The HIV-1 virus uses two primary coreceptors, CCR5 and CXCR4, in addition to CD4 to infect cells. CCR5 is the primary receptor for the transmissible, macrophage-tropic (M-tropic) variants while CXCR4 is used by the synctium-inducing (SI) variants capable of infecting T-cell lines (T- tropic). T-tropic variants emerge during the asymptomatic period of infection and are associated with more rapid disease progression and loss of CD4 T cells. The ligand for CXCR4, stromal derived factor-1 (SDF-1) has been shown to cause internalization of CXCR4, making the receptor unavailable for binding by HIV-1 variants using CXCR4 for cell entry and infection. Several studies have shown that SDF-1 is a powerful antiviral agent and blocks fusion by T- tropic/SI variants. Because of the obvious role of chemokine receptors and their ligands in HIV pathogenesis, we have screened for polymorphisms in the genes encoding both receptors and ligands using a panel of patients that are high risk, uninfected, rapid progressors to AIDS in less than 5 years, or long time survivors (no AIDS for more than 12 years). We have identified a mutation in the 3' untranslated region (UTR) of SDF-1beta cDNA that when homozygous, is highly protective against progression to AIDS and death in the first 10 years following infection. This SDF-1 variant may prevent the emergence of the more pathogenic T-tropic/SI strains that use CXCR4 as a coreceptor, thus delaying the onset of immunodeficiency and AIDS. Possible mechanisms for the function of the 3' UTR mutation are under investigation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010264-02
Application #
6101054
Study Section
Special Emphasis Panel (LGD)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code