Faculty Profile

Dr. Harris Goldstein, M.D.

Harris Goldstein, M.D.

Associate Dean for Scientific Resources

Professor, Department of Pediatrics (Pediatric Allergy & Immunology)

Professor, Department of Microbiology & Immunology

Charles Michael Chair in Autoimmune Diseases

Director, Einstein-Rockefeller-CUNY Center for AIDS Research

Areas of Research: HIV pathogenesis; TCR structure-function analysis; genetic programming of specific protective immune responses; genetic manipulation of transplanted beta cells to resist rejection

Professional Interests

Hacking the Immune System to Cure HIV Infection

Developing immunobiologics which deliver antigen-specific and co-stimulatory signals to focally activate HIV-specific CTLs. Our laboratory is utilizing novel molecular, cellular and biochemical approaches to “hack” the human immune system and amplify its activity to enable it to recognize and eliminate reactivated latent HIV-infected T cells (LHITC) and thereby achieve the functional cure of HIV-1 infection. Our lab is part of the NIH-funded Martin Delaney Collaboratory: Towards an HIV-1 Cure program established to fulfill President Barack Obama’s pledge to invest in HIV cure research. The goal of the Delaney program is to unite and synergize the research programs of highly talented investigators to accelerate the development of a safe and scalable cure for HIV. One novel approach we are pioneering is the application of new immune checkpoint modulating biologics, which stimulate the immune system to kill tumor cells and have revolutionized cancer treatment, to amplify the cytotoxic activity of HIV-specific CD8+ T cells and increase their capacity to eliminate HIV-infected cells. For this purpose, we are applying synTac (artificial immunological synapse for T-cell activation), a novel class of soluble precision-targeted immunomodulatory biologics developed by the Almo lab at Einstein. The synTac fusion proteins use a single MHC α and β2 microglobin chain containing a defined peptide (sc-pMHC) linked to a costimulatory or cytokine domain to integrate the specificity of antigen-receptor and potency of costimulatory and/or cytokine signaling (see Figure). Antigen specific T cell subpopulations are specifically activated by sc-pMHC binding to its cognate TCR which provides the primary activation signal as well as precisely delivering the costimulatory and/or cytokine signal by the linked costimulatory or cytokine domains. We have validated this approach for HIV by constructing synTac fusion proteins which target the HLA-A*0201-restricted HIV Gag epitope, SL9, linked to the costimulatory 4-1BBL molecule, SL9:4-1BBL-synTac. The SL9:4-1BBL-synTac specifically bound an SL9-specific CTL clone TCR and stimulated INF-γ and TNF-α secretion and cellular proliferation. We are extending those very promising results by developing synTac-based therapeutics linked to different costimulatory ligands and/or cytokines to identify the optimal costimulatory and cytokine signals required for the specific in vitro and in vivo activation and expansion of HIV-specific CD8+ T cells with the potential to eliminate reactivated LHITC.

Harnessing NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) as an in vivo treatment to eliminate primary latent HIV-Infected cells. Another novel strategy to cure HIV we are investigating and optimizing is amplifying NK cell cytotoxic function by treatment with various structurally enhanced cytokine constructs combined with targeting them to specifically kill reactivated latent HIV-1 infected cells by parallel treatment with molecularly engineered HIV-specific broadly neutralizing antibodies, bispecific antibodies and/or fusion proteins. We are also molecularly engineering the antigen specificity of CD8+ T cells to recognize HIV-specific epitopes and generate potent HIV-specific CD8+ cytotoxic T lymphocytes (CTLs) by transducing them with lentiviruses expressing the genes encoding the alpha and beta chain of TCRs derived from potent HIV-specific CD8+ CTLs. We are further amplifying the cytotoxic capacity of these molecularly engineered HIV-specific CTLs by evaluating which added anti-apoptotic genes or cytotoxic genes added to the TCR-expressing lentiviral vectors improved the their capacity to eliminate reactivated latent infected cells.

Utilizing humanized mice populated with latent HIV-infected T cells from patients to evaluate the efficacy of methods to cure HIV infection. Two major impediments prevent the testing of strategies to reduce HIV reservoirs and inhibit viral rebound after the cessation of antiretroviral therapy (ART): 1. The rarity of latent infected cells capable of producing infectious HIV-1; and 2. The difficulty in distinguishing latent infected cells from the majority of infected cells which contain integrated defective proviruses that cannot produce infectious virus. To evaluate the efficacy of immune system “hacking” strategies to deplete the HIV reservoir, we have established a novel humanized mouse model consisting of highly immunodeficient NSG mice intrasplenically injected with CD4+ memory T cells isolated from HIV-infected patients who are virally suppressed by ART treatment (viral loads <50 copies/ml) which include a population of latent HIV-infected cells. We demonstrated that the transplanted HIV reservoir was activated in vivo as reported for ART-suppressed individuals during treatment interruption. These mice developed high level of plasma viremia within 1 week after injection, which rose exponentially over the several weeks. We are using this mouse model to examine the effects of the aforementioned immune amplification strategies to reduce the HIV reservoir as indicated by elimination of viremia, temporal delay in the onset of the viremia and/or reduction in the amplitude of the viremia. We have also developed another humanized mouse model infectible with an infectious HIV expressing a luciferase reporter that enables us to serially visualize HIV infection in live mice by quantifying the intensity of the luciferase signal.

