Frank Maldarelli, M.D., Ph.D.
HIV DRP Host-Virus Interaction Branch
Building 10, Room 5A06
Bethesda, MD 20892-1403
Clinical Studies of HIV Drug Resistance
The Clinical Retrovirology Section develops and implements clinical protocols to elucidate mechanisms underlying the emergence of HIV drug resistance in vivo, the dynamics of infection under treatment, and the role of resistance mutations in the efficacy and failure of subsequent treatments.
In the first of three projects conducted by the Clinical Retrovirology Section, our goal is to determine the dynamics of viral replication in HIV-infected patients on suppressive antiretroviral therapy (ART). These studies are being extended in clinical trials performed at NIH and elsewhere to determine the levels of viremia when treatment regimens are either simplified or intensified. We are also exploring new strategies to decrease reservoirs of HIV-1 in infected individuals.
In a second research project, we are investigating the genetic structure of HIV populations in infected individuals. We are using the single-genome sequencing technology developed by the Translational Research Section to analyze and understand the accumulation of genetic variation in the gag/pol and env genes of HIV-1 in a number of different patient groups, including chronically infected patients, both naive and on therapy, as well as in primary and early HIV-1 infection. We are complementing existing single-genome sequencing and allele-specific PCR assays with next-generation sequencing and new single-cell assays for cell-associated HIV RNA and DNA. We are determining precise estimates of the roles of population size, genetic drift, selection, and recombination in shaping HIV populations. The goal of this study is to understand the nature of the forces (mutation, selection, drift, recombination) that mold the genetic diversity of virus populations before and after ART is introduced.
The third project is focused on elucidating the mechanisms of persistent viremia in vivo. We are conducting clinical trials of targeted interventions to characterize HIV reservoirs in individuals suppressed on ART. We are determining the role of generalized immune activation and gut-associated lymphoid tissue (GALT) on persistence using nonabsorbable antibiotics to specifically reduce gut bacteria, and studying the effects of specific antigenic activation on HIV using immunization and sampling protocols. We are also investigating the role of target cell number on HIV reservoirs by studying the effects of cytotoxic chemotherapeutics on HIV viremia, and we are investigating the role of innate immunity in HIV persistence by studying the effects of the innate immune modulator interferon alpha 2b.
Dr. Frank Maldarelli received his Ph.D. from the City University of New York and his M.D. from Mount Sinai School of Medicine. After completing his residency in internal medicine at The Columbia-Presbyterian Hospital, New York, he joined the Laboratory of Molecular Microbiology at the National Institute of Allergy and Infectious Diseases (NIAID) as a Medical Staff Fellow. In 1998, Dr. Maldarelli joined the HIV Drug Resistance Program (HIV DRP, renamed as the HIV Dynamics and Replication Program in 2015) in the National Cancer Institute (NCI) as a Staff Clinician and Head of the In Vivo Biology Group, which was later renamed the Clinical Retrovirology Section. In 2012 he was appointed as a Tenure-Track Investigator, and he was promoted to a tenured Senior Investigator position in 2018. Representing the clinical research arm of the HIV DRP, Dr. Maldarelli has established extensive collaborations between the HIV DRP in Frederick and both the NCI HIV and AIDS Malignancy Branch and the NIAID AIDS clinical research program in Bethesda. He is an Attending Physician in the NIAID/CCMD HIV service, the NCI Liaison to the Leidos HIV Molecular Monitoring Core, and a Scientific Committee Member of the International Workshop on HIV Drug Resistance. He recently served on the NIAID Institutional Review Board (as Chair and Vice-Chair), NIH Infectious Disease Advisory Board, Scientific Advisory Committee of the American Federation for AIDS Research, and Review Panel for the Henry M. Jackson Foundation for the Advancement of Military Medicine. He was a faculty member of the International Society of Infectious Diseases HIV Training Program, NIH Infectious Disease Consult Service, and Center for Bio-Medical Communications Infectious Disease Board Review Course and a lecturer in the Washington D.C. community outreach PACT Program. His awards include the NIH Director’s Group Award in 2015, Center for Cancer Research (CCR) Group Award in 2016, and multiple NIH Bench-to-Bedside and Intramural AIDS Targeted Antiviral Program (IATAP) awards. Dr. Maldarelli is the Chair of the Center for Cancer Research Non Human Primate Scientific Review Committee and currently serves on the Editorial Boards of Journal of Virology, AIDS Research and Therapy, and Frontiers in Microbiology.
Kearney MF, Spindler J, Shao W, Yu S, Anderson EM, O'Shea A, Rehm C, Poethke C, Kovacs N, Mellors JW, Coffin JM, Maldarelli F. Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy. PLoS Pathog. 2014;10(3):e1004010.
Maldarelli F, Wu X, Su L, Simonetti FR, Shao W, Hill S, Spindler J, Ferris AL, Mellors JW, Kearney MF, Coffin JM, Hughes SH. HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science. 2014;345(6193):179-83.
Josefsson L, Palmer S, Faria NR, Lemey P, Casazza J, Ambrozak D, Kearney M, Shao W, Kottilil S, Sneller M, Mellors J, Coffin JM, Maldarelli F. Single cell analysis of lymph node tissue from HIV-1 infected patients reveals that the majority of CD4+ T-cells contain one HIV-1 DNA molecule. PLoS Pathog. 2013;9(6):e1003432.
Maldarelli F, Kearney M, Palmer S, Stephens R, Mican J, Polis MA, Davey RT, Kovacs J, Shao W, Rock-Kress D, Metcalf JA, Rehm C, Greer SE, Lucey DL, Danley K, Alter H, Mellors JW, Coffin JM. HIV populations are large and accumulate high genetic diversity in a nonlinear fashion. J Virol. 2013;87(18):10313-23.
Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ, Cranmer L, O'Shea A, Callender M, Spivak A, Brennan T, Kearney MF, Proschan MA, Mican JM, Rehm CA, Coffin JM, Mellors JW, Siliciano RF, Maldarelli F. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 2009;106(23):9403-8.
Related Scientific Focus Areas
Microbiology and Infectious Diseases
This page was last updated on September 11th, 2019