Irini Sereti, M.D., Ph.D.

Section or Unit Name
Clinical and Molecular Retrovirology Section
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Section/Unit: Year Established
Section/Unit: Location
NIH Main Campus, Bethesda, MD
This Researcher/Clinician’s Person Page
Irini Sereti, M.D., Ph.D.
Parent Lab/Program
Laboratory of Immunoregulation
Program Description

The early work of the Clinical and Molecular Retrovirology Section involved studies aimed at dissecting the normal immunoregulatory mechanisms that control the human immune response to specific antigen challenges. When the AIDS epidemic emerged, H. Clifford Lane, M.D., became one of the first investigators to study immunopathogenic mechanisms of HIV disease, ultimately making seminal observations that helped establish the field of HIV immunopathogenesis.

The laboratory has used investigational therapeutic interventions to further the understanding of HIV pathogenesis and pioneered the strategies of immunologically compatible bone marrow transplantation and the adoptive transfer of lymphocytes. The lab has also examined the roles of cytokines in treating patients with HIV infection.

Selected Publications

Polizzotto, M., Nordwall, J., Babiker, A.G., Phillips, A., Vock, D.M., Eriobu, N., Khwaghe, V., Paredes, R.,Mateu, L.,Ramachandruni, S., [76 others], Lane, H.C (2022).  Hyperimmune Immunoglobulin for Hospitalized Patients With COVID-19.  The Lancet 399:530-540, 2022.

Higgs ES, Gayedyu-Dennis D, Fischer Ii WA, Nason M, Reilly C, Beavogui AH, Aboulhab J, Nordwall J, Lobbo P, Wachekwa I, Cao H, Cihlar T, Hensley L, Lane HC. PREVAIL IV: A Randomized, Double-Blind, 2-Phase, Phase 2 Trial of Remdesivir vs Placebo for Reduction of Ebola Virus RNA in the Semen of Male Survivors. Clin Infect Dis. 2021 Nov 16;73(10):1849-1856.

Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826.

Imamichi H, Smith M, Adelsberger JW, Izumi T, Scrimieri F, Sherman BT, Rehm CA, Imamichi T, Pau A, Catalfamo M, Fauci AS, Lane HC. Defective HIV-1 proviruses produce viral proteins. Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3704-3710.

Mulangu S, Dodd LE, Davey RT Jr, Tshiani Mbaya O, Proschan M, Mukadi D, Lusakibanza Manzo M, Nzolo D, Tshomba Oloma A, Ibanda A, Ali R, Coulibaly S, Levine AC, Grais R, Diaz J, Lane HC, Muyembe-Tamfum JJ; PALM Writing Group, Sivahera B, Camara M, Kojan R, Walker R, Dighero-Kemp B, Cao H, Mukumbayi P, Mbala-Kingebeni P, Ahuka S, Albert S, Bonnett T, Crozier I, Duvenhage M, Proffitt C, Teitelbaum M, Moench T, Aboulhab J, Barrett K, Cahill K, Cone K, Eckes R, Hensley L, Herpin B, Higgs E, Ledgerwood J, Pierson J, Smolskis M, Sow Y, Tierney J, Sivapalasingam S, Holman W, Gettinger N, Vallée D, Nordwall J; PALM Consortium Study Team. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019 Dec 12;381(24):2293-2303.

Di Mascio M, Srinivasula S, Kim I, Duralde G, St Claire A, DeGrange P, St Claire M, Reimann KA, Gabriel EE, Carrasquillo J, Reba RC, Paik C, Lane HC. Total body CD4+ T cell dynamics in treated and untreated SIV infection revealed by in vivo imaging. JCI Insight. 2018 Jul 12;3(13):e97880.

Visit PubMed for a complete publication listing.

Additional Information

Research Group

  • Michael Sneller – Medical Officer
  • Hiromi Imamichi– Staff Scientist
  • Marta Catalfamo – Guest Researcher
  • Vishakha Thaker– Biologist
  • Mindy Smith – Biologist
  • Hui Chen – Visiting Fellow
  • Bruktawit Goshu – Post Bac IRTA
  • Tracey Zhai – Post Bac IRTA
  • Cecile Le Saout – Special Volunteer
  • Francesca Scrimieri - Special Volunteer
  • Steven Zeichner – Special Volunteer

Affiliations 

INSIGHT (global), INA-RESPOND (Indonesia), La RED (Mexico), PREVAIL (Liberia), UCRC (Mali), PREGUI (Guinea), PALM (DRC)

Training Programs

Patents

  • Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 6,548,055. 15 Apr 2003.
  • Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 6,190,656. 20 Feb 2001.
  • Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 5,696,079. 9 Dec 1997.
  • Lane HC, Kovacs JA, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 5,419,900. 30 May 1995.

