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Stephen Hughes Received 2017 Distinguished Research Career Award from The Ohio State University Center for Retrovirus Research
Stephen Hughes was selected by the Center for Retrovirus Research of The Ohio State University to receive the 2017 Distinguished Research Career Award. This annual award honors the distinguished research career of a scientist working in the field of retrovirology. The retrovirologist is nominated by student and faculty members of the Center for Retrovirus Research and as part of the award recognition is invited to give a special lecture to all members of the Ohio State University biomedical research community.
Stephen Hughes receives Career Award crystal from members of the Center for Retrovirus Research. Shown from left are Center for Retrovirus Research Director Patrick Green, Stephen Hughes, and Li Wu.
Photo courtesy of The Ohio State University Center for Retrovirus Research
Fifth Annual David Derse Memorial Lecture and Award
The Fifth Annual David Derse Memorial Lecture and Award presentation was held on November 9, 2016, at the National Cancer Institute campus in Frederick, Maryland, to honor David Derse's outstanding research accomplishments and to stimulate the exchange of innovative ideas that Dr. Derse was well known for promoting throughout his scientific career. The Annual David Derse Memorial Lecture and Award is sponsored by the HIV DRP, with support from Hye Kyung Chung-Derse, the National Cancer Institute, the Foundation for NIH, and colleagues and friends of Dr. Derse who contributed to the memorial fund in his honor.
Michael H. Malim, D.Phil. (Department of Infectious Diseases, King's College London) delivered the fifth lecture in this annual series. The title of his presentation was "Replication Deficiencies Pinpoint HIV-Host Interactions."
Dr. Malim received his D.Phil. in Biochemistry from Oxford University in 1987, and started working on HIV/AIDS later that year as a postdoctoral fellow at Duke University in North Carolina. In 1992 he joined the faculty at the University of Pennsylvania, and after nine years in Philadelphia, returned to his native U.K. to establish the Department of Infectious Diseases at King’s College London. Dr. Malim still holds this position, and is also Head of the Division of Immunology, Infection and Inflammatory Disease, as well as Director of the Medical Research Council (MRC) Doctoral Training Partnership in Biomedical Sciences. He has served on many grant and fellowship review panels, including at NIH, amfAR, MRC, and the Wellcome Trust. He is currently a Section Editor for the Open Access journal PLoS Pathogens, and an Editor for Virology.
Dr. Malim’s laboratory utilizes molecular genetic, cultured cell, biochemical, structural, bioinformatic, and cohort-based methodologies to study the biological principles that underpin HIV replication and pathogenesis (AIDS). Over the course of the last 25 years, one fruitful approach that his group has employed has been to study "context-dependent" deficiencies in virus replication. These may be recognized through the analysis of viral mutants/variants, cell-type or species-specific effects, and altered cell culture conditions, and, simplistically, can be attributable to the absence of cellular dependency factors that promote replication, or the expression of natural inhibitors or suppressors. With this in mind, Dr. Malim and his colleagues discovered APOBEC3G as a cell-encoded inhibitor of HIV infection that is encapsidated into viral particles and acts through the combined effects of viral cDNA (cytidine-to-uridine) hypermutation and the suppression of reverse transcription, and they identified MX2 (MXB) as a cellular, interferon-inducible, capsid-specific suppressor of HIV nuclear import. Importantly, the HIV-encoded Vif protein mediates evasion from APOBEC3G, whereas there is no apparent escape pathway from MX2. In contrast, interspecies comparisons of HIV particle assembly have highlighted key points of regulation, and ongoing proteomic-based experiments are identifying novel cellular proteins that promote this key late step of the virus life cycle. For more information about Dr. Malim and his research program, see https://kclpure.kcl.ac.uk/portal/michael.malim.html.
A live-captioned videocast of the lecture and award presentation was available on the NIH Videocasting website; to view the videocast, click here. This videocast will also be archived at the same site.
Stephen Hughes, Frank Maldarelli, and Mary Kearney Received 2016 Center for Cancer Research Group Award
Frank Maldarelli, and
Mary Kearney received a Center for Cancer Research Group Award in September 2016 for their recent work demonstrating that clonally expanded CD4+ T cells can be a reservoir of infectious HIV-1. This work contributes in important ways to our understanding of the HIV reservoir in patients on combination antiretroviral therapy and is transformative both in terms of our basic understanding of HIV latency and in terms of efforts to devise strategies that might be able to cure HIV infection.
2016 HIV DRP Think
The HIV DRP hosted the 19th Annual Think Tank Meeting on April 20, 2016, at the National Cancer Institute at Frederick. Covering topics related to HIV, AIDS, and retrovirus biology, this event brings together investigators from NCI, NIH, and academic institutions
in the mid-Atlantic region with research interests related to the HIV DRP's
goals for a stimulating day of short presentations and discussion. Since its inception
in 1998, the HIV DRP Think Tank Meeting has been very successful at fostering collaborations
among these intramural and extramural investigators in the retrovirology community.
The HIV DRP provided 2016 DRP Think Tank Travel Awards (two $1,000 travel stipends) to Mauricio Comas-Garcia (Rein lab) and Mariia Novikova (Freed lab), whose presentations were judged by a seven-member panel as the two most meritorious talks by NCI fellows. Yang Liu (Hu lab) and Emiko Urano (Freed lab) were the recipients of HIV DRP Think Tank Travel Awards in 2015 (provided by the HIV DRP). Recipients of the HIV DRP Think Tank Travel Awards in previous years (provided by the Center of Excellence in HIV/AIDS & Cancer Virology, Center for Cancer Research, NCI) include Joanna Sztuba-Solinska (Le Grice lab) and Francesco Simonetti (Maldarelli lab) in 2014, Joanna Sztuba-Solinska (Le Grice lab) and Chris Case (KewalRamani lab) in 2013, Hyun Hu (KewalRamani lab) and Weizao Chen (Dimitrov lab) in 2012, Kayoko Waki (Freed lab) and Cristina Bergamaschi (Pavlakis lab) in 2011, and Muthukumar Balasubramaniam (Freed lab) and Michal Legiewicz (Le Grice lab) in 2010.
