During the past year we have obtained over 60 isolates of HIV-1 from over 40 patients, many of whom have been on prolonged therapy with AZT (3'- azido, 3'-deoxythymidine, zidovudine) for AIDS or advanced AIDS-related complex. We have also developed a plaque reduction assay in a CD4-HeLa cell line that permits reproducible quantitative assays of drug sensitivity of these isolates. Fifty percent inhibitory (ID50) values of 18 isolates from untreated individuals ranged between 0.01muM and 0.05muM. In contrast, most isolates from patients who had received AZT for 6 months or more exhibited decreased sensitivity characterized by changes in ID50 and ID95 values, with isolates from several patients (5/15) showing 100-fold increases in ID50. The latter isolates were also insensitive to the related compound, 3'-azido, 3'deoxyuridine (AZdU), but not to the other antiretroviral compounds, dideoxycytidine (ddC), didehydrodideoxythymidine (d4T), carbovir or foscarnet (PFA). With the documentation of this potentially important phenotype and with the availability of methods to make additional isolates from other patients and to assay reliably for drug sensitivity, a number of research objectives can be pursued. We plan:
Specific Aim 1 : To determine the mechanism of drug resistance.
Specific Aim 2 : To conduct genetic characterization of the resistance mutation(s).
Specific Aim 3 : To determine the mechanism by which phosphatidylAZT maintains its activity against AZT resistant isolates of HIV.
Specific Aim 4 : To determine the virulence and in vivo susceptibility to AZT of the sensitive/resistant isolates of HIV.
Specific Aim 5 : To determine the frequency of emergence of AZT resistant mutants at different stages of disease.
Specific Aim 6 : To determine the frequency of emergence of resistant isolates during therapy with drugs other than AZT.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI029164-01
Application #
3143920
Study Section
(ARR)
Project Start
1989-09-30
Project End
1994-07-31
Budget Start
1989-09-30
Budget End
1990-07-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Hightower, George K; Wong, Joseph K; Letendre, Scott L et al. (2012) Higher HIV-1 genetic diversity is associated with AIDS and neuropsychological impairment. Virology 433:498-505
Mehta, Sanjay R; Kosakovsky Pond, Sergei L; Young, Jason A et al. (2012) Associations between phylogenetic clustering and HLA profile among HIV-infected individuals in San Diego, California. J Infect Dis 205:1529-33
Pacold, Mary E; Pond, Sergei L Kosakovsky; Wagner, Gabriel A et al. (2012) Clinical, virologic, and immunologic correlates of HIV-1 intraclade B dual infection among men who have sex with men. AIDS 26:157-65
Ances, Beau; Vaida, Florin; Ellis, Ronald et al. (2011) Test-retest stability of calibrated BOLD-fMRI in HIV- and HIV+ subjects. Neuroimage 54:2156-62
Mehta, Sanjay R; Nguyen, Vu T; Osorio, Georgina et al. (2011) Evaluation of pooled rapid HIV antibody screening of patients admitted to a San Diego Hospital. J Virol Methods 174:94-8
Morris, Sheldon R; Little, Susan J; Cunningham, Terry et al. (2010) Evaluation of an HIV nucleic acid testing program with automated Internet and voicemail systems to deliver results. Ann Intern Med 152:778-85
May, Susanne; Gamst, Anthony; Haubrich, Richard et al. (2010) Pooled nucleic acid testing to identify antiretroviral treatment failure during HIV infection. J Acquir Immune Defic Syndr 53:194-201
Butler, David M; Delport, Wayne; Kosakovsky Pond, Sergei L et al. (2010) The origins of sexually transmitted HIV among men who have sex with men. Sci Transl Med 2:18re1
Ances, Beau M; Vaida, Florin; Yeh, Melinda J et al. (2010) HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. J Infect Dis 201:336-40
Hightower, George K; Letendre, Scott L; Cherner, Mariana et al. (2009) Select resistance-associated mutations in blood are associated with lower CSF viral loads and better neuropsychological performance. Virology 394:243-8

Showing the most recent 10 out of 139 publications