Visit the U.S. Patent and Trademark Office for a complete patent listing.

Major Areas of Research
  • Pathogenesis of HIV infection emphasizing mechanisms of immunodeficiency
  • Immunologic approaches to therapy for HIV infection
  • Emerging Infectious Diseases (COVID-19; Ebola)

Irini Sereti, M.D., Ph.D.

Section or Unit Name
Immunopathogenesis Section
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This Researcher/Clinician’s Person Page
Irini Sereti, M.D., Ph.D.
Parent Lab/Program
Laboratory of Immunoregulation
Program Description

The Immunopathogenesis Section investigates the cellular and molecular mechanisms underlying the immune dysfunction caused by HIV infection. Several major projects ongoing in the section are described below.

Role of HIV envelope-target cell interactions in the pathogenesis of HIV infection (Lead Investigators: James Arthos, Ph.D., and Claudia Cicala, Ph.D.)

The primary aim of this project is to better understand the role of the HIV envelope protein in HIV pathogenesis. To that end, we have focused on the complex interplay between the viral envelope and several of the known cell surface receptors to which it binds (CD4, CCR5, CXCR4, integrin α4β7). Understanding the complexities and significance of the signaling processes that gp120 mediates will enhance our understanding of HIV-1 pathogenesis and may facilitate the discovery of new strategies for the treatment and prevention of HIV-1 disease. The finding that gp120 engages integrin α4β7, the gut-homing receptor, opens up many new and potentially important questions. Because α4β7 mediates leukocyte homing to gut-associated lymphoid tissue (GALT), which is a principal site of HIV replication during the acute phase of infection, we explored the role of α4β7-expressing CD4+ T cells in HIV transmission. We previously determined that human α4β7high CD4+ T cells are highly susceptible in vitro to productive infection by HIV, in part because α4β7high CD4+ T cells are enriched with metabolically active cells. We then tested this hypothesis in a non-human primate in vivo model of HIV/SIV infection and determined that an antibody specific for α4β7 prevented transmission in a rhesus macaque model of mucosal transmission. In addition, we have investigated the interaction between HIV and α4β7 on primary B cells. We have learned that some of the defects associated with HIV disease result from direct interactions between gp120 and receptors on B cells. These findings have relevance to our understanding of early HIV transmission and viral dissemination, particularly in GALT, providing new avenues of investigation regarding the potential role of α4β7+ as a therapeutic target against HIV infection.

Major Findings

  • HIV-1 envelope binds to, and signals through α4β7 integrin, the gut mucosal homing receptor for peripheral T cells.
  • The HIV envelope protein gp120 binds to a conformationally active form of α4β7 on CD4+ T cells. This binding is independent of the binding of envelope to the CD4 molecule. Because the function of α4β7 is intimately linked to GALT, where HIV replicates at high levels especially in acute/early infection, the specific affinity observed suggests that envelope-α α4β7 interactions play an important role in HIV pathogenesis.
  • α4β7high CD4+ T cells are more susceptible to productive infection by HIV than are α4β7low/neg CD4+ T cells, in part because this cellular subset is enriched with metabolically active cells.
  • Removal of N-linked glycosylation sites in HIV envelopes results in large increases in the specific affinity of gp120 for α4β7. Several envelopes derived from viruses isolated shortly after transmission react with α4β7 to a substantially higher level than do the great majority of envelopes derived from viruses isolated in the chronic phase of infection. These results suggest that mucosal transmission may frequently involve a relative requirement for the productive infection of α4β7+ CD4+ T cells.
  • Targeting α4β7 significantly reduces intravaginal mucosal transmission and subsequent tissue dissemination of SIV in a non-human primate model of HIV/AIDS. This supports our hypothesis that α4β7+/CD4+ T cells can play an important role in mucosal transmission of HIV.
Selected Publications

Fauci AS, Marston HD. Ending the HIV-AIDS Pandemic--Follow the Science. N Engl J Med. 2015 Dec 3;373(23):2197-9.