HIV DRP Think Tank Program:
Rilpivirine and Doravirine Have Complementary Efficacies against NNRTI-Resistant HIV-1 Mutants
APOBEC3 Proteins Can Co-Mutate the Same HIV Genomes
HIV-1 Interactions with the Nuclear Pore Complex
Host Cell Factors That Regulate ALV Integration
A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain
An Evolved RNA Recognition Motif That Suppresses HIV-1 Tat-TAR Dependent Transcription
Rewiring of Stress Response Networks by the Retrotransposon Tf1 Improves the Survival of S. pombe when Exposed to Cobalt Chloride
Co-Localization of HIV Gag and Unspliced Viral RNA at Stalled Transcription Complexes
Structure-Function Analysis of the HIV-1 Rev Response Element
Binding of HIV-1 Gag to psi+ and psi- RNAs: Specific vs Non-Specific Interactions
Bypassing the HIV-1 Regulation: RNA Encapsidation Independent of the NC Domain
The PPIP(122-125) Motif in HIV-1 Capsid Is an Essential Assembly and Maturation Element
Effect of TB Co-Infection on HIV Population Genetics
Sustained HIV Release by CD4+ T Cells during Latency Disruption
A Small Fraction of Proviruses in Clonal Cell Populations Express Unspliced HIV RNA In Vivo
Impact of Cytotoxic T Lymphocytes on the Landscape of Defective HIV-1 Proviruses
Stephen Hughes Featured in CCR Connections Article
Stephen Hughes was featured in a recent issue of the Center for Cancer Research publication CCR Connections.
[The following excerpt is from the article "Viral Activity," published 14 December 2015 in CCR Connections, Volume 9, No. 2.]
In the last four decades, HIV has gone from being an unknown killer to the cause of a manageable chronic disease. Stephen Hughes, Ph.D., Chief of CCR’s Retroviral Replication Laboratory, began his study of retroviruses before HIV was identified, but quickly made the virus the main focus of his research career. Hughes is internationally recognized for his work on two of the three essential enzymes in the HIV life cycle: reverse transcriptase (RT) and integrase (IN). His work has shed light on the emergence of drug resistance and, more recently, the nature of reservoirs of HIV that persist despite combination antiretroviral therapy. He has also used engineered host proteins that redirect HIV integration as tools for understanding eukaryotic chromatin organization. [More]
Fourth Annual David Derse Memorial Lecture and Award
The Fourth Annual David Derse Memorial Lecture and Award presentation was held on November 17, 2015, at the National Cancer Institute campus in Frederick, Maryland, to honor David Derse's outstanding research accomplishments and to stimulate the exchange of innovative ideas that Dr. Derse was well known for promoting throughout his scientific career. The Annual David Derse Memorial Lecture and Award is sponsored by the HIV DRP, with support from Hye Kyung Chung-Derse, the National Cancer Institute, the Foundation for NIH, and colleagues and friends of Dr. Derse who contributed to the memorial fund in his honor.
Quentin J. Sattentau, Ph.D. (The Sir William Dunn School of Pathology, University of Oxford) delivered the fourth lecture in this annual series. The title of his presentation was "Multiplicity and Mechanism in HIV Cell-Cell Spread."
Dr. Sattentau obtained his B.Sc. in microbiology from the University of Bristol (1980) and his Ph.D. in virology and immunology of HSV-1 from the University of London (1985). Postdoctoral studies on the interaction of HIV-1 with CD4 were done with Peter Beverley at University College London and in Richard Axel’s HHMI lab at Columbia University. In 1992 Dr. Sattentau took up a tenured post as CNRS Director of Research at the Centre d’Immunologie in Marseille, France, where he worked on HIV-1 envelope glycoprotein structure, function, and interaction with neutralizing antibodies. He returned to the U.K. in 1999 as Senior Lecturer at Imperial College. In 2003 he joined the University of Oxford, where he is Professor of Immunology at The Sir William Dunn School of Pathology and tutorial fellow at Magdalen College Oxford. He is the Virology section editor of F1000Prime, editorial board member of a number of journals, and grant reviewer for multiple funding bodies, including the NIH, and he serves on various committees and scientific advisory boards. His recent research is mainly based around two broad areas: investigating the mechanisms by which HIV-1 spreads cell-to-cell, and designing strategies to elicit broadly neutralizing antibodies by vaccination. At the University of Oxford he teaches courses on infection and immunity to biomedical science students and chairs the third-year medicine course. He lives in Oxford on a frequently flooded island on the river Thames with his (more famous) scientist wife and three children.
Dr. Sattentau has worked for 30 years on two major research topics: understanding HIV-1–receptor interactions and mechanisms of viral spread, and investigating HIV-1 envelope glycoprotein function and neutralizing antibody mechanism and induction. Notable past contributions include mapping regions of CD4 interactive with HIV-1 gp120, characterizing receptor-activated conformational changes in the viral envelope glycoproteins required for fusion, and defining the intact HIV-1 envelope glycoprotein trimer as the essential target of neutralizing antibodies. His lab was the first to describe the HIV-1–T cell virological synapse and its function in 2004, and subsequently characterized essential elements of the cell biology and virology of this mode of spread and its inhibition. In 2008 his lab reported on the macrophage–T cell virological synapse and showed that macrophages efficiently transfer virus to T cells via transient adhesive contacts.
A more recent (2014) discovery revealed that macrophages selectively capture HIV-1–infected dying T cells and in doing so become efficiently infected themselves by a diversity of viruses, including founder viruses. These findings have implications for the spread and formation of HIV-1 reservoirs in vivo, for evasion of antiretroviral therapy and neutralizing antibody attack, and for pathogenesis, including the induction of harmful inflammation in immune tissues and the brain. His lab, which currently consists of five members, uses cross-disciplinary techniques to address these research questions, including molecular and cellular immunology and virology and advanced imaging. For more information about Dr. Sattentau and his research program, see http://users.path.ox.ac.uk/~qsattentau/index.htm.
A captioned videocast of the lecture and award presentation has been archived on the NIH Videocasting website; to view the videocast, click here.
