Individuals infected with HIV-1 display a wide range in rates of disease progression. Rare individuals show no evidence of disease even after more than ten years of infection. These long term nonprogressors (LTNP) generally exhibit extremely low levels of HIV-1 in the circulation and maintain normal numbers of CD4 T-cells. Our studies are intended to examine individual cases of long-term non-progressive HIV-1 infection in great detail. We propose to investigate the hypothesis that many LTNP are infected with attenuated viral strains with identifiable, uniform and persistent genetic defects. Subjects will include asymptomatic, untreated adults and adolescents who have had stable and normal CD4 T-cell counts for more than 10 years of HIV-1 infection and vertically infected children with normal CD4 T-cell counts after 5 or more years of infection. Virological studies will include measurement of viral load, and phenotypic characterization of primary viral isolates with assays of tropism, cytopathogenicity and replication kinetics. Long distance amplification of proviral DNA will be undertaken to generate infectious clones directly from cultured virus of non-progressors to use in full length sequence analyses. Primary isolates which replicate poorly will be analyzed to determine the genetic basis of the defects. For those LTNP from whom virus cannot be isolated, targeted sequence analyses and functional studies will be performed on accessory and envelope genes. The effects of accessory gene sequence defects, if uniformly present, will be further characterized in functional assays. Envelope sequences will be studied with chimeric reconstructions to measure properties of tropism, infectivity and cytopathogenicity. These studies will provide fundamental insight into the relative importance and functional roles of individual genes and gene regions in the natural setting of human HIV-1 infection. Overall, this information will be useful for the further development of attenuated HIV-l strains for vaccine trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039400-03
Application #
2672694
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1996-07-01
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pediatrics
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Pikora, Cheryl A; Wittish, Christine; Desrosiers, Ronald C (2006) p6gag of human and simian immunodeficiency viruses is tolerant to small in-frame deletions downstream of the late domain. Virology 346:479-89
Farrow, Melissa A; Somasundaran, Mohan; Zhang, Chengsheng et al. (2005) Nuclear localization of HIV type 1 Vif isolated from a long-term asymptomatic individual and potential role in virus attenuation. AIDS Res Hum Retroviruses 21:565-74
Hiebenthal-Millow, Kirsten; Greenough, Thomas C; Bretttler, Doreen B et al. (2003) Alterations in HIV-1 LTR promoter activity during AIDS progression. Virology 317:109-18
Schindler, Michael; Wurfl, Stephanie; Benaroch, Philippe et al. (2003) Down-modulation of mature major histocompatibility complex class II and up-regulation of invariant chain cell surface expression are well-conserved functions of human and simian immunodeficiency virus nef alleles. J Virol 77:10548-56
Haran, John P; Greenough, Thomas C; Luzuriaga, Katherine et al. (2002) Enhanced culture method for detection of replication-competent virus in peripheral blood mononuclear cells of HIV type 1-infected individuals. AIDS Res Hum Retroviruses 18:577-83
Newstein, M C; Desrosiers, R C (2001) Effects of reverse-transcriptase mutations M184V and E89G on simian immunodeficiency virus in Rhesus monkeys. J Infect Dis 184:1262-7
Forte, S E; Somasundaran, M; Sullivan, J L (2000) Attenuation of human immunodeficiency virus type 1 cytopathic effects by replacing a 424-bp region of envelope from a noncytopathic biological clone. AIDS Res Hum Retroviruses 16:125-37
Greenough, T C; Brettler, D B; Kirchhoff, F et al. (1999) Long-term nonprogressive infection with human immunodeficiency virus type 1 in a hemophilia cohort. J Infect Dis 180:1790-802
Kirchhoff, F; Easterbrook, P J; Douglas, N et al. (1999) Sequence variations in human immunodeficiency virus type 1 Nef are associated with different stages of disease. J Virol 73:5497-508
Kirchhoff, F; Greenough, T C; Hamacher, M et al. (1997) Activity of human immunodeficiency virus type 1 promoter/TAR regions and tat1 genes derived from individuals with different rates of disease progression. Virology 232:319-31