This is a revised application by Dr. David Camerini from the University of Virginia to study the role of CCR5-tropic HIV-1 isolates in HIV pathogenesis. The applicant will use the SCID-hu mouse model bearing human thymus/liver grafts to study the pathogenic effects of these isolates. Previously characterized R5 HIV-1 isolates from patients during pre-AIDS and AIDS stages of HIV-1 infection will be evaluated for the molecular determinants and mechanisms of pathogenesis in SCID-hu model. The R5-pre AIDS HIV-I isolates are not cytopathic to thymocytes whereas R5-AIDs isolates cause depletion of thymocytes in the SCID-hu model.
The Specific aim 1 will be to map the regions of R5-AIDS which confer pathogenicity by developing recombinant infectious viruses. Initially, the focus will be on the envelope gene since it harbors molecular determinants for cell tropism and cytopathicity. The hypothesis to be tested is that changes in the env gene account for the increase in pathogenic potential of these isolates.
The Specific aim 2 will test the hypothesis that these genetic changes could lead to increased affinity to CCR5 and/or broadened co-receptor usage by the R5-AIDs isolates. The recombinant viruses will be tested for the receptor usage.
The Specific aim 3 will test the hypothesis that HIV-1 mediated signaling through CCR5 will allow infection of resting memory T cells and some thymocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI047729-01A1
Application #
6213536
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Plaeger, Susan F
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$306,600
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Olivieri, Kevin C; Scoggins, Robert M; Broderick, Brooks et al. (2008) Nef does not contribute to replication differences between R5 pre-AIDS and AIDS HIV-1 clones from patient ACH142. Retrovirology 5:42
Olivieri, Kevin; Scoggins, Robert M; Bor, Yeou-cherng et al. (2007) The envelope gene is a cytopathic determinant of CCR5 tropic HIV-1. Virology 358:23-38
Choudhary, Shailesh K; Walker, Russell M; Powell, Douglas M et al. (2006) CXCR4 tropic human immunodeficiency virus type 1 induces an apoptotic cascade in immature infected thymocytes that resembles thymocyte negative selection. Virology 352:268-84
Choudhary, Shailesh K; Choudhary, Neelima R; Kimbrell, Katherine C et al. (2005) R5 human immunodeficiency virus type 1 infection of fetal thymic organ culture induces cytokine and CCR5 expression. J Virol 79:458-71
Taylor Jr, J R; Kimbrell, K C; Scoggins, R et al. (2001) Expression and function of chemokine receptors on human thymocytes: implications for infection by human immunodeficiency virus type 1. J Virol 75:8752-60