My laboratory studies the replication and immunology of the human immunodeficiency virus (HIV).
Two areas of particular interest are the interactions between virus strains as a result of multiple infection of cells and the contribution of unintegrated viruses to HIV replication, diversification and immunology.
Multiple infection and viral interactions. When a cell is infected with more than one virions, there are several consequences which can be of benefit or harm to the virus and the host. Firstly, genetic recombination between divergent viruses contributes to HIV evolution, the emergence of drug resistance and immune escape. Secondly, the viruses can influence each other directly, increasing virus expression, decreasing latency and increasing cell death. Thirdly, the presentation of viral antigens to the immune system can be altered. Using a variety of cellular, molecular and immunological techniques, many of which are unique to my laboratory, we are studying each of these processes and their contributions to the replication and pathogenesis of HIV.
Unintegrated HIV. As member of the retrovirus family of viruses, HIV must integrate its DNA into the DNA of the cells which it infects. However, this process is prone to failure, resulting in the great majority of HIV DNA, up to 99%, remaining in an unintegrated state within cells, called uDNA. We have defined a novel pathway for HIV replication which involves uDNA and which promotes virus evolution, persistence and disease. This work is funded by a 5 year $1.9 million grant from the National Institute of Allergy and Infectious Diseases at the NIH. Gene expression from uDNA sensitizes cells to elimination by the immune system, and in collaboration with researchers at the University of Alabama at Birmingham, we are examining how cytotoxic T cells (CTL) recognize and kill cells containing uDNA.
Modeling HIV replication. 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, pathogenesis and immunology.
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.
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 Levy, D. N. (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.
Book Chapters:
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.
