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Project Title: Analysis of intrapatient SARS-Cov-2 genetic variation
NIAID Principal Investigator: Eli Boritz, M.D., Ph.D
Chief, Virus Persistence and Dynamics Section, IL, VRC
Pamela Costner, R.N.
301-451-8715
vaccines@nih.gov
NIAID supports and conducts research to identify new vaccine candidates to prevent a variety of infectious diseases, including those for which no vaccines currently exist. NIAID-supported research also aims to improve the safety and efficacy of existing vaccines. Explore the links below to learn more about NIAID’s efforts to design, develop and evaluate new and improved vaccines to protect against specific infectious diseases.
The mission of the Immunology Laboratory (IML) is to investigate novel aspects of the cellular immune response to pathogens in support of the rational development of a vaccine against HIV and other lethal human viral pathogens. It is the goal of the IML to rapidly advance the latest information on ways of manipulating the immune response to HIV into practical applications in clinical trials of prophylactic and therapeutic vaccines. In support of this effort, we emphasize a detailed analysis of the strength, breadth, plasticity, phenotype, and functional characteristics of the cellular immune response to HIV during natural infection and how it does or does not differ from the immune response during other viral infections or that is generated after vaccination.
View all research conducted at the Vaccine Research Center (VRC)
Theodore C. Pierson, Ph.D., Acting Chief
Director, Vaccine Research Center
The research efforts of the Virology Laboratory (VL) focus on understanding the cellular and molecular regulation of viral gene expression, HIV replication, entry into the cell, development of improved HIV envelope immunogens, optimization of immune responses to gene-based vaccination, and correlates of immune protection, with the goal of developing rationally designed vaccines against HIV, influenza, Ebola/Marburg, and other emerging and re-emerging infectious diseases. Various elements of vaccine design and delivery, including optimization of vector and protein design, adjuvants, dosing, and methods and routes of delivery, are studied. Other areas of research address mechanisms of viral gene regulation, assembly of viruses, viral cell interactions, and insight into the regulation of eukaryotic gene expression.
View all research conducted at the Vaccine Research Center (VRC)
The VL is developing active and passive approaches for HIV vaccine development. For active approaches, the VRC continues to focus on critical issues in HIV-1 immunogen and vaccine design. The VRC has increased its major efforts on isolating broadly neutralizing mAbs, identifying and characterizing the structures of vulnerable viral epitopes, and designing immunogens to elicit potent, broadly neutralizing antibodies against HIV-1. In the realm of passive immunity, parallel efforts are underway to understand the ability of broadly neutralizing antibodies to confer passive protection by direct administration or via gene-based antibody expression. Building upon its work with VRC01, the VL has isolated multiple anti-CD4 binding site antibodies and resolved the structural identity of several HIV-1 epitopes. This structural biology work continues to drive the VRC’s approach of targeted design of active vaccine immunogens. Research on the role of cellular immunity in active immunization, its influence on humoral immunity, and the ability of CD8 cells to prevent infection is also ongoing.
The VRC is strongly emphasizing the development of novel influenza vaccines, with particular emphasis on developing a “universal” flu vaccine. The influenza research group has expanded its efforts to develop gene-based prime-boost immunization against influenza viruses and develop new vaccine strategies to induce broadly neutralizing, cross protective antibodies against influenza virus. Development of new vaccine candidates and new vector systems for antigen delivery, viral vector construction and development, structure-based protein immunogen design, and evaluation of vaccine candidates for their effectiveness in inducing potent and broad immune responses in different animal models and in human clinical trials are all important aspects of the goals of the influenza research group.
Eli Boritz, M.D., Ph.D.
The goal of the VPDS is to help develop means of targeting virus reservoirs and reducing disease progression in people living with HIV. One path toward this goal is to clarify the fundamental biology of HIV persistence during antiretroviral therapy (ART). Motivated by the genetic and functional diversity within key cellular reservoirs for the virus, we are developing high-throughput methods for characterizing large numbers of single cells and viruses in great detail. Topics under investigation include the unique genetic programs expressed by infected cells; heterogeneity among individual infected cells as measured using “omics” tools; and the use of virus genetic analysis to detect critical events that may not be directly observable in vivo. We are investigating these issues both in individuals treated with standard-of-care ART and in study participants receiving experimental HIV cure-directed therapies.
Dr. Boritz began his HIV research career in the mid-1990s as a summer student in the laboratory of Dr. John K. Rose. An interest in fundamental and translational studies of host-virus interactions then led him to pursue combined M.D./Ph.D. training at University of Colorado Health Sciences Center in Denver. He completed his Ph.D. in the Immunology Program studying HIV-specific CD4 T-cell responses with Dr. Cara Wilson. After an internship and residency in Internal Medicine at Johns Hopkins Hospital, he came to NIAID as a fellow in infectious diseases. Following the clinical portion of his fellowship, he joined Dr. Daniel Douek's laboratory at Vaccine Research Center, where he worked to understand the cellular and molecular events that allow HIV reservoirs to persist in vivo. He joined the NIH faculty to establish the VPDS in 2017.