Fauci AS, Marston HD. Toward an HIV vaccine: A scientific journey. Science. 2015 Jul 24;349(6246):386-7.

Chun TW, Moir S, Fauci AS. HIV reservoirs as obstacles and opportunities for an HIV cure. Nat Immunol. 2015 Jun;16(6):584-9.

Kardava L, Moir S, Shah N, Wang W, Ho J, Wilson R, Buckner CM, Santich BH, Kim LJY, Spurlin EE, Nelson AK, Wheatley AK, Harvey CJ, McDermott AB, Wucherpfennig KW, Chun TW, Tsang JS, Li Y, Fauci AS. Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals. J Clin Invest. 2014 Aug;124(8):3352-63.

Byrareddy SN, Kallam B, Arthos J, Cicala C, Nawaz F, Hiatt J, Kersh EN, McNicholl JM, Hanson D, Reimann KA, Brameier M, Walter L, Rogers K, Mayne AE, Dunbar P, Villinger T, Little D, Parslow TG, Santangelo PJ, Villinger F, Fauci AS, Ansari AA.Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection. Nat Med. 2014 Dec;20(12):1397-400.

Jelicic K, Cimbro R, Nawaz F, Huang da W, Zheng X, Yang J, Lempicki RA, Pascuccio M, Van Ryk D, Schwing C, Hiatt J, Okwara N, Wei D, Roby G, David A, Hwang IY, Kehrl JH, Arthos J, Cicala C, Fauci AS. The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression. Nat Immunol. 2013 Dec;14(12):1256-65.

Visit PubMed for a complete publication listing.

Additional Information

Patents

Arthos J, Good D, Cicala C, Fauci AS, inventors; The United States of America, as represented by the Secretary, Department of Health and Human Services, assignee. Use of antagonists of the interaction between HIV GP120 and A4B7 integrin. United States patent US 9,193,790. 2015 Nov 24.

Arthos J, Cicala C, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Fusion protein including of CD4. United States patent US 7,368,114. 2008 May 6.

Scala G, Chen X, Cohen OJ, Fauci AS, inventors; The United States of America as represented by the Secretary of the Department of Health and Human Services, assignee. HIV related peptides. United States patent US 6,911,527. 2005 Jun 28.

Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 6,548,055. 2003 Apr 15.

Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 6,190,656. 2001 Feb 20.

Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 5,696,079. 1997 Dec 9.

Visit the U.S. Patent and Trademark Office for a complete patent listing.

Major Areas of Research
  • Role of HIV envelope signaling in viral replication and immune dysfunction
  • Novel approaches to the inhibition of HIV binding and entry into CD4+ T cells

H5N1 Milk Detection Study

The purpose of this study is to determine whether drinking pasteurized milk (milk heated to kill harmful germs) that contains inactive particles of a flu virus called A(H5) could lead to the detection of the virus in the nose or throat.

Contact Information

Office/Contact: Daniel Graciaa, MD, MPH, MSc
Phone: 404-712-1370
Email: dsgraci@emory.edu
 

A Study to Evaluate the Safety and Immunogenicity of Two Doses of a Novel H5 Central Antigen mRNA-LNP in Healthy Adults

The primary objective of this study is to assess the safety of two doses of H5 AC-Anhui RNA vaccine or H5-Astrakhan RNA vaccine administered intramuscularly in healthy adults (18-49 years).

Safety and Immunogenicity of Stabilized CH505 TF chTrimer Vaccination in Adults Living With HIV-1 on Suppressive Antiretroviral Therapy

The objective of this study is to assess the safety, tolerability, and immunogenicity of a vaccination with stabilized CH505 TF chTrimer admixed with 3M-052-AF + Aluminum hydroxide (Alum), to assess the effect of CH505 TF chTrimer vaccine as a therapeutic vaccine in adults living with HIV-1 on suppressive antiretroviral therapy (ART) with the aim of inducing new HIV-1 Envelope (Env) B-cell neutralizing immune responses.

Contact Information

Office/Contact: Aleen Khodabakhshian
Phone: 310-557-3798
Email: akhodabakhshian@mednet.ucla.edu
 

First-in-Human PfSPZ-LARC2 Vaccination/CHMI

The primary objective of this study is to assess the tolerability and safety of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation.

