Greenberg ML, McDanal CB, Stanfield-Oakley SA, Jin L, Tremblay C, Sista P, Hirsch M, Matthews TJ; Conference on Retroviruses and Opportunistic Infections.
Program Abstr 8th Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 8th 2001 Chic Ill. 2001 Feb 4-8; 8: 184 (abstract no. 473).
Duke Univ Med Ctr, Durham, NC.
Background: The fusion inhibitors (FIs) T-20 and T-1249 are currently in Phase III and Phase I/II clinical trials, respectively. The mechanism of action of these FIs targets a structural transition in the viral envelope glycoprotein gp41 required for membrane fusion and virus entry. Genetic analysis of resistant virus isolates supports this mechanism. A recent report suggested that virus tropism and coreceptor preference modulate virus sensitivity to T-20 (J. Virol.74: 8358). To further test this possibility, a large number of primary isolates were characterized for FI sensitivity and coreceptor usage. Methods: Virus infectivity assays included infectious center assays in cMAGI cells, p24 levels in activated PBMCs, and a luciferase reporter gene assay for envelope-pseudotyped virus. Virus isolates were obtained from an ongoing T-20 clinical trial, T20-205 (111 isolates), an acute seroconvertor study (33 isolates), and from the NIAID Reagent Repository. Virus stocks were prepared in activated PBMCs. Isolates were typed for coreceptor phenotype using either (a) relative infectious titer in MAGI (expresses CXCR4 (X4)) versus cMAGI cells (expresses X4 and CCR5 (R5)), (b)SI/NSI phenotype in MT-2 cells, or (c)U87 cells expressing CD4 in conjunction with either CXCR4 or CCR5. In addition, cloned pseudotyped viruses containing genetically linked envelopes (from serial patient isolates) representing X4, R5, and dual-tropic viruses were evaluated. Results: The geometric mean IC50 concentrations for T-20 from the T20-205 clinical isolates were 14 ng/ml and 12 ng/ml for X4-tropic and R5-tropic isolates, respectively. Similar potencies were noted for viruses from the other cohorts, including paired NSI-SI isolates from patients whose viruses switched coreceptor phenotype. The T-1249 IC50 on average was about 4-fold lower than that of T- 20 but also displayed no differences between the X4 and R5 isolates. Three pseudotyped viruses containing full-length envelope clones from the same patient were equally sensitive to the FIs despite each clone exhibiting X4, R5 and dual X4/R5 phenotypes. Conclusion: Virus coreceptor usage does not modulate sensitivity to the FIs T20 and T1249.
Publication Types:
Keywords:
- AIDS Dementia Complex
- Acquired Immunodeficiency Syndrome
- Antigens, CD4
- CASP4 protein, human
- Caspases
- HIV Infections
- HIV-1
- Humans
- Receptors, CCR5
- Receptors, CXCR4
- Virus Diseases
- Viruses
- immunology
- therapy
Other ID:
UI: 102244256
From Meeting Abstracts