HIV DRP Conference on "Approaches to a Functional Cure for HIV Infection"
The HIV DRP Conference on "Approaches to a Functional Cure for HIV Infection" was held on October 20, 2015, at the National Cancer Institute campus in Frederick, Maryland. The HIV DRP hosted this half-day conference to showcase the latest findings on achieving long-term control of HIV infection in the absence of antiretroviral therapy (ART). The presentations were focused on recent progress in blocking HIV transmission, quantifying viral reservoir size and rebound kinetics, identifying potential biomarkers that predict the timing of viral rebound after stopping ART, and developing immune-potentiating compounds, effector antibodies, and other novel immunological approaches.
Invited speakers in the outstanding program included Dan Barouch (Beth Israel Deaconess Medical Center and Ragon Institute of MGH, MIT, and Harvard), Ed Berger (Laboratory of Viral Diseases, NIAID, NIH), Michael Farzan (The Scripps Research Institute), Alex Marson (University of California, San Francisco), Robert Siliciano (Johns Hopkins University School of Medicine and Howard Hughes Medical Institute), and James B. Whitney (Beth Israel Deaconess Medical Center and Ragon Institute of MGH, MIT, and Harvard). To view the agenda, click here.
Eric Freed Appointed as Director of HIV DRP
Eric Freed was appointed as the Director of the HIV DRP.
His new position was announced by Lee Helman [Acting Director of the NCI Center for Cancer Research (CCR) and Scientific Director for Clinical Research, CCR] and Glenn Merlino (Acting Scientific Director for Basic Research, CCR). In their August 2015 announcement, Drs. Helman and Merlino also expressed their thanks to Stephen Hughes, former Director of the HIV DRP, for his dedication and outstanding leadership of the Program since 2005. Dr. Hughes will remain Chief of the Retroviral Replication Laboratory and Acting Chief of the Host-Virus Interaction Branch.
Abdul Waheed Appointed as Lead Guest Editor for Special Issues of Molecular Biology International and Current Topics in Medicinal Chemistry
Abdul Waheed was appointed as the Lead Guest Editor in 2012 for a special issue of Molecular Biology International on Host-Pathogen Interactions of Retroviruses, and in 2014 for a special issue of Current Topics in Medicinal Chemistry on Current and Emerging Drug Targets for Human Immunodeficiency Virus.
Alan Rein Elected to American Academy of Microbiology
Alan Rein was elected to the American Academy of Microbiology (AAM) in 2014. AAM Fellows are recognized as distinguished scientists who are "elected through a highly selective, annual, peer review process, based on their records of scientific achievement and original contributions that have advanced microbiology....Each elected Fellow has built an exemplary career in basic and applied research, teaching, clinical and public health, industry or government service."
Eric Freed Appointed as Deputy Director of HIV DRP
Eric Freed was appointed as the Deputy Director of the HIV DRP. Robert Wiltrout, Director of the NCI Center for Cancer Research, announced Dr. Freed's new appointment as Deputy Director of the HIV DRP, citing his important role in the research, mentorship, and outreach activities of the HIV DRP since he joined the Program in 2003. Further details of Dr. Wiltrout's announcement are featured in the NCI at Frederick Poster newsletter.
Third Annual David Derse Memorial Lecture and Award
The Third Annual David Derse Memorial Lecture and Award presentation was held on November 18, 2014, at the National Cancer Institute campus in Frederick, Maryland, to honor David Derse's outstanding research accomplishments and to stimulate the exchange of innovative ideas that Dr. Derse was well known for promoting throughout his scientific career. The Annual David Derse Memorial Lecture and Award is sponsored by the HIV DRP, with support from Hye Kyung Chung-Derse, the National Cancer Institute, the Foundation for NIH, and colleagues and friends of Dr. Derse who contributed to the memorial fund in his honor.
Walther Mothes, Ph.D. (Yale University School of Medicine) delivered the third lecture in this annual series. The title of his presentation was "Seeing Is Believing – Visualizing Individual Steps of the Retroviral Life Cycle."
Dr. Mothes studied chemistry (Diploma 1993) and received a Ph.D. in cell biology (Humboldt University Berlin 1998) for his studies on protein secretion and membrane protein integration at the endoplasmic reticulum under the mentorship of Tom Rapoport at Harvard Medical School. As a Jane Coffin Childs Fellow for Medical Research, Dr. Mothes completed his postdoctoral training on retroviral entry with John Young and James Cunningham before he started his own laboratory at Yale University in 2001. He was awarded a Hellman Family Fellowship in 2002, and a Searle Scholarship in 2003. Dr. Mothes was promoted to Associate Professor in 2007 and received Tenure in 2011.
Dr. Mothes’ laboratory is interested in various aspects of viral spread and pathogenesis of HIV-1 and other retroviruses. Retroviruses can efficiently spread from cell to cell through contact zones, called virological and infectious synapses. The Mothes lab has contributed to understanding this process by directly visualizing the formation of cell-cell contacts between infected and uninfected cells, the polarization of virus assembly toward cell-cell contact sites, and the active transfer of viral infection to neighboring cells. A major current interest of the laboratory is to monitor viral spread and aspects of retroviral pathogenesis directly in living animals using multi-photon laser scanning microscopy. The laboratory is also applying single-molecule imaging to understand how conformational events in the HIV-1 envelope protein lead to fusion between viral and cellular membranes. A detailed understanding of these processes will permit the rational design of vaccines and antiviral therapies that prevent virus spreading and the infection of new cells. For more information about Dr. Mothes and his research program, see http://medicine.yale.edu/lab/mothes/index.aspx.
A captioned videocast of the lecture and award presentation has been archived on the NIH Videocasting website; to view the videocast, click here. The lecture and award presentation are also featured in a recent issue of The Poster newsletter (link to article).
HIV DRP Conference on "Virus Structure: Putting the Pieces Together"
The HIV DRP Conference on "Virus Structure: Putting the Pieces Together" was held on October 21, 2014, at the National Cancer Institute campus in Frederick, Maryland. The HIV DRP hosted this half-day conference to showcase the latest findings on the structural biology of viruses, with a particular emphasis on imaging macromolecular structures and deciphering how viral and host proteins interact to mediate pathogenesis. Exploring new technologies that enhance the sensitivity of imaging systems will provide valuable information about the structure and dynamics of macromolecular assemblies to aid the design of more effective antiviral therapies.
