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Faculty Information

David N Levy, PHD

David N. Levy, PhD

Associate Professor
Basic Science and Craniofacial Biology
Room 921 Dental Center, 421 First Avenue
Phone: 212-998-9287
Fax: 212-995-3250


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 pioneered study of HIV-1 recombination, Vpr (1)(2), the development of widely utilized and distributed research tools, including reporter viruses and latently infected cell lines that enable direct single cell analysis of HIV replication, latency and pathogenesis. Currently, we combine in vitro, ex vivo and in vivo approaches to study viral dynamics and novel replication mechanisms (1)(2)(3) and regulatory pathways that we have discovered. I have been NIH R01 funded since 2004.

HIV suppression of the transcription factor Foxo1 in resting CD4+ T cells, the master regulator of T cell quiescence and homing: Although HIV replicates most efficiently in activated CD4+ T cells, during early infection resting CD4+ T cells constitute the majority of infected cells. Resting CD4+ T cells also comprise the most important latent reservoir, making HIV infection an incurable disease with the treatments that are currently available. HIV faces a series of challenges in order to replicate in resting CD4+ T cells. The low metabolic activity of these cells presents an obstacle that is partially met by the ability of HIV to increase their activation status. This is achieved through the combined effects of Env, Tat and Nef on cell signaling cascades, particularly PI3K/Akt. We recently reported that HIV-1 infection of resting CD4+ T cells results in the suppression of the activity of Foxo1, a transcription factor that regulates many processes in resting T cells, including maintenance of T cell quiescence, migration, survival and differentiation. We found that suppression of Foxo1 activity involves PI3K/Akt activation, and that Foxo1 suppression facilitates HIV-1 replication. HIV-1 suppression of Foxo1 down modulates CD62L (L-selectin), a cell surface receptor that is required for T cell migration in to lymph nodes. These findings have broad ramifications for how HIV replicates and causes disease. Foxo1 is implicated in several cancers and metabolic disorders, is a target for drug development, and we believe that the manipulation of Foxo1 by these approaches may have utility in treating HIV infection. We are actively investigating the molecular mechanism of HIV suppression of Foxo1, how this affects virus replication, and how intervention in the HIV/Foxo1 nexus may be therapeutically useful. These studies utilize a combined approach employing in vitro systems, as well as the humanized mouse model of HIV infection (in collaboration with Dr. Moriya Tsuji, Aaron Diamond AIDS Research Center), and analysis of acutely infected rhesus macaques (in collaboration with Dr. Elizabeth Connick, U. Colorado, Denver).

Two novel replication pathways utilizing unintegrated HIV genomes: As a member of the retrovirus family, HIV integrates its DNA into cells' chromosomal DNA. However, this integration process is prone to failure, and it has been known almost since the discovery of the virus that the great majority of HIV DNA remains in an unintegrated state within cells. This viral DNA (uDNA) has been considered a dead end waste product without relevance to the natural history of HIV. We have established that uDNA is competent as a template for de novo virus production through two mechanisms.

We recently demonstrated that when HIV infects a resting CD4+ T cell, uDNA is generated that can function as a template for de novo virus production. We demonstrated that uDNA establishes a stable reservoir of latent genomes in resting CD4+ T cells from which virus production can be recruited by T cell activation many weeks after infection. We are investigating the response of uDNA to agents (PKC agonists, histone deacetylase inhibitors, P-TEFb agonists, etc.) that are under investigation as potential curative therapies. We have found that inhibiting HIV-1 integration enhances the production of latently infected cells by shunting viral genomes to the less cytopathic unintegrated pathway of replication. Models of HIV latency which utilize direct infection of resting CD4+ cells must accommodate these findings, and we are investigating how uDNA contributes to these systems. We also reported that the HIV-1 Vpr protein must be delivered into infected cells at the time of infection in order for the unintegrated HIV DNA to be competent for viral expression. We are investigating the molecular pathways by which Vpr, a known transactivator and a chromatin-associated protein, enables gene expression from uDNA. These studies combine in vitro systems, a humanized mouse model of HIV infection (in collaboration with Dr. Moriya Tsuji, Aaron Diamond AIDS Research Center) as well as analysis of acutely infected rhesus macaques (in collaboration with Dr. Elizabeth Connick, U. Colorado, Denver).

