 12:591–601, 2003.

Chiu YL, Witkowska HE, Hall SC, Santiago M, Soros VB, Esnault C, Heidmann T, Greene WC. High-molecular-mass APOBEC3G complexes restrict Alu retrotransposition. Proc. Natl. Acad. Sci. USA. 103:15588–15593, 2006. PMCID: PMC1592537

Williams SA, Chen L-f, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC. NF-κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 25:139–149, 2006. PMCID: PMC1356344

Soros VB, Yonemoto W, Greene WC. Newly synthesized APOBEC3G is incorporated into HIV virions, inhibited by HIV RNA, and subsequently activated by RNase H. PLoS Path. 3:e15, 2007. PMCID: PMC1796622

Santiago ML, Montano M, Benitez R, Messer RJ, Yonemoto W, Chesebro B, Hasenkrug KJ, Greene WC. APOBEC3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection. Science 321:1343–1346, 2008. PMCID: PMC2701658

Roan NR, Münch J, Arhel N, Mothes W, Neidleman J, Kobayashi A, Smith-McCune K, Kirchhoff F, Greene WC. The cationic properties of SEVI underlie its ability to enhance human immunodeficiency virus infection. J. Virol. 83:73–80, 2009. PMCID: PMC2612336

Roan NR, Sowinski S, Münch J, Kirchhoff F, Greene WC. The aminoquinoline surfen inhibits action of semen-derived enhancer of viral infection (SEVI). J. Biol. Chem. 285:1861–1869, 2010. PMCID: PMC2804344

Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML, Hebbler AM, Greene WC. Abortive HIV infection mediates CD4 T-cell depletion and inflammation in human lymphoid tissue. Cell 143:789–801, 2010. PMCID: PMC3026834

Wissing S, Montano M, Garcia-Perez JL, Moran JV, Greene WC. Endogenous APOBEC3B restricts LINE-1 retrotransposition in transformed cells and human embryonic stem cells. J. Biol. Chem 286:26427–26437 2011. PMCID: PMC3196128

Lassen KG, Hebbeler AM, Bhattacharyya D, Lobritz MA, Greene WC. A flexible model of HIV-1 latency permitting evaluation of many primary CD4 T-cell reservoirs. PLoS One 7:e30176, 2012. PMCID: PMC3265466

Roan NR, Müller JA, Liu H, Chu S, Arnold F, Stürzel C, Walther P, Dong M, Witkowska E, Kirchhoff F, Münch F, Greene WC. Peptides released by physiological cleavage of semen coagulum proteins form amyloids that enhance HIV infection. Cell Host Microbe 10:541–550, 2011. PMCID: PMC3257029