Faculty Information

David N. Levy, PhD

Associate Professor
Molecular Pathobiology
Room 921 Dental Center, 421 First Avenue
Phone: 212-998-9287
Fax: 212-995-3250
E-mail: dnlevy@nyu.edu

Visit the Levy Lab website >>>
 

Education

PhD, Immunology, University of Pennsylvania, Philadelphia, PA 1994
BA, Biology, Williams College, Williamstown, MA 1985
 

Research Interests / Professional Overview

My laboratory studies the replication, pathogenesis and immunology of the human immunodeficiency virus (HIV). In prior years I have pioneered the study of HIV-1 infection of resting CD4 T cells, genetic recombination, latency, Vpr, expression from unintegrated HIV-1 genomes, and analysis of HIV-1 replication dynamics. HIV-1 replication in resting CD4 T cells, latency, Vpr and viral dynamics are current interlocking interests of my laboratory. Resting CD4 T cells represent early important targets of infection and they carry the largest known latent viral reservoir. Vpr, latency and unintegrated genomes all intersect with resting CD4 T cells in ways my laboratory is now uncovering.

Bringing these topics together is the epigenetic regulation of HIV-1 replication. Once the HIV-1 RNA genome is delivered into a cell, it undergoes conversion to a DNA copy by the process of reverse transcription. The viral DNA is then integrated into the cell’s nuclear DNA, thus enabling the virus to persist for the life span of the cell. In order for RNA transcription to occur, the viral DNA must be associated with nucleosomes, complexes of histone proteins that the DNA wraps. The study of HIV-1 gene expression and latency has focused extensively on understanding these nucleosomes and the post-translational modifications of their histones that regulate transcription. However, when and how nucleosomes are initially installed on the viral DNA, and which cellular and viral factors influence these early events is not well understood. My laboratory is studying these processes.

We have determined that the viral genome is associated with nucleosomes rapidly, contemporaneous with completion of reverse transcription and prior to integration (manuscript in preparation). This rapid chromatinization suggests an early target for development of anti-viral therapeutics. Several prior published studies from our laboratory have demonstrated that HIV-1 genomes which fail to integrate are capable of high-level gene expression in resting CD4 T cells and even de novo virus production. Our studies are now demonstrating that these genomes are epigenetically regulated similarly to integrated proviruses but nevertheless with important differences.

We have found that HIV-1 Vpr, a small 96 amino acid protein that is incorporated into virions and delivered into cells at the time of infection, influences the structure of HIV-1 chromatin. Vpr enhances the installation of favorable histones and of histone post-translational modifications that enable transcription. Without Vpr, fewer HIV-1 genomes are transcriptionally active and are either latent or transcriptionally unresponsive to stimulation. Vpr is required for gene expression from unintegrated genomes in resting T cells. Without Vpr, latent integrated genomes are less responsive to stimulation that normally activates transcription. Understanding how Vpr performs these functions and what the contribution of Vpr to the overall establishment of productive vs. latent infection is a prime focus of my laboratory. This work will soon be funded by a 5-year R01 grant from the NIH beginning in early 2019.

We are also studying the influence of HIV-1 transmission modalities to viral replication dynamics. This project is funded by the NSF through 2020. RNA viruses are characterized by a high mutation rate, allowing them to rapidly diversify and readily adapt to environmental challenges, which makes them a near-ideal model system to test evolutionary and selection theories that are difficult to approach in more complex organisms. Typically, virus genomes are considered as isolated entities, however, multiple infection (coinfection) of cells is a common occurrence. Coinfection results in a series of poorly understood social interactions, which have the power to shape evolutionary trajectories. For example, genetically divergent viruses of the same species can help or inhibit each other, and they can exchange genetic material. HIV-1 represents a highly tractable experimental system for this purpose. HIV-1 multiple infection is promoted by cell-to-cell contact and the formation of virological synapses, where multiple viruses are simultaneously transferred from one cell to another. In contrast, spread via the release of free virus particles promotes single infection. The relative occurrence of synaptic and free virus transmission, and hence infection multiplicity, can be manipulated in vitro through various means including viral mutants that are deficient in cell free infection and by physical interference with cell to cell contact. In collaboration with Dr. Dominik Wodarz, University of California, Irvine, we are performing a series of integrated experimental and mathematical analyses to tease apart these complex processes.