In addition to his activities in the research lab, Dr. Boritz serves as a core faculty member for the NIAID Infectious Diseases Fellowship Program, an attending physician on the NIAID Infectious Diseases Consult Service, and an HIV clinic preceptor for first-year Infectious Diseases fellows.
Mohammad Abu-Laban
Postdoctoral Fellow
Ph.D., Biomedical Engineering – Pennsylvania State University
M.S., Biological and Agricultural Engineering – Louisiana State University
B.S., Chemical Engineering – Louisiana State University
Aisha AlJanahi
Postdoctoral Fellow
Ph.D., Biochemistry and Molecular Biology – NIH/Georgetown University GPP
M.S., Biochemistry and Molecular Biology/Bioinformatics – Georgetown University
B.S., Medical Laboratory Technology – University of Dammam
Elham (Ellie) Bayat-Mokhtari
Postdoctoral Fellow
Ph.D., Statistics – University of Montana
M.S., Mathematical Statistics – Ferdowsi University of Mashhad
B.S., Applied Statistics – Ferdowsi University of Mashhad
Sung Hee Ko
Postdoctoral Fellow
Ph.D., Mechanical Engineering – Pohang University of Science & Technology
M.S., Mechanical Engineering – Pohang University of Science & Technology
B.S., Mechanical Engineering – Pusan National University
Miranda (Max) Lee
Postbaccalaureate Fellow
B.A., Biochemistry – Mount Holyoke College
Prakriti Mudvari
Scientist
Ph.D., Molecular Medicine – George Washington University
M.S., Genomics and Bioinformatics – George Washington University
B.S., Biology – Bowling Green State University
Liliana Pérez Rodriguez
Scientist
Ph.D., Physiology & Integrative Biology – UMDNJ/Rutgers University
B.S., Biology – University of Puerto Rico
Hannah Shepard
Postbaccalaureate Fellow
B.S., Biology, Global Health – Duke University
Ko SH, Bayat Mokhtari E, Mudvari P, Stein S, Stringham CD, Wagner D, Ramelli S, Ramos-Benitez MJ, Strich JR, Davey Jr. RT, Zhou T, Misasi J, Kwong PD, Chertow DS, Sullivan NJ, and Boritz EA. High-throughput, single-copy sequencing reveals SARS-CoV-2 spike variants coincident with mounting humoral immunity during acute COVID-19. PLoS Pathog. 2021 Apr 8;17(4):e1009431.
Asokan M, Dias J, Liu C, Maximova A, Ernste K, Pegu A, McKee K, Shi W, Chen X, Almasri C, Promsote W, Ambrozak DR, Gama L, Hu J, Douek DC, Todd JP, Lifson JD, Fourati S, Sekaly RP, Crowley AR, Ackerman ME, Ko SH, Kilam D, Boritz EA, Liao LE, Best K, Perelson AS, Mascola JR, Koup RA. Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody. Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18754-18763.
Shen CH, DeKosky BJ, Guo Y, Xu K, Gu Y, Kilam D, Ko SH, Kong R, Liu K, Louder MK, Ou L, Zhang B, Chao CW, Corcoran MM, Feng E, Huang J, Normandin E, O'Dell S, Ransier A, Rawi R, Sastry M, Schmidt SD, Wang S, Wang Y, Chuang GY, Doria-Rose NA, Lin B, Zhou T, Boritz EA, Connors M, Douek DC, Karlsson Hedestam GB, Sheng Z, Shapiro L, Mascola JR, Kwong PD. VRC34-Antibody Lineage Development Reveals How a Required Rare Mutation Shapes the Maturation of a Broad HIV-Neutralizing Lineage. Cell Host Microbe. 2020 Apr 8;27(4):531-543.e6.
Pérez L, Anderson J, Chipman J, Thorkelson A, Chun TW, Moir S, Haase AT, Douek DC, Schacker TW, and Boritz EA. Conflicting evidence for HIV enrichment in CD32+ CD4 T cells. Nature. 2018 Sep;561(7723):E9-E16.
Petrovas C, Ferrando-Martinez S, Gerner M, Pegu A, Deleage C, Ambrozak A, Del Río-Estrada P, Paris R, Boswell K, Ruiz-Mateos E, Boritz E, Giannikaki E, Leal M, Ablanedo-dTerrazas Y, Rivero A, Gonzalez-Hernandez LA, Reyes-Teran G, Docobo F, Pantaleo G, Douek DC, Betts MR, Estes JD, Germain R, Mascola J and Koup RA. Cytolytic follicular CD8 T cells accumulate in HIV and kill infected cells in vitro via bispecific antibodies. Sci Transl Med. 2017 Jan 18;9(373):eaag2285.
