Jason Hataye

National Institute of Allergy and Infectious Diseases

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Richard A. Koup

National Institute of Allergy and Infectious Diseases

Joseph P. Casazza

National Institute of Allergy and Infectious Diseases

Amarendra Pegu

National Institute of Allergy and Infectious Diseases

David R. Ambrozak

National Institutes of Health

John R. Mascola

National Institute of Allergy and Infectious Diseases

Gary J. Nabel

National Institutes of Health

John-Paul Todd

National Institutes of Health

Constantinos Petrovas

National Institute of Allergy and Infectious Diseases

Wanwisa Promsote

National Institutes of Health

Cassandra Almasri

National Institutes of Health

Cooperative Institutions

National Institutes of Health

National Institute of Allergy and Infectious Diseases

Institut de Recherche Vaccinale

Government of the United States of America

Frequentis (Germany)

Sanofi (United States)

Harvard University

Sunesis (United States)

National Cancer Institute

University of Washington

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Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies

Science Translational Medicine (2017)

Constantinos Petrovas Sara Ferrando‐Martínez Michael Y. Gerner Joseph P. Casazza Amarendra Pegu

LN inflammation in chronic HIV is associated with accumulation of follicular CD8 T cells that could be redirected to kill infected cells.

10.1126/scitranslmed.aag2285

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Citations (147)

Development of Serine Protease Inhibitors Displaying a Multicentered Short (<2.3 Å) Hydrogen Bond Binding Mode: Inhibitors of Urokinase-Type Plasminogen Activator and Factor Xa

Journal of Medicinal Chemistry (2001)

Erik Verner B.A. Katz Jeffrey R. Spencer Darin A. Allen Jason Hataye

Novel scaffolds that bind to serine proteases through a unique network of short hydrogen bonds to the catalytic Ser195 have been developed. The resulting potent serine protease inhibitors were designed from lead molecule 2-(2-hydroxyphenyl)1H-benzoimidazole-5-carboxamidine, 6b, which is known to display several modes of binding. For instance, 6b can recruit zinc and bind in a manner similar to that reported by bis(5-amidino-2-benzimidazolyl)methane (BABIM) (Nature 1998, 391, 608-612).(1) Alternatively, 6b can bind in the absence of zinc through a multicentered network of short (<2.3 A) hydrogen bonds. The lead structure was optimized in the zinc-independent binding mode toward a panel of six human serine proteases to yield optimized inhibitors such as 2-(3-bromo-2-hydroxy-5-methylphenyl)-1H-indole-5-carboxamidine, 22a, and 2-(2-hydroxybiphenyl-3-yl)-1H-indole-5-carboxamidine, 22f. Structure-activity relationships determined that, apart from the amidine function, an indole or benzimidazole and an ortho substituted phenol group were also essential components for optimal potency. The affinities (K(i)) of 22a and 22f, for example, bearing these groups ranged from 8 to 600 nM toward a panel of six human serine proteases. High-resolution crystal structures revealed that the binding mode of these molecules in several of the enzymes was identical to that of 6b and involved short (<2.3 A) hydrogen bonds among the inhibitor hydroxyl oxygen, Ser195, and a water molecule trapped in the oxyanion hole. In summation, novel and potent trypsin-like serine protease inhibitors possessing a unique mode of binding have been discovered.

Amidine

Oxyanion hole

Benzimidazole

Serine Proteinase Inhibitors

10.1021/jm0100638

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A scalable RNA RT-PCR based assay to quantify latency disruption in HIV-1 infected cells from patients on antiretroviral therapy (VIR1P.1001)

The Journal of Immunology (2014)

Jason Hataye Joseph P. Casazza David R. Ambrozak Eli Boritz Takuya Yamamoto

Abstract Antiretroviral therapy suppresses HIV-1 replication but virus persists in stable reservoirs. A facile way to quantify cells in such reservoirs is HIV DNA PCR, however most of these cells are unlikely to ever produce replication-competent virus. On the other hand, viral outgrowth assays provide virologic realism, but are resource intensive. Detection of RNA by RT-PCR provides some virologic realism while allowing for high throughput. We present a method in which flow cytometry purified CD4+ T cells from patients on antiretroviral therapy are placed in limiting dilution culture for 4 days. The cells are stimulated with antibodies to CD2, CD3, and CD28 and viral replication is inhibited with efavirenz. Viral RNA is purified from the culture media using a paramagnetic nanoparticle based method that is scalable for robotics. Real time quantitative RT-PCR is performed with an HIV gag primer and probe set. This assay detects as few as 47 copies of HIV RNA induced from a single cell from the ACH-2 cell line. Using resting memory CD4+ T cells from patients on antiretroviral therapy, the frequency of induced HIV RNA production varied from 1 in 40,000 cells to fewer than 1 in 1,000,000. There was no correlation between frequency of HIV RNA producing cells and frequency of proviral DNA. This assay represents a scalable method for quantifying the frequency of HIV producing cells from patients with viral suppression and for evaluating reservoir elimination strategies for such patients.

