This laboratory is pursuing three lines of investigation in the area of HIV-1 pathogenesis and prevention.

1. Viral genetic evolution. These studies have been undertaken on the premise that longitudinal analysis of the genetic evolution of HIV-1 will provide insights into host-virus interactions that cannot be readily determined by direct examination of host factors. HIV-1 replicates to high levels in infected hosts and is continuously mutating to adapt to the host environment, which is usually also changing in ways that do not favor viral replication (for example, by developing an immune response to the virus). Because the virus is a "moving target" for the immune system, it is difficult to know the relevance for the currently replicating virus of a given immune response that might be detected in an infected individual. For technical reasons it is very difficult to assay immune responses to the most recent viral mutant. On the other hand, phylogenetic analysis of viral evolution can tell us how the population of viruses that infect a given individual is being influenced by the host and how the virus is adapting to the host changes. These types of studies have revealed qualitative differences in the host-virus interaction between individuals with rapidly and slowly progressive disease and suggest strategies that might be employed for eradicating virus from infected individuals with greatly reduced viral loads.

2. Sexual transmission of HIV-1 using infected cells. A mouse model of vaginal transmission of HIV-1 using infected cells has been developed in our laboratory. No other model currently exists for examining the role of either HIV-1 or SIV infected cells by the sexual route, and transmission by infected cells is likely to be important mechanism of HIV-1 spread. This model system will permit us to examine different strategies that might be developed for interrupting this route of transmission.

3. Development of candidate HIV-1 vaccines. We are examining the immunogenicity and protective efficacy of synthesized virus-like particles containing pro-viral DNA encoding specific HIV genes and coated with polypeptides designed to mimic the potential envelope three dimensional structures that would result from the full range of mutations that could occur within a highly immunogenic region of the envelope gene.

Molecular Microbiology and Immunology HIV pathogenesis evolution SCID mouse microbicide vaccine

Templeton, A.R. R. A. Reichert, A. E. Weisstein, X.-F. Yu, and R. B. Markham. Selection in Context: Patterns of Natural Selection in the Evolution of the Glycoprotein 120 region of HIV-1 in Infected Individuals Followed Over Time. Genetics. 2004. In press.

Neuveut, C., R. M. Scoggins1, D. Camerini1, R. B. Markham, and K.-T. Jeang, Requirement for the second coding exon of Tat in the optimal replication of macrophage-tropic HIV. J. Biomed. Sci. 10(6 Pt 1): p. 651-60. 2003.

Khanna, K.V.,, K. J. Whaley, L. Zeitlin, T. R. Moench, K. Mehrazar, L. D. Shultz, R. A. Cone, Z. Liao, J. E. K. Hildreth, L. Shultz, T. Hoen, and R. B. Markham. Vaginal Transmission of Cell-Associated HIV-1 in the Mouse is Blocked by a Topical, Membrane-Modifying Agent. Journal of Clinical Investigation 109: 205-211. 2002.

Khanna, K.V., D. Ford, Z. Wang, J. Hildreth, L. Ratner, , X.-F. Yu. and R.B. Markham Differences among HIV-1 variants in their ability to elicit secretion of TNF-á. J. Immunol. 164:1408-1415, 2000.

Carneiro, M., C. Lyles, A. Templeton, A. E. Weisstein, M. Safaeian, H. Farzadegan, J. B. Margolick,, D. Vlahov, X.-F. Yu and R.B. Markham. The Effect of Drug Injection Behavior among HIV-1 Seroconverters on Viral Genetic Evolution. J. Infect. Dis. 180:1025-32, 1999.

Markham, R. B., W.-C. Wang, A. Weisstein, A. Munoz, Z. Wang,A. Templeton, D. Vlahov, J. B. Margolick, T. Quinn, H. Farzadegan, and X.-F. Yu. Patterns of HIV-1 evolution in individuals with differing rates of CD4 T cell decline. Proc. Natl. Acad. Sci. USA 95:12568-12573, 1998

Markham, R.B., D. Schwartz, A. Templeton, J. B. Margolick, H. Farzadegan, D. Vlahov, and X.F. Yu. Selective transmission of human immunodeficiency virus type 1 variants to SCID mice reconstituted with human peripheral blood mononuclear cells. J. Virol. 70:6947-6954, 1996.

Smith, S.M., R.B. Markham, and K.T. Jeang. A gain_of_function approach for controlled attenuation of virus: HIV_1 that expresses HSV_1 thymidine kinase. Proc. Natl. Acad. Sci. 93:7955-7960, 1996.

Markham, R.B., X_F Yu, H. Farzadegan, and D. Vlahov. Human immunodeficiency virus type 1 env and p17gag sequence variation in polymerase chain reaction positive, seronegative injection drug users. J. Infect. Dis. 171:797_804, 1995.

Markham, R.B., A.J. Ruff, J. Gomez, D. Hoover, J. Coberly, J. Desmormeaux, E. Holt, R. Boulos, and N.A. Halsey. Maternal IgG1 and IgA Antibody to V3 loop consensus sequence and maternal-infant HIV-1 transmission. Lancet. 343:390-391. 1994.

Tyor, W.R., C. Power, H. Gendelman, and R.B. Markham. A model of HIV encephalitis in SCID mice. Proc. Natl. Acad. Sci. 90:8658-8662. 1993.