Invited speakers in the outstanding program included Angela Gronenborn (University of Pittsburgh), Owen Pornillos (University of Virginia), Erica Ollmann Saphire (The Scripps Research Institute), Jacek Skowronski (Case Western Reserve University), Joseph Sodroski (Dana-Farber Cancer Institute), and Michael F. Summers (HHMI/University of Maryland, Baltimore County). To view the agenda, click here.
HIV DRP Conference on "Host Factors and Cofactors in HIV Infection"
The HIV DRP Conference on "Host Factors and Cofactors in HIV Infection" was held on February 25, 2014, at the Center for Cancer Research (CCR), National Cancer Institute (NCI) in Frederick, Maryland. The HIV DRP sponsored this conference with support from the CCR Center of Excellence in HIV/AIDS & Cancer Virology and the NCI Office of HIV and AIDS Malignancy to showcase the latest findings on host factors and cofactors in HIV infection. Understanding the interplay of HIV with both positively and negatively restricting cellular proteins, as well as the influence of cofactors in the etiology of HIV infection, will lead to new insights into the mechanisms involved in the pathogenesis of HIV disease.
Invited speakers in the outstanding program included Michael Emerman (Fred Hutchinson Cancer Research Center), John Guatelli (University of California San Diego and the VA San Diego Healthcare System), Welkin Johnson (Boston College), Jacek Skowronski (Case Western Reserve University), and Yong Xiong (Yale University). In addition to research presentations by these distinguished scientists, the conference concluded with a round-table discussion addressing future developments and opportunities for antiviral strategies and insights into novel mechanisms of carcinogenesis.
Eric Freed Appointed as Guest Editor for Special Issue of Journal of Molecular Biology
Eric Freed was appointed as Guest Editor for the special issue of Journal of Molecular Biology dedicated to Antiviral Innate Immunity. Part 1 of this special issue was published in December 2013; Part 2 was published in March 2014 and included an editorial overview written by Dr. Freed and fellow Guest Editor Michael Gale.
Second Annual David Derse Memorial Lecture and Award
The Second Annual David Derse Memorial Lecture and Award presentation was held on November 12, 2013, at the National Cancer Institute campus in Frederick, Maryland, to honor David Derse's outstanding research accomplishments and to stimulate the exchange of innovative ideas that Dr. Derse was well known for promoting throughout his scientific career. The Annual David Derse Memorial Lecture and Award is sponsored by the HIV DRP, with support from Hye Kyung Chung-Derse, the National Cancer Institute, the Foundation for NIH, and colleagues and friends of Dr. Derse who contributed to the memorial fund in his honor.
Chou-Zen Giam, Ph.D. (Uniformed Services University of the Health Sciences) delivered the second lecture in this annual series. The title of his presentation was “Outcomes of HTLV-1 Infection: Senescence, Latency, Reactivation, and Pathogenesis.”
Dr. Giam is Professor and Vice Chair of the Department of Microbiology and Immunology at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. He has served on the editorial boards of the American Society for Microbiology, Journal of Virology, and Retrovirology and has been appointed as a member of numerous NIH study sections and scientific panels, including the Scientific Advisory Committee of the American Foundation for AIDS Research and Pediatric AIDS Foundation. He has more than 27 years of experience investigating the molecular biology and pathogenesis of human viruses, with a long-standing interest in HTLV-1 and HIV, and more recently Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV-8).
Dr. Giam’s research program is focused on the mechanisms of action of viral regulatory proteins and how they impact cellular mRNA transcription, cell cycle control, and signal transduction pathways to affect viral replication and pathogenesis, especially oncogenesis. Transcription factors of the NF-kappaB/Rel family, which are critical for the proliferation of lymphocytes and the expression of genes that mediate inflammatory and immune responses, are often aberrantly activated in human cancers, especially leukemia, where they confer survival and proliferation advantages. Through the study of the HTLV-1 trans-activator/oncoprotein, Tax, Dr. Giam’s laboratory found that persistent and potentially oncogenic activation of I-kappaB kinases (IKKs)/NF-kappaB by Tax triggers a cellular senescence checkpoint response that is induced by hyperactivated p65/RelA and mediated by two cyclin-dependent kinase inhibitors, p21 and p27, in a p53- and pRb-independent manner. This checkpoint response is often impaired in cancer cells with constitutively activated NF-kappaB. His results suggest that the antisense protein of HTLV-1, HBZ, which downregulates NF-kappaB and HTLV-1 trans-activation by Tax, would mitigate or prevent Tax-induced senescence. This prediction has been borne out experimentally: Tax promotes robust HTLV-1 replication, potent NF-kappaB activation, and senescence, while HBZ attenuates Tax-driven viral replication and NF-kappaB activation to allow proliferation of infected cells and persistent infection. His laboratory’s data support the notion that inactivation of the senescence checkpoint facilitates chronic NF-kappaB hyperactivation, a critical step in leukemia development. His current efforts are concentrated on understanding how chronic NF-kappaB activation induces cellular senescence and how the senescence checkpoint becomes impaired in cancer cells whose NF-kappaB signaling pathway is chronically activated. He is also establishing cell-free systems to elucidate the mechanism by which Tax activates IKKs and investigating the role of HBZ in HTLV-1 viral latency. For more information about Dr. Giam and his research program, see http://www.usuhs.mil/faculty/chouzengiam-mic.html.
A captioned videocast of the lecture and award presentation has been archived on the NIH Videocasting website; to view the videocast, click here. The lecture and award presentation are also featured in The Poster newsletter (link to article).
Review Article on HIV Reverse Transcriptase Designated One of Most Well-Read Minireviews in Journal of Biological Chemistry
A 2012 review article in the Journal of Biological Chemistry (JBC) by Stuart Le Grice was acknowledged in April 2013 as one of the most well-read JBC Minireviews since their first publication in 1988. Dr. Le Grice's article — "Human Immunodeficiency Virus Reverse Transcriptase: 25 Years of Research, Drug Discovery, and Promise" — has been read a total of 1,190 times in the past 6 months since its original publication in October 2012. In comparison, typical JBC articles published within the past year have been read an average of 667 times.
Dr. Le Grice's article reviews the advances in HIV reverse transcriptase research over the last quarter century and extension of this research into future drug discovery programs. To view the article, click here.