10.4049/jimmunol.192.supp.74.15

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Nuclear Export of Vpr Is Required for Efficient Replication of Human Immunodeficiency Virus Type 1 in Tissue Macrophages

Journal of Virology (2003)

Michael P. Sherman Carlos M. C. de Noronha L. Eckstein Jason Hataye Pamela Mundt

Retroviruses must gain access to the host cell nucleus for subsequent replication and viral propagation. Human immunodeficiency virus type 1 (HIV-1) and other primate lentiviruses are distinguished from the gammaretroviruses by their ability to infect nondividing cells such as macrophages, an important viral reservoir in vivo. Rather than requiring nuclear membrane breakdown during cell division, the HIV-1 preintegration complex (PIC) enters the nucleus by traversing the central aqueous channel of the limiting nuclear pore complex. The HIV-1 PIC contains three nucleophilic proteins, matrix, integrase, and Vpr, all of which have been implicated in nuclear targeting. The mechanism by which Vpr can display such nucleophilic properties and yet also be available for incorporation into virions assembling at the plasma membrane is unresolved. We recently characterized Vpr as a nucleocytoplasmic shuttling protein that contains two novel nuclear import signals and an exportin-1-dependent nuclear export signal (NES). We now demonstrate that mutation of this NES impairs the incorporation of Vpr into newly formed virions. Furthermore, we find that the Vpr NES is required for efficient HIV replication in tissue macrophages present in human spleens and tonsils. These findings underscore how the nucleocytoplasmic shuttling of Vpr not only contributes to nuclear import of the HIV-1 PIC but also enables Vpr to be present in the cytoplasm for incorporation into virions, leading to enhancement of viral spread within nondividing tissue macrophages.

Nuclear export signal

Nuclear pore

10.1128/jvi.77.13.7582-7589.2003

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Citations (43)

Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease

Bioorganic & Medicinal Chemistry Letters (2002)

David Sperandio Anthony R. Gangloff Joane Litvak Richard Goldsmith Jason Hataye

NS3

Protease inhibitor (pharmacology)

Serine Proteinase Inhibitors

10.1016/s0960-894x(02)00680-7

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Citations (40)

Tracking epitope-specific T cells

Nature Protocols (2009)

James Moon Hunghao Chu Jason Hataye Antonio J. Pagán Marion Pepper

Adoptive Cell Transfer

Streptamer

10.1038/nprot.2009.9

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Citations (278)

A trispecific Ab directed to HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections

Research Square (Research Square) (2022)

Wanwisa Promsote Ling Xu Jason Hataye Giulia Fabozzi Kylie March

Abstract The main barrier to HIV virus eradication is the presence of long-lived HIV-1 that persists in latent reservoirs. Current efforts have focused on HIV cure interventions that “shock and kill” virally infected cells to purge the latent pool. Latency reversing agents (LRAs) induce viral activation leading to immune cell recognition and clearance of latently-infected cells. Though several clinical trials with LRAs have demonstrated that activation of viral gene expression is possible in vivo , limited or no clearance of the reactivated cells has been observed. The identification of molecules that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represents an alternative promising approach. Here, we developed and evaluated a trispecific antibody that targets three independent proteins: (1) the HIV envelope, (2) the T cell antigen CD3, and (3) the co-stimulatory molecule CD28. For targeting HIV Env, we used the broadly reactive CD4-binding site monoclonal antibody (mAb), N6. We found that an antibody with all three specificities (N6/αCD3-αCD28), significantly increased antigen-specific T-cell activation and cytokine release in both CD4 + and CD8 + T cells. Co-culturing CD4 + T cells with autologous CD8 + T cells isolated from ART suppressed HIV + donors in the presence of N6/αCD3-αCD28, resulted in activation of latently-infected cells and enhancement of the cytolytic activity of CD8 + T cells to eliminate the cells expressing reactivated HIV. This trispecific antibody mediated CD4 + and CD8 + T-cell activation in non-human primates and was well tolerated in vivo , confirming its activity and safety in a relevant animal model. This HIV-directed antibody is therefore merits further development as a potential intervention for the eradication of latent HIV infection.

10.21203/rs.3.rs-1930540/v1

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Naïve and Memory CD4 ⁺ T Cell Survival Controlled by Clonal Abundance

Science (2006)

Jason Hataye James Moon Alexander Khoruts Cavan Reilly Marc K. Jenkins

Immunity to a plethora of microbes depends on a diverse repertoire of naïve lymphocytes and the production of long-lived memory cells. We present evidence here that low clonal abundance in a polyclonal repertoire favors the survival and activation of naïve CD4 + T cells as well as the survival of their memory cell progeny. The inverse relation between clonal frequency and survival suggests that intraclonal competition could help maintain an optimally diverse repertoire of T cells and an optimal environment for the generation of long-lived memory cells.

Polyclonal antibodies

10.1126/science.1124228

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Citations (350)

Sustained HIV release by single persisting CD4 + T cells during latency disruption

Journal of Virus Eradication (2015)

Jason Hataye Joseph P. Casazza David R. Ambrozak Eli Boritz Tatsuya Yamamoto

10.1016/s2055-6640(20)31300-5

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Citations (2)

Activation and lysis of human CD4 cells latently infected with HIV-1

Nature Communications (2015)

Amarendra Pegu Mangaiarkarasi Asokan Lan Wu Keyun Wang Jason Hataye

Abstract The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. Here we report an approach to reduce the viral reservoir by activating dormant viral gene expression and directing T lymphocytes to lyse previously latent, HIV-1-infected cells. An immunomodulatory protein was created that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. CD3 engagement by the protein can stimulate T-cell activation that induces proviral gene expression in latently infected T cells. It further stimulates CD8 T-cell effector function and redirects T cells to lyse these previously latent-infected cells through recognition of newly expressed Env. This immunomodulatory protein could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals.

10.1038/ncomms9447

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Citations (95)