Laboratory Personnel

• Hongtao Zhang, PhD, Postdoctoral Fellow
• Josephine Garcia, Laboratory assistant

Current Funding

NIH/NIAID 1R01AI145753        02/01/2019 - 01/31/2024
Establishing HIV-1 chromatin in resting T cells
Role: PI

NIH/NIDA 1R61DA047011        08/15/2018 - 05/31/2023
Using Omics to Understand the Effects of Drug Abuse on HIV Latent Reservoir.
Role: Co-investigator

NSF/NIGMS 1662096               09/01/17-08/31/20
Collaborative Research: Infection Multiplicity and Virus Evolution, from Experiments to Large Scale Multi-Population Stochastic Computations.
PI: Komarova/Levy

 

Representative Publications

Complete listing available on the NYU Health Sciences Library site.

Search PubMed for articles.

Wodarz D, Levy DN, Komarova NL. (2018) Multiple infection of cells changes the dynamics of basic viral evolutionary processes. Evolution Letters In Press.

He S, Fu Y, Guo J, Spear M, Yang J, Trinité B, Qin C, Fu S, Jiang Y, Zhang Y, Zhang Z, Xu J, Dind H, Levy DN, Chen W, Petricoin III, E, Liotta LA, Shang H, Wu Y. (2018) Cofilin Hyperactivation in HIV Infection and Targeting the Cofilin Pathway Using an Anti-α4β7 Integrin Antibody. Science Translational Medicine In Press.

Wodarz D, Skinner, PJ, Levy DN, Connick E. (2018) Virus and CTL dynamics in the extra-follicular and follicular tissue compartments in SIV-infected macaques. PLOS Computational Biology In Press.

Chan CN, Trinité B, Levy DN. (2017) Potent inhibition of HIV-1 replication in resting CD4 T cells by resveratrol and pterostilbene. Antimicrobial Agents and Chemotherapy 61(9): e00408-17.

Wodarz D, Levy DN. (2017) Pyroptosis, superinfection, and the maintenance of the latent reservoir in HIV-1 infection. Nature Scientific Reports 7:3834-3843.

Miller SM, Miles B, Guo K, Folkvord J, Meditz AL, McCarter M, Levy DN, MaWhinney S, Santiago M, Connick E. (2017) Follicular regulatory T cells are highly permissive to R5-tropic HIV-1. J Virol 91(17): e00430-17.

Miles B, Miller SM, Folkvord JM, Levy DN, Rakasz EG, Skinner PJ, Connick E. (2016) Follicular Regulatory CD8 T Cells Impair the Germinal Center Response in SIV and Ex Vivo HIV Infection. PLoS Pathogens 12(10):e1005924.

Kohler SL, Pham MN, Folkvord JM, Arends T, Miller SM, Miles B, Meditz AL, McCarter M, Levy DN, Connick E. (2016) Germinal Center T Follicular Helper Cells Are Highly Permissive to HIV-1 and Alter Their Phenotype during Virus Replication. J Immunol 196(6):2711-22.

Chan CN, Trinité B, Lee CS, Mahajan S, Wodarz D, Bansal A, Sabbaj S, Goepfert PA,  Levy DN. (2016) HIV-1 latency and virus production from unintegrated genomes following direct infection of resting CD4 T cells. Retrovirology 13(1):1.

Trinité B, Chan CN, Lee CS, Levy DN. (2015). HIV-1 Vpr- and Reverse Transcription-Induced Apoptosis in Resting Peripheral Blood CD4 T Cells and Protection by Common Gamma-Chain Cytokines. J Virol 90(2):904-16.

DeMaster, L, Liu, X., VanBelzen, D., Trinité, B., Zheng, L., Agosto, L., Migueles, S., Connors, M., Sambucetti, L., Levy, D. N., Pasternak, A., and U. O'Doherty. (2015). A Subset of CD4/CD8 Double-Negative T Cells Expresses HIV Proteins in Patients on Antiretroviral Therapy. J. Virol. 90(5):2165-79.

Miles, B., Miller, S., Folkvord, J. M., Kimball, A., Chamanian, M., Meditz, A., Arends, T., McCarter, M. D., Levy, D. N., Rakasz, E. G., Skinner, P. J., and E. Connick. (2015). “Follicular regulatory T cells impair follicular T helper cells in HIV and SIV infection.” Nature Communications. 6:8608.

Galloway, N. L. K., Doitsh, G., Monroe, K. M., Yang, Z., Munoz-Arias, I., Levy, D. N., and W. C. Greene. (2015). Cell-to-cell transmission of HIV-1 is required to trigger pyroptotic death of lymphoid derived CD4 T cells. Cell Reports. 12:1-9.