Investigating the pathogenesis of NeuroAIDS and role of illicit drug use in accelerating infection and neurological dysfunction. The mechanisms by which HIV infection and meth disrupt the blood-brain barrier (BBB), stimulate migration of HIV infected monocytes into the CNS and induce neuroinflammation and the impact of ART on these processes are not fully delineated. This is a highly significant area of research relevant to NIH high priority topics of HIV/AIDS research, understanding the basic biology of HIV pathogenesis causing immune dysfunction and chronic inflammation and addressing the impact of HIV-associated comorbidities including neurological complications. We are also using a novel transgenic mouse we developed, hu-CD4/R5/cT1 mice, which circumvents major entry and transcription blocks preventing murine HIV-1 infection by targeting transgenic expression of human CD4, CCR5 and cyclinT1 genes to CD4+ T cells and myeloid-committed cells. These mice develop disseminated HIV-1 infection after intravenous HIV-1 injection and local HIV-1 infection after intravaginal inoculation. We are utilizing these mice to evaluate the in vivo efficacy of novel HIV-1 vaccines. In addition, we are using these transgenic mice to evaluate the mechanisms by which co-infection facilitates HIV-1 acquisition and to determine the efficacy of different preventive therapies. By crossing the hu-CD4/R5/cT1 mice with another novel transgenic mouse line we developed, which expresses a full-length HIV provirus that produces infectious HIV, we are investigating the effect of drugs of abuse on disrupting the BBB and facilitating the entry of HIV-infected inflammatory cells into the brain and evaluating the capacity of antibodies to adhesion molecules to prevent the transmigration of HIV-infected inflammatory cells into the brain.

Selected Publications

Bardhi A, Wu Y, Chen W, Zhu Z, Zheng JH, Wong H, Jeng E, Jones J, Ochsenbauer C, Kappes JC, Dimitrov DS, Ying T, Goldstein H. Potent in vivo NK cell-mediated elimination of HIV-1-Infected cells mobilized by a gp120-bispecific and hexavalent broadly neutralizing fusion protein. J. Virology 2017: pii: JVI.00937-17. doi: 10.1128/JVI.00937-17. [Epub ahead of print].

Flerin NC, Chen H, Glover TD, Lamothe PA, Zheng JH, Fang JW, Ndhlovu ZM, Newell EW, Davis MM, Walker BD, Goldstein H. T-Cell Receptor (TCR) Clonotype-Specific Differences in Inhibitory Activity of HIV-1 Cytotoxic T-Cell Clones Is Not Mediated by TCR Alone. J. Virology 2017;91:e02412-16. doi: 10.1128/JVI.02412-16.

Thomas T, Seay K, Zheng JH, Zhang C, Ochsenbauer C, Kappes JC, Goldstein H. High-Throughput Humanized Mouse Models for Evaluation of HIV-1 Therapeutics and Pathogenesis. Methods Mol Biol. 2016;1354:221-35. doi: 10.1007/978-1-4939-3046-3_15

Seay K, Khajoueinejad N, Zheng JH, Kiser P, Ochsenbauer C, Kappes JC, Herold B, Goldstein H. The vaginal acquisition and dissemination of HIV-1 infection in a novel transgenic mouse model is facilitated by coinfection with HSV-2 and is inhibited by microbicide treatment. J. Virology 2015;89:9559-9570. doi: 10.1128/JVI.01326-15.

Seay K, Church C, Zheng JH, Deneroff K, Ochsenbauer C, Kappes JC, Liu B, Jeng EK, Wong HC, Goldstein H. In vivo activation of human NK Cells by treatment with an Interleukin-15 superagonist potently inhibits acute in vivo HIV-1 infection in humanized mice. J. Virology 2015;89:6264-6274. doi: 10.1128/JVI.00563-15.

Costantini LM, Irvin SC, Kennedy SC, Guo F, Goldstein H, Herold BC, Snapp EL. Engineering and exploitation of a fluorescent HIV-1 gp120 for live cell CD4 binding assays. Virology. 2015 476:240-248. doi: 10.1016/j.virol.2014.12.019.

Nixon B, Fakioglu E, Stefanidou M, Wang Y, Dutta M, Goldstein H, Herold BC. Genital herpes simplex virus type 2 infection in humanized HIV-transgenic mice triggers HIV shedding and is associated with greater neurological disease. J Infect Dis. 2014;209:510-22. doi: 10.1093/infdis/jit472.

Seay K, Qi X, Zheng JH, Zhang C, Chen K, Dutta M, Deneroff K, Ochsenbauer C, Kappes JC, Littman DR, Goldstein H. Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. PLoS ONE. 2013;8(5):e63537. doi: 10.1371/journal.pone.0063537.


More Information About Dr. Harris Goldstein

Einstein-Rockefeller-CUNY Center for AIDS Research

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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Forchheimer Building, Room 408
Bronx, NY 10461

Tel: 718.430.2156

Research Information

In the News

Can an Immune Strategy Used to Treat Cancer Also Wipe Out HIV Infections?

Harris Goldstein, M.D., describes his new research, in Science Translational Medicine, that uses genetically reprogrammed T cells to successfully fight HIV infection in mice. Dr. Goldstein is professor of pediatrics and of microbiology & immunology and director of the Einstein-Rockefeller-CUNY Center for AIDS Research.

NBC News quotes Dr. Harris Goldstein on the Trump Administration's new initiative to eliminate the HIV epidemic in the U.S.

More media coverage