Review Article on HIV-1 Reverse Transcriptase Designated a Top Cited Article in Journal of Molecular Biology
A 2009 review article by Stephen Hughes (HIV Dynamics and Replication Program) and his collaborators Eddy Arnold (Rutgers University), Stefan Sarafianos (University of Missouri), and Michael Parniak (University of Pittsburgh) was recently recognized as one of the five top cited articles in Journal of Molecular Biology from 2009 to 2011. The article — "Structure and Function of HIV-1 Reverse Transcriptase: Molecular Mechanisms of Polymerization and Inhibition" — presents an overview of structural, biological, and virological studies of wild-type and drug-resistant mutant forms of HIV-1 reverse transcriptase in complex with inhibitors or substrates. These studies have provided valuable insights into the mechanisms of inhibition and drug resistance of HIV-1 and have guided the design of more effective treatments against HIV. To view the article, click here.
HIV DRP Conference on "Trafficking of Viral Macromolecules"
The HIV DRP Conference on "Trafficking of Viral Macromolecules" was held in December 2012 at the Center for Cancer Research (CCR), National Cancer Institute in Frederick, Maryland. The HIV DRP hosted this conference, with financial support from the CCR Center of Excellence in HIV/AIDS & Cancer Virology, to showcase the latest findings on viral macromolecule trafficking. Our goal was to gain insights into the mechanisms of macromolecule trafficking in a variety of virus systems, which will aid in the development of new and more effective antiviral therapies.
Invited speakers in the outstanding program included Paul Ahlquist (Howard Hughes Medical Institute and Morgridge Institute for Research, University of Wisconsin – Madison), Scott D. Emr (Cornell University), Stephen Goff (Howard Hughes Medical Institute and Columbia University), David Grunwald (University of Massachusetts Medical School, Department of Biochemistry and RNA Therapeutics Institute), and Brett Lindenbach (Yale University School of Medicine).
First Annual David Derse Memorial Lecture and Award
The First Annual David Derse Memorial Lecture and Award was held in December 2012 to honor David Derse's outstanding research accomplishments and to stimulate the exchange of innovative ideas that Dr. Derse was so well known for promoting throughout his scientific career. The Annual David Derse Memorial Lecture and Award is sponsored by the HIV DRP, with support from Hye Kyung Chung-Derse, the National Cancer Institute, the Foundation for NIH, and colleagues and friends of Dr. Derse who contributed to the memorial fund in his honor.
Patrick L. Green (The Ohio State University) delivered the inaugural lecture in this series at the Center for Cancer Research, National Cancer Institute in Frederick, Maryland. The title of his presentation was “HTLV-1 transforming genes: Tax versus Hbz.”
Dr. Green is Professor and Associate Dean for Research and Graduate Studies, College of Veterinary Medicine, Director of the Center for Retrovirus Research, and Leader of the Comprehensive Cancer Center Viral Oncology Program at The Ohio State University. He also helps facilitate the operation of the Clinical and Translational Science Award (CTSA)-funded Center for Clinical and Translational Science Comparative Animal Core. Dr. Green has over 25 years of research experience in the field of murine and human retroviral pathogenesis with more specific focus on human T-cell leukemia virus (HTLV). He has been appointed as a member of numerous NIH study sections and scientific panels and currently serves as Editor of AIDS Research and Human Retroviruses and as a member of the editorial boards of Retrovirology and Journal of Virology. Dr. Green has been recognized with a number of honors that include the International Retrovirology Association Award and the Pfizer Award for Research Excellence as well as designation as an American Cancer Society Fellow, Leukemia Society of America Scholar, American Association for the Advancement of Science (AAAS) Fellow, American Society for Microbiology Fellow, Ohio State University Distinguished Scholar, and member of the Board of Trustees of the Leukemia/Lymphoma Society.
For more information about Dr. Green and his research program, see http://vet.osu.edu/PatrickGreen.
A captioned videocast of the lecture and award presentation has been archived on the NIH Videocasting website; to view the videocast, click here.
Vinay Pathak Received NIH Asian and Pacific Islander American Organization Award
Vinay Pathak was the recipient of the 2012 NIH Asian and Pacific Islander American Organization (APAO) Award for outstanding accomplishments in biomedical research. Each year, the APAO honors two outstanding individuals in the NIH Asian and Pacific American community: one for Scientific Achievement, recognizing scientists who have made significant accomplishments in biomedical research; and the second for Leadership Excellence, recognizing non-scientists who exemplify leadership excellence by example, mentorship, and empowerment of Asian and Pacific Americans to promote diversity and support the overall mission of NIH. Dr. Pathak received his Scientific Achievement award at the NIH APAO annual awards ceremony in December 2012.
NIH APAO Award for Scientific Achievement — December 10, 2012
from left to right: Eric Zhou (Vice President of APAO 2012),
Vinay Pathak, and Rashmi Gopal-Srivastava (Chair, APAO Award Committee)
Report on De-Discovery of the Retrovirus XMRV Designated a Fast Breaking Paper by Science Watch in 2012 and Selected as a Top CCR Science Advance in 2011
The July 2011 Science report on the de-discovery of the retrovirus XMRV by the laboratory of Vinay Pathak (HIV DRP), in collaboration with John Coffin (Tufts University), Wei-Shau Hu (HIV DRP), and Hsing-Jien Kung and Clifford Tepper (University of California, Davis), was designated a Fast Breaking Paper in Microbiology by Science Watch in 2012. This designation was based on a recent analysis by Thomson Reuters Web of Science, which found that their report "displayed a higher bimonthly citation increase than any other paper of comparable age and type in its field." In addition to this paper (Paprotka et al., Recombinant origin of the retrovirus XMRV, Science 333: 97-101, 2011), their findings were highlighted in a press release by the National Cancer Institute and news features in the New York Times, Washington Post, and Nature. The study was also selected as one of the top two Center for Cancer Research (CCR) Science Advances of the year in Virology and, as a result of his work on XMRV, first-author Tobias Paprotka won the 2011 Norman P. Salzman Memorial Award in Virology.