Thierry, S., Munir, S., Thierry, E., Subra, F., Leh, H., Zamborlini, A., Saenz, D., Levy, D. N., Lesbats, P., Saib, A., Parissi, V., Poeschla, E., Deprez, E., Delelis, O. (2015). Integrase inhibitor reversal dynamics indicate unintegrated HIV-1 DNA initiate de novo integration. Retrovirology. 12:24.

Lau J. W., Levy D. N., Wodarz D. Contribution of HIV-1 genomes that do not integrate to the basic reproductive ratio of the virus. (2015). J Theor Biol. 367:222-229.

Haas, M. K., Levy, D. N., Folkvord, J. M., Connick, E. Distinct Patterns of Bcl-2 Expression Occur in R5- and X4-tropic HIV-1-Producing Lymphoid Tissue Cells Infected Ex vivo. (2015). AIDS Res Hum Retroviruses. 31:298-304.

Trinité, B., Chan, C. N., Lee, C. S., Mahajan, S., Luo, Y., Muesing, M. A., Folkvord, J. M., Pham, M., Connick, E. and D. N. Levy. (2014). Suppression of Foxo1 activity and down-modulation of CD62L (L-selectin) in HIV 1 infected resting CD4 T cells. PLoS One. 9(10):e110719.

Wodarz D., Chan C. N., Trinité B., Komarova N. L., and D. N. Levy. (2014). On the laws of virus Spread through cell populations. J. Virol. 88: 13240–13248.

Weiden, M. D., Hoshino, S., Levy, D. N., Li, Y., Kumar, R., Burke, S. A., Dawson, R., Hioe, C. E., Borkowsky, W., Rom, W. N., and Y. Hoshino. Adenosine Deaminase Acting on RNA-1 (ADAR1) Inhibits HIV-1 Replication in Human Alveolar Macrophages. (2014). PLoS One. 9(10): e108476.

Trinité, B., Ohlson, E.C., Voznesensky, I., Rana, S. P., Chan, C.N., Mahajan, S., Alster, J., Burke, S. A., Wodarz, D., and D. N. Levy. (2013). An HIV 1 replication pathway utilizing reverse transcript products that fail to integrate. J. Virol. 87:12701-20.

Komarova, N. L., Levy, D. N. and D. Wodarz. (2013). Synaptic transmission and the susceptibility of HIV infection to anti-viral drugs. Sci. Rep. 3:2103

Komarova, N. L., Anghelina, D., Voznesensky, I., Trinité, B., Levy, D. N. and D. Wodarz. (2013). Relative contribution of free virus and synaptic transmission to the spread of HIV through target cell populations. Biol. Letters. 9:20121049.

Komarova, N. L., Levy, D. N. and D. Wodarz. (2012). Effect of synaptic transmission on viral fitness in HIV infection. PLoS One. 7(11):e48361.

Cummings, K. W., Levy, D. N., D. Wodarz. (2012). Increased burst size in multiply infected cells alters basic infection dynamics. Biology Direct. 7:16.

Meditz, A. L., Haas, M. K., Folkvord, J. M., Melander, K., Young, R., McCarter, M., MaWhinney, S., Campbell, T., Weinberg, A., Coakley, E., Levy, D. N., E. Connick. (2011). HLA-DR+CD38+ T Lymphocytes Express High Levels of CCR5 and Produce the Majority of R5-tropic HIV-1 in Human Lymph Nodes. Journal of Virology. J Virol. 85:10189-200

Wodarz, D. and D. N. Levy. (2011). Effect of multiple infection of cells on the evolutionary dynamics of HIV in vivo: implications for host adaptation mechanisms. Experimental Biology and Medicine. 236: 926–937.

Del Portillo, A., Tripodi, J., Najfeld, V., Wodarz, D., Levy, D. N., B. K. Chen. (2011). Multiploid inheritance of HIV-1 during cell-to-cell infection. J. Virol. 85:7169–7176.

Wodarz, D. and D. N. Levy. (2011). Effect of different modes of viral spread on the dynamics of multiply infected cells in human immunodeficiency virus infection. Journal of the Royal Society Interface. 8:289-300.

Bansal, A., Carlson, J., Yan, J., Olusimidele, T. A., Schaefer, M., Sabbaj, S., Bet, A., Levy, D. N., Heath, S., Walker, B. D., Ndung'u, T., Goulder, P. J., Heckerman, D., Hunter, E., P. A. Goepfert. (2010). CTL response and evolutionary changes to HIV-1 cryptic epitopes derived from antisense transcription. J. Exp. Med. 207:51-59.

