Mary F. Kearney, Ph.D.
- Center for Cancer Research
- National Cancer Institute
- Building 535, Room 310
- Frederick, MD 21702-1201
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 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 Section, which aims to understand the genetics, evolution, and persistence of HIV and other RNA viruses and to design new approaches toward targeting and killing infected cells. Currently, she also serves as a member of the NIH Women Scientists Advisors (WSA) Executive Committee and a member of the CCR WSA Committee; these groups promote career development and address issues affecting women scientists. Dr. Kearney was appointed as HIV DRP Deputy Director of Translational/Clinical Research in 2021.
Areas of Expertise
1) drug resistance, 2) viral persistence, 3) HIV residual viremia, 4) HIV cure, 5) viral evolution, 6) viral genetics
Studies of Clinical Resistance
The Translational Research Section (TRS) is primarily responsible for advancing the clinical and translational research efforts of the HIV DRP by developing and applying new technologies to characterize and identify the sources of persistent HIV-1 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 Frank Maldarelli in the Clinical Retrovirology Section, in consultation with John Coffin of Tufts University and John Mellors of the University of Pittsburgh, the TRS 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 individuals 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 TRS aims to reveal sources of persistent virus production on ART and the sources of rebound viremia after stopping ART. The TRS 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 donors to characterize the genetics of viremia in individuals on and off ART.
Determining the frequency of rare, drug-resistant variants in untreated individuals can provide important insights into the emergence of drug resistance and into the effective population size of HIV-1. The TRS 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 TRS 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 before and after exposure to ART to investigate the impacts of HIV-1 diversity, low-frequency drug-resistant variants, and effective population size on the response to treatment.
Combined HIV-1 sequence and integration site analysis informs viral dynamics and allows reconstruction of replicating viral ancestors
Mary F. Kearney, Ph.D.
Dr. Kearney received her Ph.D. in Biology at Catholic University in 2007 under the direction of 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 (HIV DRP, renamed 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 (renamed the Translational Research Section in 2020), where she oversees a team that investigates viral genetics and expression in vivo, the sources of persistent HIV 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 drug-resistance mutations in HIV and other RNA viruses. In 2019 she was promoted to Senior Scientist. Dr. Kearney was awarded the NIH Director’s Award and NCI Group Award in 2012, the NCI Director's Award in 2015, the CCR Group Award in 2016, and the NIH Director’s Award in 2019 and 2021. She was nominated by CCR Director Tom Misteli and selected to receive an individual 2021 NCI Director's Award in recognition of her initiative and accomplishments to improve workplace wellness through exemplary leadership and mentoring. 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 for the Center for AIDS Research Symposium at the University of Pennsylvania in 2019, and was elected to the NIH Women Scientists Advisors (WSA) in 2018. She has been a member of the CCR WSA Committee since 2018 and served as its Chair in 2020. She is currently serving as Chair of the NIH WSA Scholars Symposium, a member of the NIH WSA Executive Committee, an advisor to the Biomedical Science and Bioinformatics Program at Hood College, and Guest Editor of the Viruses Special Issue on “Mechanisms of Viral Persistence.” Dr. Kearney is the recipient of four Bench-to-Bedside Awards, three NIH Intramural AIDS Targeted Antiviral Program Awards, a U.S.–South Africa Initiative U01 Grant, an Office of AIDS Research Congressional Award, and an NCI Flex Technology Award. In 2021 Dr. Kearney was appointed as HIV DRP Deputy Director of Translational/Clinical Research.
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Proviral Sequence Database (PSD)
Despite the success of antiretroviral therapy (ART), HIV-1 persists in reservoirs and viremia rebounds if treatment is interrupted. To facilitate understanding of the genetic structure and dynamics of the HIV-1 reservoir, we developed a public database, Proviral Sequence Database (PSD), for the storage and meta-analyses of near full-length (NFL) HIV-1 genomic RNA and proviral sequences that persist in donors on ART or that rebound after ART is interrupted (described in Retrovirology 13: 47, 2016). This relational database contains information about host characteristics, treatment, HIV-1 sequences, and tools for sequence annotation/features. PSD was developed by bioinformatics analysts Wei Shao and Jigui Shan (Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc.) in consultation with investigators John M. Coffin (Tufts University); Mary F. Kearney and Wei-Shau Hu (HIV DRP); and John W. Mellors (University of Pittsburgh). PSD can be accessed at the website https://psd.cancer.gov.