The focus of this study was xenotropic murine leukemia virus–related virus (XMRV), a retrovirus that was isolated in 2006 from a human prostate cancer and later reported to be present in 6–27% of human prostate cancers and in the peripheral blood of 67% of chronic fatigue syndrome patients. The assertion that XMRV is circulating in the human population was challenged by several studies that failed to detect XMRV in multiple cohorts of prostate cancer and chronic fatigue syndrome patients or healthy controls. Drs. Pathak and Coffin and their research teams hypothesized that an understanding of when and how XMRV first arose might help explain the discrepant results. They studied human prostate cancer cell lines CWR22Rv1 and CWR-R1, which produce XMRV virtually identical to the viruses recently found in patient samples, as well as their progenitor human prostate tumor xenograft (CWR22) that had been passaged in mice. The Pathak lab detected XMRV infection in the two cell lines and in the later passage xenografts, but not in the early passages. In particular, they found that the host mice contained two proviruses, PreXMRV-1 and PreXMRV-2, which share 99.92% identity with XMRV over long stretches of their genomes. Their results showed that XMRV was not present in the original CWR22 tumor but was generated by recombination of two proviruses during tumor passaging in mice, between 1993 and 1996. The probability that an identical recombinant was generated independently is negligible (~10-12).
These findings refuted the idea that XMRV is a human pathogen and showed that the association of XMRV with prostate cancer and chronic fatigue syndrome was due to laboratory contamination of human samples with the laboratory-derived virus as well as contaminating mouse DNA. To view the original publication of this study in Science and related articles, click here.
The designation of Dr. Pathak's publication as a Fast Breaking Paper in Microbiology by Science Watch was highlighted on the home page of the Frederick National Laboratory for Cancer Research (FNL) website (link to news article) and in a recent issue of The Poster newsletter (link to Noteworthy Paper feature).
XMRV Working Group Received NIH Director's Award
Presentations at the Cold Spring Harbor Retroviruses Meeting in May 2009 suggested that xenotropic murine leukemia virus-related virus (XMRV), a novel gammaretrovirus with a potential link to prostate cancer and chronic fatigue syndrome, might be present in ~3% of the U.S. population, raising both public health issues and concern for contamination of the nation's blood supply. In response, the Intramural Research Program (IRP) of the National Cancer Institute immediately formed a multidisciplinary XMRV Working Group and charged the group with developing, implementing, and making available diagnostic reagents for rapid, accurate, and reliable detection of XMRV nucleic acids, antigens, and infectious virus. The group developed an action plan, and within three months, the SAIC Protein Expression Laboratory reported construction of 40 recombinant clones expressing all XMRV antigens and their subsequent purification for use as immunological reagents in December 2009. Importantly, these reagents were also made available (through the NIH AIDS Reagent Program) to the extramural community to accelerate XMRV research and allow sharing of a common set of reagents. A parallel effort in the HIV Dynamics and Replication Program resulted in establishing an assay to quantify XMRV DNA (from tissue) and RNA (from plasma) in November and December 2009, respectively. Since ultrasensitive XMRV nucleic acid detection methods were not available, this required in-house development and standardization, using the existing manpower and financial resources of the HIV DRP. In response to the need for "authentic" viral antigens for the development and standardization of immunological reagents by the Viral Technology Laboratory, the large-scale virus culture facilities of the SAIC AIDS and Cancer Virus Program were recruited for XMRV production. Finally, researchers of the HIV DRP developed the DERSE indicator cell line for detection of infectious XMRV. In contrast to traditional virological methods, this novel assay reduced the time needed to detect low levels of replicating XMRV in cell culture from months to a matter of weeks.
Subsequent studies have demonstrated that XMRV does not pose a threat to public health. Despite this, events between October 2009 and October 2010 highlighted the ability of dedicated scientists of the IRP to respond very quickly to a potential public health crisis by assembling a multidisciplinary team with a single goal of rapidly preparing, standardizing, and making available reagents for diagnostic virology. In every instance, reagents were prepared with existing manpower and resources, and without a serious interruption in the normal work flow or productivity of each group involved. Their non-XMRV work continued unimpeded. The success of this effort relied on close cooperation between all groups to establish and meet important deadlines. In addition to their individual contributions, the XMRV Working Group made reagents and technologies available to the general scientific community, and performed additional diagnostic analysis of samples supplied by federal, intramural, and extramural laboratories. In February 2012, the external XMRV Working Group (the Blood XMRV Scientific Research Working Group) received a Special Recognition Award from the Department of Health and Human Services, recognizing their exemplary team performance for "evaluating XMRV, a potential threat to the blood supply." In July 2012, members of the IRP XMRV Working Group were similarly recognized for their outstanding work by receiving the NIH Director's Award.
The IRP XMRV Working Group included:
Stuart Le Grice, HIV DRP
Alan Rein, HIV DRP
Vineet KewalRamani, HIV DRP
Mary Kearney, HIV DRP
James Hartley, Protein Expression Laboratory, SAIC-Frederick
Rachel Bagni, Viral Technology Laboratory, SAIC-Frederick
Jeffrey Lifson, AIDS and Cancer Virus Program, SAIC-Frederick
The NIH Director's Award to the IRP XMRV Working Group was highlighted on the home page of the Frederick National Laboratory for Cancer Research (FNL) website (link to news article) and in a recent issue of The Poster newsletter (link to NIH Director's Award feature).
Annual Symposium on Antiviral Drug Resistance: Targets and Mechanisms
The 12th Annual
Symposium on Antiviral Drug Resistance: Targets and Mechanisms was held in November
2011 at The Hotel Hershey in
Hershey, Pennsylvania. Sponsored by the University of Pittsburgh and co-sponsored
by the HIV DRP, NCI, this annual meeting brought together researchers
in a variety of virus systems to exchange new information on viral targets for
therapy, on antiviral drugs, and on resistance to these drugs. The focus was on
specific molecular targets, their normal structure and function, their interactions
with antiviral drugs, and the evolutionary basis and specific mechanisms of viral
resistance. Organized by molecular target, the program included presentations
by invited speakers as well as oral and poster presentations selected from submitted
on Development of System to Redirect HIV-1 Integration Selected as a Top CCR Science Advance in 2010
A recent study by
Stephen Hughes and his colleagues, in collaboration with researchers at the Dana-Farber Cancer Institute and the Rockefeller University, was selected as one of the two top Center for Cancer Research
(CCR) Science Advances of the year in Virology. Using lens epithelium-derived growth factor fusion proteins, the research team developed a system to redirect HIV-1 DNA integration. This study has two important implications. First, the system can be used to better understand the interactions of important chromatin-binding domains in living cells, which will help to define the distribution of factors on chromatin and how this contributes to important cellular processes, including development, differentiation, and cancer. Second, the ability to direct the sites of retroviral DNA integration away from regions of the genome that contain actively expressed genes has the potential to make gene therapy with retroviral vectors considerably safer. The study showed that proviruses integrated away from active genes are expressed in short-term experiments. Additional details about the study, originally reported in the Proceedings of the National Academy of Sciences USA (PDF), are provided in a PNAS Commentary (PDF) and a CCR Connections article.
