Mary Kearney, Ph.D.
Dr. Kearney conducts research on the emergence of HIV drug resistance, the persistence of HIV during antiretroviral treatment (ART), and the sources of rebound viremia after stopping ART. Her studies, in collaboration with the Clinical Retrovirology Section led by Dr. Frank Maldarelli, have demonstrated that a diverse population of HIV-infected cells persist during ART, that some infected cells proliferate despite ART, and that residual viremia during ART can result from viral expression from these cells. Dr. Kearney heads the Translational Research Unit, which aims to understand the genetics, evolution, and persistence of HIV and to design new approaches towards targeting and killing HIV-infected cells.
Studies of Clinical Resistance
The Translational Research Unit (TRU) is primarily responsible for advancing the clinical and translational research efforts of the Host-Virus Interaction Branch by developing and applying new technologies to characterize and identify the sources of persistent HIV-1 viremia despite antiretroviral therapy (ART) and to evaluate the effect of HIV-1 genetic diversity, expression, and low-frequency drug resistance mutations on the response to ART. Working closely with Dr. Frank Maldarelli in the Clinical Retrovirology Section, in consultation with Dr. John Coffin of Tufts University and Dr. John Mellors of the University of Pittsburgh, the TRU collaborates with research groups worldwide to perform studies of HIV-host interactions, viral persistence during therapy, sources of rebound viremia, and the evolution of resistance.
HIV-1 persists in patients on ART despite suppression to very low levels and usually rebounds to pretherapy levels if ART is stopped. The mechanisms that allow viremia to persist during therapy are not well understood. Their elucidation is imperative if HIV-1 infection is ever to be cured. Cellular reservoirs that harbor HIV-1 genomes and express viral RNA during ART are likely long-lived, proliferating cells that were infected prior to initiating therapy. By investigating the genetics of HIV-1 plasma RNA and cellular HIV-1 DNA and RNA, the TRU aims to reveal sources of persistent virus production on ART and the sources of rebound viremia after stopping ART. The TRU developed the gold-standard assays that allow for sequencing of HIV RNA and DNA in single virions and in single infected cells. These assays are applied to blood and tissues from HIV-1-infected donors to characterize the genetics of viremia in patients on and off ART.
Determining the frequency of rare, drug-resistant variants in untreated patients can provide important insights into the emergence of drug resistance and into the effective population size of HIV-1. The TRU previously developed an allele-specific PCR (ASP) assay capable of detecting specific drug resistance mutations present in 0.1-0.001% of the total virus population. More recently, the TRU developed an ultrasensitive single-genome sequencing (uSGS) assay that provides sequence information from thousands of HIV variants present in donors’ plasma, providing templates to investigate the linkage of drug resistance mutations and to perform studies on HIV-1 evolution. Ongoing studies include applying these and other ultrasensitive methods under development to samples collected from women before and after exposure to single-dose nevirapine (NVP) and in patients initiating standard-of-care ART to investigate the impacts of HIV-1 diversity, low-frequency drug-resistant variants, and effective population size on the response to ART.
Selected Key Publications
- J Clin Invest. 127: 3827-3834, 2017. [ Journal Article ]
Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART.Proc Natl Acad Sci U S A. 114: E3659-E3668, 2017. [ Journal Article ]
Origin of rebound plasma HIV includes cells with identical proviruses that are transcriptionally active before stopping of antiretroviral therapy.J Virol. 90: 1369-1376, 2016. [ Journal Article ]
Well-mixed plasma and tissue viral populations in RT-SHIV-infected macaques implies a lack of viral replication in the tissues during antiretroviral therapy.Retrovirology. 12: 93, 2015. [ Journal Article ]
- PLoS Pathog. 10: e1004010, 2014. [ Journal Article ]
Dr. Mary Kearney received her Ph.D. in Biology at Catholic University in 2007 under the direction of Drs. John Coffin, Sarah Palmer, and Venigalla Rao. She received The Benedict T. DeCicco Award for Excellence in Graduate Research in 2008. In 2001 she joined the HIV Drug Resistance Program (renamed as the HIV Dynamics and Replication Program in 2015) as a Biologist in the Virology Core. In 2008 she was promoted to Head of the Translational Research Unit (TRU) where she oversees a team that investigates HIV genetics and expression in vivo, the sources of persistent viremia during antiretroviral therapy (ART), the sources of rebound viremia after stopping ART, the mechanisms for maintaining the HIV reservoir, and the mechanisms for the emergence of HIV drug resistance mutations. Dr. Kearney was awarded the NIH Director’s Award and NCI Group Award in 2012, the NCI Director's Award in 2015, and the CCR Group Award in 2016. She was a consultant to the World Health Organization from 2010 to 2016, was the keynote speaker for the launch of the Bioinformatics Program at Hood College in 2015, and currently serves as an advisor to the Bioinformatics Program and Biology Department at Hood College. Dr. Kearney is the recipient of three Bench-to-Beside Awards, three NIH Intramural AIDS Targeted Antiviral Program Awards, and a U.S.–South Africa Initiative U01 Grant. In 2018 she was elected as a Frederick representative of Women Science Advisors for the NCI.
|Michael Bale||Postbaccalaureate Fellow (CRTA)|
|Valerie Boltz M.S.||Research Biologist|
|Jenna Hasson||Prebaccalaureate Fellow (CRTA)|
|Andrew Musick||Postbaccalaureate Fellow (CRTA)|
|Aurelie Niyongabo||Postbaccalaureate Fellow (CRTA)|
|Sean Patro Ph.D.||Postdoctoral Fellow (CRTA)|
|Wei Shao Ph.D.||Programmer / Analyst (Contr)|
|Jonathan Spindler||Research Biologist|
|Ann Wiegand M.S.||Research Biologist|
Young Investigator Awards, Conference on Retroviruses and Opportunistic Infections
Andrew Musick received a Young Investigator Award to present his research findings at the 2017 Conference on Retroviruses and Opportunistic Infections. This highly selective travel scholarship is awarded to postdoctoral fellows and students whose abstracts are accepted for presentation at the conference.
2015 NCI Director's Award
Members of the NCI HIV Integration Sites Analysis (ISA) team received a group award at the NCI Director's Award ceremony in November 2015 "for discoveries on HIV survival during antiretroviral therapy, revealing the importance of integration site and clonal expansion." The ISA group award recipients included Stephen Hughes, Andrea Ferris, Shawn Hill, Mary Kearney, Frank Maldarelli, Wei Shao, and Jonathan Spindler (HIV DRP); Francesco Simonetti (University of Milan); John Coffin (Tufts University); John Mellors (University of Pittsburgh); and David Wells, Ling Su, and Xiaolin Wu (Leidos Biomedical Research, Inc.).
XMRV Working Group Received NIH Director's Award
Presentations at the 2009 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 in an issue of The Poster newsletter (link to NIH Director's Award feature).
Award for Excellence in Graduate Research, Catholic University of America
Mary Kearney was awarded the Benedict T. DeCicco Award for Excellence in Graduate Research in 2008 by the Biology Faculty of the Catholic University of America.