Hioe, C., Visciano, M. L., Kuman, R., Liu, J., Levy, D. N., Tuen, M. (2009). The use of immune complex vaccines to enhance antibody response against neutralizing epitopes on HIV-1 envelope gp120. Vaccine. 28:352-360.

Wodarz, D. and D. N. Levy. (2009). Multiple infection of cells and the evolutionary dynamics of cytotoxic T lymphocyte escape mutants. Evolution. 63:2326:2339.

Gelderblom, H. C., Vatakis, D., Burke, S. A., Lawrie, S., Bristol, G. A., D. N. Levy. (2008). Viral complementation allows HIV-1 replication without integration. Retrovirology. 5:60.
Accompanying commentary on article: Y. Wu. (2008). Retrovirology. 5:61.

Wodarz, D. and D. N. Levy. (2007). Human immunodeficiency virus evolution towards reduced replicative fitness in vivo and the development of AIDS. Proc. Royal Soc. B. 274:2481-2490.

Decker, J. M., Bibollet-Ruche, F., Wei, X., Wang, S., Levy, D. N., Derdeyn, C. A., Allen, S., Hunter, E., Saag, M. S., Hoxie, J., Hahn, B. H., Kwong, P. D., Robinson, J. E., and G. M. Shaw. (2005). Antigenic Conservation and Immunogenicity of the HIV Co-Receptor Binding Site. J. Exp. Med. 201:1407-1419.

Levy, D. N., Aldrovandi, G. M., Kutsch, O., and G. M. Shaw. (2004). Dynamics of HIV–1 recombination in its natural target cells. Proc. Natl. Acad. Sci. USA. 101:4204-4209.
Journal cover article.

Gao, F., Chen, Y., Levy, D. N., Conway, J. A., Kepler, T. B., and H. Hui. (2004). Unselected mutations in the human immunodeficiency virus type 1 genome are mostly non-synonymous and often deleterious. J. Virol. 78:2426-2433.

Kutsch, O., Levy, D. N., Kosloff, B. R., Shaw, G. M., and E. N. Benveniste. (2003). CD154-CD40 induced reactivation of latent HIV–1. Virology. 314:261-270.

Kutsch, O., Benveniste, E. N., Shaw, G. M., and D. N. Levy. (2002). Direct and quantitative single-cell analysis of human immunodeficiency virus type 1 reactivation from latency. J. Virol. 76:8776-8786.
Refaeli, Y., Levy, D. N., and Weiner, D. B. (1995). The glucocorticoid receptor type II complex is a target of the HIV-1 vpr gene product. Proc. Natl. Acad. Sci. USA. 92:321-3625.

Levy, D. N., Refaeli, Y., and Weiner, D. B. (1995). Extracellular vpr protein increases cellular permissiveness to human immunodeficiency virus type 1 replication and reactivates virus from latency. J. Virol. 69:1243-1252.

Levy, D. N., Refaeli, Y., and Weiner, D. B. (1994). Serum vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA. 91:10873-10877.

Levy, D. N., Fernandes, L. S., Williams, W. V., and Weiner, D. B. (1993). Induction of cell differentiation by human immunodeficiency virus 1 vpr. Cell. 72:541-550.
Journal cover article.

Book Chapters and Monographs

Levy, D. N., Refaeli, Y., and Weiner, D. B. (1995). The vpr regulatory gene of HIV. Transacting functions of human retroviruses; Current Topics in Microbiology and Immunology. Vol. 193. pp. 209-236. Springer-Verlag, Berlin. Chen, I.S.Y, Koprowski, H., Srinivasan, A, and Vogt. P.A., eds.

Levy, D. N. and Weiner, D. B. (1993). HIV-1 regulatory gene function analysis in a rhabdomyosarcoma cell line. pp. 243-249. Vaccines93, Modern Approaches to New Vaccines Including the Prevention of AIDS. Cold Spring Harbor Laboratory Press. Cold Spring Harbor, New York, N.Y.

Levy, D. N. and Weiner, D. B. (1993). Synthetic peptide-based vaccines and antiviral agents including HIV/AIDS as a model system. pp. 219-267. Biologically Active Peptides: Design, Synthesis, and Utilization. Williams, W.V. and Weiner, D.B., Eds. Technomic Publishing Company, Malvern, PA.