David Derse Memorial Conference
The David Derse Memorial Conference was held in June 2010 at the NCI-Frederick Conference Center in Frederick, Maryland. The HIV DRP, in collaboration with the Center of Excellence in HIV/AIDS & Cancer Virology at the National Cancer Institute, hosted this conference in memory of David Derse, head of the Retrovirus Gene Expression Section. Invited speakers included colleagues and collaborators, from around the world as well as from the local scientific community, whose work intersects with Dr. Derse's scientific career. The presentations were on recent advances in retroviral research, with a special focus on HTLV-1.
Invited speakers who participated in this conference included Charles Bangham (Wright-Fleming Institute, Imperial College London), Genoveffa Franchini (Vaccine Branch, National Cancer Institute-Bethesda), Chou-Zen Giam (Uniformed Services University of the Health Sciences), Robert Gorelick (AIDS and Cancer Virus Program, National Cancer Institute-Frederick), Reuben Harris (University of Minnesota), Kathryn Jones (Laboratory of Experimental Immunology, National Cancer Institute-Frederick), Susan Marriott (Baylor College of Medicine), Walther Mothes (Yale University School of Medicine), Cynthia Pise-Masison (Laboratory of Cellular Oncology, National Cancer Institute-Bethesda), and William Switzer (Centers for Disease Control and Prevention). Members of the Derse laboratory — Gisela Heidecker, Batsukh Dorjbal, Anna Ilinskaya, and Vladimir Pak — presented their latest research findings as well.
Vinay Pathak Appointed as Guest Editor for Special Issue of Viruses
Vinay Pathak was appointed as the Guest Editor for the HIV
Drug Resistance special issue of Viruses,
published in 2010.
Stuart Le Grice Co-Hosted Russian Delegation Tour of NCI-Frederick HIV/AIDS Research
February 2010, Stuart
Le Grice, Barry O'Keefe, and
Dimiter Dimitrov hosted a tour of the NCI-Frederick
HIV/AIDS research facilities by a Russian delegation of scientists and government
officials. The delegation was shown the single-genome sequencing facilities of
the HIV DRP, the large-scale virus production facilities of
the AIDS and Cancer Virus Program, the protein chemistry facilities of the Molecular
Targets Laboratory, and the natural products repository of the Developmental Therapeutics
second component of the tour involved a meeting with the Russian delegation at the National Institutes of Health Office of AIDS Research (OAR)
in Bethesda, where future collaborative actions were discussed. These visits were
coordinated by the OAR as a follow-up to the United States-Russia Workshop on
HIV Prevention Science, which was conducted in October 2009 in Moscow
and sponsored by the OAR in collaboration with the Russian Ministry of Health
and Social Development.
Tours involving an international delegation at
this level are relatively rare at NCI-Frederick. The primary goal of the tour
and accompanying lectures was to highlight the strength and depth of the NCI HIV/AIDS
research effort. A second goal was to discuss mechanisms to increase communication
and collaboration between U.S. and Russian scientists.
Members of the
Russian delegation included Valery Charushin, Director of the I.Y. Postovsky
Institute of Organic Synthesis and Chairman of the Ural Branch, Russian Academy
of Sciences; Valeriy Chereshnev, Chairman of the Committee of Science and Innovations,
State Duma of the Russian Federation; Ilyia Drozdov, Director General of the State
Research Center of Virology and Biotechnology, VECTOR; Azha Gaydarova, Research
Fellow in the Sechenov Medical Academy of Moscow; Eduard Karamov, Galina Kornilaeva,
and Tatiana Pavlova, Senior Researchers in the Ivanovsky Institute of Virology,
Russian Academy of Medical Sciences; Igor Sidorovich, Head of the AIDS Immunobiology
Department, Institute of Immunology, Ministry of Health and Social Development;
and Alexander Tatarintsev and Ali Turgiev, General Manager and Research Director,
respectively, of Laboratory Diagnostics Co., Moscow State University Science Park.
tour was highly successful from the NCI perspective and was greatly appreciated
by the Russian delegation. Delegates were particularly impressed by the participation
of NCI-based Russian scientists ( Olga Nikolaitchik, Elena Chertova, and Ekaterina
Goncharova), who conducted the tour in their native language.
As a result
of this tour, several initiatives are under consideration, including sabbatical
visits of Russian scientists to laboratories at NCI-Frederick and reciprocal visits
of U.S. scientists to Russia to provide logistical support to establish new collaborations.
Stuart Le Grice Invited to Co-Edit Special Issue of Current Topics in Medicinal
Stuart F.J. Le Grice was invited
to co-edit, with A. Jun Komano (National Institute of Infectious Diseases,
Japan), a special issue of Current
Topics in Medicinal Chemistry dedicated to HIV therapy.
Eric Freed Appointed as Editor-in-Chief of Viruses
Eric Freed was appointed as the first Editor-in-Chief of Viruses,
a new open-access journal that provides an advanced forum for studies of viruses.
The journal's broad scope includes all classes of viruses, viral epidemiology,
virus-like agents, vaccines, and antiviral drugs.
Stephen Oroszlan Honored for Research on HIV Protease
Oroszlan, Scientist Emeritus, was honored at the Symposium on HIV Protease and
Beyond: The Past, Present, and Future of HIV Structural Biology, held at NCI-Frederick
in January 2009. Organized by the NCI Center of Excellence in HIV/AIDS & Cancer
Virology with support from the Center for Cancer Research and NIH Intramural AIDS
Targeted Antiretroviral Program, the Symposium commemorated the 20th anniversary
of the publication of the crystal structure of HIV protease, a turning point in
the utilization of structural information for drug design. The relationship between
structural biology and drug design for other HIV targets was also highlighted
at the Symposium.
the opening session, Michael Gottesman (NIH Deputy Director for Intramural
Research) presented an award to Dr. Oroszlan in recognition of his many contributions
to our understanding of the structure of retroviruses, and for his seminal work
on viral proteases. Dr. Oroszlan gave the opening keynote talk, describing the
key events in retroviral protease research and the discovery of HIV protease.