Retrovirus Integration Database (RID)
A database on retrovirus integration sites is now available for use by intramural and extramural investigators. The Retrovirus Integration Database (RID) was developed by bioinformatics analysts Wei Shao and Jigui Shan (Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc.) in consultation with John M. Coffin (Tufts University) and HIV DRP investigators Stephen H. Hughes, Frank Maldarelli, and Mary F. Kearney (described in AIDS Res. Hum. Retroviruses 36: 1, 2020). RID can be accessed at the website https://rid.ncifcrf.gov.
We developed a program, HIV-DRLink, that works in conjunction with the Stanford HIV Drug Resistance Database to rapidly report linked and unlinked HIV-1 drug-resistance mutations in large data sets generated by single-genome sequencing methods that eliminate PCR-based recombination and nucleotide mixtures (described in in AIDS Res. Hum. Retroviruses 36: 942, 2020). HIV-DRLink is a necessary tool to further investigate the effect of single versus linked preexisting drug-resistance mutations on the outcome of antiretroviral therapy. HIV-DRLink was developed by bioinformatics analyst Wei Shao (Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc.) in consultation with John M. Coffin (Tufts University) and HIV DRP investigators Mary F. Kearney and Frank Maldarelli.
Sequence Overrepresentation (SOR) Index
The Sequence Overrepresentation (SOR) index measures whether or not a cluster of identical sequences within a population is larger than expected by chance given the overall diversity of the population. Briefly, the SOR index (described in Proc. Natl. Acad. Sci. USA 116: 25891, 2019) compares the probability of finding N identical sequence pairs in a set of sequence pairs that have a Poisson distribution with average given by the average p-distance of the supplied sequence set. The sequence set supplied to the SOR webpage should be prealigned and devoid of any sequences that would produce artificially high genetic distances — e.g., hypermutants and outgroup consensus sequences. Output of the SOR webpage is a bar graph showing the distribution of pairwise distances within the supplied dataset (if requested) and a table of p-values with their associated rake sizes and IDs. The SOR index and webpage were developed by postbaccalaureate fellow Michael Bale (HIV DRP) and investigator Brian Luke (Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc.) in consultation with investigators John M. Coffin (Tufts University) and Mary F. Kearney (HIV DRP). An R script version of the web app and the supporting web app code are available at https://github.com/michaelbale.
The characterization of the HIV-1 reservoir, which consists of replication-competent integrated proviruses that persist on antiretroviral therapy (ART), is made difficult by the rarity of intact proviruses relative to those that are defective. While the only conclusive test for the replication competence of HIV-1 proviruses is carried out in cell culture, genetic characterization of genomes by near full-length PCR and sequencing can be used to determine whether particular proviruses have insertions, deletions, or substitutions that render them defective. Proviruses that are not excluded by having such defects can be classified as genetically intact and, possibly, replication competent. Identifying and quantifying proviruses that are potentially replication competent is important for the development of strategies toward a functional cure. However, to date, there are no programs that can be incorporated into deep-sequencing pipelines for the automated characterization and annotation of HIV genomes. Existing programs that perform this work require manual intervention, cannot be widely installed, and do not have easily adjustable settings. In collaboration with Gert van Zyl and Imogen Wright (University of Stellenbosch) and John M. Coffin (Tufts University), HIV DRP investigators Mary F. Kearney, Wei-Shau Hu, and Michael Bale and bioinformatics analyst Wei Shao (Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc.) developed HIVIntact as a python-based software tool that characterizes genomic defects in near full-length HIV-1 sequences, allowing putative intact genomes to be identified in silico (described in Retrovirology 18: 16, 2021). Unlike other applications that assess the genetic intactness of HIV genomes, this tool can be incorporated into existing sequence-analysis pipelines and applied to large next-generation sequencing datasets. The HIVIntact pipeline and test data may be downloaded from a public GitHub repository (https://github.com/ramics/HIVIntact under an open-source MIT license.
HIV-1 proviral single-genome sequencing by limiting-dilution PCR amplification is important for differentiating the sequence-intact from defective proviruses that persist during antiretroviral therapy (ART). Intact proviruses may rebound if ART is interrupted and are the barrier to an HIV cure. Oxford Nanopore Technologies (ONT) sequencing offers a promising, cost-effective approach to the sequencing of long amplicons such as near full-length HIV-1 proviruses, but the high diversity of HIV-1 and the ONT sequencing error render analysis of the generated data difficult. Mary F. Kearney (HIV DRP) collaborated with Imogen Wright and Gert van Zyl (University of Stellenbosch) to develop NanoHIV as a new tool that uses an iterative consensus generation approach to construct accurate, near full-length HIV-1 proviral single-genome sequences from ONT data (described in Cells 10: 2577, 2021. The NanoHIV pipeline and scripts may be downloaded from a public GitHub repository at https://github.com/ramics/NanoHIV