Boritz EA, Darko S, Swaszek L, Wolf G, Wells D, Wu X, Henry AR, Laboune F, Hu J, Ambrozak D, Hughes MS, Hoh R, Casazza JP, Vostal A, Bunis D, Nganou-Makamdop K, Lee JS, Migueles SA, Koup RA, Connors M, Moir S, Schacker T, Maldarelli F, Hughes SH, Deeks SG, and Douek DC. Multiple Origins of Virus Persistence during Natural Control of HIV Infection. Cell. 2016 Aug 11;166(4):1004-1015.
VPDS was established with a mission to help develop means of targeting virus reservoirs and reducing disease progression in people living with HIV. One path toward this goal is to clarify the fundamental biology of HIV persistence during antiretroviral therapy (ART). Motivated by the genetic and functional diversity within key cellular reservoirs for the virus, VPDS develops and applies high-throughput methods for characterizing large numbers of single cells and viruses in great detail. Topics under investigation include the unique genetic programs expressed by infected cells; heterogeneity among individual infected cells as measured using “omics” tools; and the use of virus genetic analysis to detect critical events that may not be directly observable in vivo. We are investigating these issues both in individuals treated with standard-of-care ART and in study participants receiving experimental HIV cure-directed therapies.
Since the start of the COVID-19 pandemic, VPDS has also begun to apply core laboratory technologies to SARS-CoV-2 and other emerging viruses. These studies aim to define mutational properties and patterns of in vivo genetic variation that may help understand the potential of emerging viruses to acquire resistance against immune responses and medical countermeasures.
Clark IC, Mudvari P, Thaploo S, Smith S, Abu-Laban M, Hamouda M, Theberge M, Shah S, Ko SH, Pérez L, Bunis DG, Lee JS, Kilam D, Zakaria S, Choi S, Darko S, Henry AR, Wheeler MA, Hoh R, Butrus S, Deeks SG, Quintana FJ, Douek DC, Abate AR, Boritz EA. HIV silencing and cell survival signatures in infected T cell reservoirs. Nature. 2023 Jan 4. Online ahead of print.
Stein SR, Ramelli SC, Grazioli A, Chung JY, Singh M, Yinda CK, Winkler CW, Sun J, Dickey JM, Ylaya K, Ko SH, Platt AP, Burbelo PD, Quezado M, Pittaluga S, Purcell M, Munster VJ, Belinky F, Ramos-Benitez MJ, Boritz EA, Lach IA, Herr DL, Rabin J, Saharia KK, Madathil RJ, Tabatabai A, Soherwardi S, McCurdy MT; NIH COVID-19 Autopsy Consortium; Peterson KE, Cohen JI, de Wit E, Vannella KM, Hewitt SM, Kleiner DE, Chertow DS. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature. 2022 Dec;612(7941):758-763.
Ko SH, Bayat Mokhtari E, Mudvari P, Stein S, Stringham CD, Wagner D, Ramelli S, Ramos-Benitez MJ, Strich JR, Davey Jr. RT, Zhou T, Misasi J, Kwong PD, Chertow DS, Sullivan NJ, and Boritz EA. High-throughput, single-copy sequencing reveals SARS-CoV-2 spike variants coincident with mounting humoral immunity during acute COVID-19. PLoS Pathog. 2021 Apr 8;17(4):e1009431.
Asokan M, Dias J, Liu C, Maximova A, Ernste K, Pegu A, McKee K, Shi W, Chen X, Almasri C, Promsote W, Ambrozak DR, Gama L, Hu J, Douek DC, Todd JP, Lifson JD, Fourati S, Sekaly RP, Crowley AR, Ackerman ME, Ko SH, Kilam D, Boritz EA, Liao LE, Best K, Perelson AS, Mascola JR, Koup RA. Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody. Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18754-18763.
Pérez L, Anderson J, Chipman J, Thorkelson A, Chun TW, Moir S, Haase AT, Douek DC, Schacker TW, and Boritz EA. Conflicting evidence for HIV enrichment in CD32+ CD4 T cells. Nature. 2018 Sep;561(7723):E9-E16.
Boritz EA, Darko S, Swaszek L, Wolf G, Wells D, Wu X, Henry AR, Laboune F, Hu J, Ambrozak D, Hughes MS, Hoh R, Casazza JP, Vostal A, Bunis D, Nganou-Makamdop K, Lee JS, Migueles SA, Koup RA, Connors M, Moir S, Schacker T, Maldarelli F, Hughes SH, Deeks SG, and Douek DC. Multiple Origins of Virus Persistence during Natural Control of HIV Infection. Cell. 2016 Aug 11;166(4):1004-1015.
HIV Cure Transformative Science Group (TSG), AIDS Clinical Trials Group (ACTG)
NIAID SARS-CoV-2 Assessment of Viral Evolution (SAVE) Program
Delaney AIDS Research Enterprise (DARE)
Virology Working Group, Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC), Infectious Diseases Clinical Research Program (IDCRP), Uniformed Services University
NIAID Infectious Diseases Fellowship Program