He has been awarded three U.S. patents and one European patent on HIV protease.
His numerous honors include the award of a Doctor Honoris Causa Degree from the
University of Debrecen Medical School in 1993, election to the Hungarian Academy
of Sciences as a Foreign Associate in 1994, a Retroviral Retrospective Symposium
to Honor Dr. Stephen Oroszlan held at Hood College in 1994, and the Mór Kaposi
Research Foundation Award in 2000.
on HIV-1 Trafficking Selected as Top 2008 CCR Science Advance in HIV/AIDS
Eric Freed and his colleagues on "Real-Time Visualization of HIV-1 Gag
Trafficking in Infected Macrophages" was selected as the top CCR Science Advance of the year in HIV/AIDS research. Featured in a CCR
In the Journals article, Dr. Freed's study "demonstrates that HIV-1 particles
are retained in internal reservoirs within host cells from which they can be rapidly
released at opportune times, such as when contact is established with uninfected
cells....The results of this study may set the groundwork for the development
of new HIV treatments based on interruption of intracellular viral trafficking."
To view the original publication of this study in PLoS Pathogens,
DRP Hosts Visitors Observing BL2*/BL3 Work
Nancy Chung (second from right) in the BL2* staging area with (from left to right)
Margaret Lange, Eleftherios Michailidis, and Bruno Marchand
HIV DRP hosted several members of the laboratories of
Donald Burke and Stefan Sarafianos from the University of Missouri to demonstrate
the BL2*/BL3 practices and protocols used in the HIV DRP. Nancy Chung in
Vineet KewalRamani's group conducted the training for the visitors,
which included Dr. Burke and fellows Margaret Lange, Bruno Marchand, and Eleftherios
Michailidis. In addition to demonstrating experiments using GHOST cell infections
with live HIV-1, Dr. Chung demonstrated TZM cell titrations, which are commonly
used by laboratories conducting research on antiviral inhibitors. Observing the
BL2*/BL3 work firsthand proved very helpful to the guests; in Dr. Burke's words,
"there were a thousand little details that can only be learned by watching it
Articles and Press Releases
Press Releases and Related Articles on HIV-1 Maturation Inhibitors
following articles describe the identification and development of HIV-1 maturation inhibitors, a novel class of antiretroviral drug candidates, in collaboration with Eric Freed's lab in the HIV DRP, National Cancer Institute
(to view the articles, click on the titles below):
January 2012 Press Release from DFH Pharma:
DFH Pharma to Collaborate With National Cancer Institute to Develop Second-Generation HIV Maturation Inhibitor Drugs
2006 Article in the Boston Globe:
Chinese Herb May Yield Drug for AIDS
To view the
published results of a study elucidating the mechanism of action of PA-457, go
Natl. Acad. Sci. USA 100: 13555-13560, 2003 (PDF - 384KB).
News Articles on Recent PNAS Paper by Host-Virus Interaction Branch
following news articles highlight a PNAS paper published in March 2008 by a collaborative
team including members of the Host-Virus Interaction Branch (Sarah Palmer, Frank
Maldarelli, Ann Wiegand, John
Mellors) on the persistence of low-level viremia for at least 7 years
in HIV-infected patients on potent antiretroviral therapy (to view the articles,
click on the titles below):
HIV 'hides from drugs for years'
HIV Can Hide in Cells for Years
original article by Palmer et al. describing the study (Proc. Natl. Acad. Sci.
USA 105: 3879-3884, 2008):
Low-level viremia persists for at least 7
years in patients on suppressive antiretroviral therapy (PDF - 664KB)
Center of Excellence in HIV/AIDS & Cancer Virology
Center of Excellence in HIV/AIDS and Cancer Virology (CEHCV) was formed in 2006
within the Center for Cancer Research, NCI. The mission of the CEHCV is to facilitate
and rapidly communicate advances in the discovery, development, and delivery of
antiviral and immunologic approaches for the prevention and treatment of HIV infection,
AIDS-related malignancies, and cancer-associated viral diseases.
Stuart Le Grice, a Principal Investigator in the HIV DRP, was appointed Head of the CEHCV. Further details are available at the
conjunction with the 2005 Think
Tank Meeting, the HIV DRP hosted the third Invited
Student Symposium on April 6. After attending the Think Tank Meeting, the following
senior graduate students from outside the NIH community presented short talks
on their retrovirology research to the HIV DRP staff and convened with the Program's
faculty for informal discussions.
(Volker Vogt Laboratory, Cornell University)
(Celia Schiffer Laboratory, University of Massachusetts Medical School)
(Michael Summers Laboratory, Howard Hughes Medical
Institute and University of Maryland Baltimore County)
(Michael Emerman Laboratory, Fred Hutchinson Cancer Research Center)
(Stephen Goff Laboratory, Howard Hughes Medical Institute
and Columbia University College of Physicians and Surgeons)
(John Mellors Laboratory, University of Pittsburgh School of Medicine)
(Jeremy Luban Laboratory, Columbia University College of Physicians
Eric Freed Appointed as Guest Editor for Special Issue of Virus Research
The cover image
was reprinted from Virus
Research, Vol. 106, No. 2, Copyright 2004, with permission from
Elsevier. The original source of the artwork was Proc. Natl. Acad. Sci. USA
99: 955-960, 2002 (Copyright 2002, National Academy of Sciences, U.S.A.).
Eric Freed served as Guest Editor for the December 2004 issue of
Research, which was devoted to mechanisms of enveloped virus
budding. In addition to writing the preface
(PDF - 33KB) to this special issue, Dr. Freed solicited chapters
from leading investigators studying a range of enveloped viruses, edited the chapters,
and coordinated the review process. He also contributed a chapter on retrovirus
and Freed, pp. 87-102, PDF - 443KB) and provided the artwork for
the journal's cover,
showing an electron micrograph of TSG-5' inhibiting HIV-1 budding.
modified: 2 April 2017