In the second mechanism, when a uDNA genome is co-resident in a cell with an integrated provirus, the integrated provirus provides factors that complement the uDNA genome, enabling it to generate genomic RNA that is packaged into virions produced by the integrated provirus. This enables uDNA to enhance the number of replicating genomes that contribute to viral diversity and genetic recombination. Our studies of uDNA replication through co-infection is funded by a 5 year R01 grant from the National Institute of Allergy and Infectious Diseases at the NIH.

The influence of multiple infection and synaptic transmission on viral replication dynamics: HIV can transmit between cells via cell-free viral particles or through direct contact between cells resulting in the formation of virological synapses. While cell-free transmission generally delivers few or single virions into cells, synaptic transmission entails delivery of multiple virions. This multiple infection of cells has important implications for viral persistence, evolution and pathogenesis. Genetic recombination between divergent viruses contributes to HIV evolution, the emergence of drug resistance and immune escape. Additionally, during co-infection viruses can influence each other directly, increasing virus expression, decreasing latency and increasing cell death. Using a variety of cellular, molecular and immunological techniques, many of which are unique to my laboratory, we are examining each of these processes and their contributions to the replication and pathogenesis of HIV. In collaboration with Dr. Dominik Wodarz, University of California, Irvine, we are applying the knowledge gained from our laboratory experiments to the development of quantitative models of HIV replication and pathogenesis. We are funded for this work by a 4 year NIH/NIAID R01 grant.

Lab Personnel

  • Benjamin Trinite, Ph.D., Post Doctoral Fellow
  • Chi Chan, Ph.D, Post Doctoral Fellow
  • Caroline Lee, Lab Assistant
  • Akanksha Ananad, NYU Polytechnic student assistant

Current Funding

HIV-1 Replication without integration. NIH/NIAID R01 AI078783

Virus Dynamics and Multiple Infection of Cells: Computational and Experimental Analysis. NIH/NIAID/NIGMS R01 AI093998

Representative Publications

Complete listing available on the NYU Health Sciences Library site.

Search PubMed for articles.

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. J Theor Biol. 2014. ePub ahead of print.

Trinite, B., Chan, C. N., 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.

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. 2014. Aids Research and Human Retroviruses. In Press.

Wodarz, D., Chan, C.N., Trinite, B., Komarova, N.L., and D. N. Levy. (2014). On the laws of virus spread through cell populations. Journal of Virology. J Virol 88: 13240-13248.

Weiden, M., Hoshino, S., Kimura T., Li, Y., Levy, D. N., Burke, S. A., Borkowsky, W., Rom, W.N., and Y. Hoshino. Interferon-γ Induces Adenosine Deaminase acting on RNA-1 (ADAR1) to inhibit HIV-1 Replication in Human Macrophages. PLoS One. 9(10):e108476.

Trinite, 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. Journal of Virology. 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., Trinite, 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., D. N. Levy., B. K. Chen. (2011). Multiploid inheritance of HIV-1 during cell-to-cell infection. Journal of Virology, 85:7169-7176.

Wodarz, D. and D. N. Levy. (2010). 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.

Commentary on Gelderblom et al. in Retrovirology.

Wodarz, D. and D. N. Levy. (2007). HIV coinfection and viral evolution towards reduced replicative fitness: a requirement for 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.

Kutsch, O., Levy, D. N., Bates, P. J., Decker, J., Kosloff, B. R., Shaw, G. M., Priebe, W., and E. N. Benveniste. (2004). Bis-anthracycline antibiotics target HIV-1 tat transactivation. Antimicrob. Agents Chemother. 48:1652-1663.

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.

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. Beneveniste. (2003).
CD154-CD40 induced reactivation of latent HIV-1. Virology. 314:261-270.

Kutsch, O., Beneveniste, 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.

Agadjanyan, M. G., Trivedi, N. N., Kudchodkar, S., Bennet, M., Levine, W., Lin, A., Boyer, J., Levy, D., Ugen, K. E., Kim, J. J., and Weiner, D. B. (1997). An HIV type 2 DNA vaccine induces cross-reactive immune responses against HIV type 2 and SIV. AIDS Res. Hum. Retroviruses. 13:1561-1572.

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.