Phase 1 Study on Bioavailability, Food Effect, and Drug-Drug Interaction of ALG-097558 Tablets in Healthy Volunteers

The aim of this multi-part Phase 1 study is to evaluate the drug-drug interaction (DDI) potential of ALG-097558 via co-administration with a P-gp substrate (dabigatran) and a CYP3A4 inhibitor/P-gp inhibitor (itraconazole).

Master Protocol for Evaluating Multiple Infection Diagnostics for Ciprofloxacin-Resistant Neisseria Gonorrhoeae

The goal of this study is to learn if a few investigational tests can correctly find the gene mutation (mutant allele gyrA 91F) that predicts ciprofloxacin resistance in clinical specimens that harbor Neisseria gonorrhoeae.

Contact Information

Office/Contact: Lina Castro, PHM, MPH, M(ASCP)CM, TS (ABB)
Phone: 415-554-2800
Email: lina.castro@sfdph.org
 

Using the NIAID Data Ecosystem Discovery Portal to Search Across Data Repositories

Data Science Dispatch |

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NIAID has developed a platform to help researchers find data related to infectious and immune-mediated disease (IID) across multiple data repositories. The NIAID Data Ecosystem Discovery Portal is a centralized hub cataloging millions of datasets from over 50 sources.

Researchers can use the Discovery Portal to find data, resources, and computational tools from different repositories. This can save them time otherwise spent combing through multiple sources and help them find datasets they weren’t aware of previously.

The Discovery Portal includes resources from IID and generalist repositories. Representative resources include NIAID-sponsored repositories such as AccessClinicalData@NIAID, ImmPort, and VDJServer, as well as repositories funded outside of NIAID but relevant to IID research. Resources in the Discovery Portal include a diverse array of data types spanning multiple domains of IID research, including -omics data, clinical data, epidemiological data, pathogen-host interaction data, flow cytometry, imaging, and other experimental data.

The Discovery Portal supports NIAID objectives of maximizing the impact of scientific data, reducing duplication of efforts in research, and promoting data reuse, data transparency and compliance with data-sharing policies. The portal aligns with many of the principles of findable, accessible, interoperable, and reusable (FAIR) data practices by making data easier to find and access.

Using metadata to drive discovery

The NIAID Data Ecosystem Discovery Portal does not contain data itself. Instead, it contains detailed information about IID datasets and resources drawn from metadata. Users can then access the resources through external links.

The portal uses metadata to support several key features:

  • Search and Discovery: Users can rapidly search millions of datasets across both IID and generalist repositories using the Search or Advanced Search options. Metadata categories such as funding source, repository, and conditions of access help filter search results and identify relevant research data.
  • Metadata Compatibility: Each individual dataset in the Discovery Portal has a “metadata compatibility score,” which displays specific metadata elements collected for a given resource.  Additionally, the Discovery Portal has metadata compatibility visualizations which capture the breadth of metadata at the repository level. This information can help researchers and data contributors quickly understand a repository’s metadata structure, aiding in decisions about where to deposit or retrieve resources.
  • Downloadable Metadata: The portal has buttons that allow users to download metadata to perform meta-analyses.

The Discovery Portal is working to fill missing or incomplete metadata fields (such as Pathogen Species, Health Condition, and Host Species) by augmenting and standardizing metadata fields to provide more of this necessary information for users.

New Program Collection tool and other features

One of the new features of the NIAID Data Ecosystem Discovery Portal is the “Program Collection” filter. These are groups of datasets contributed by specialized NIAID research programs and initiatives. The Discovery Portal displays the Program Collection filter on the search page, and current efforts are focused on expanding Program Collection data.

The Program Collection filter allows researchers to discover high-quality, program-specific data relevant to their area of interest and find collections that align with the broader objectives of NIAID’s strategic research efforts. The feature also amplifies the scientific contributions of participating networks and increases the likelihood of researchers using these datasets. 

Using the Sources page of the Discovery Portal can also help researchers and data providers make informed decisions about different repositories where they can deposit their data.

The Discovery Portal is now connected to National Center for Biotechnology Information (NCBI) databases through NCBI LinkOut. When NCBI database content is linked to data described in the Portal, a link to the related Portal entry can be found on the NCBI page.

Learn more by visiting the Discovery Portal, reviewing the Getting Started page, and exploring the Knowledge Center. 

Preclinical Models of Infectious Disease Microphysiological Systems (MPS)

NIAID provides preclinical services using human cell-based MPS and organoids to test promising therapeutic candidates that combat viruses of biodefense (pandemic) concern.
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