Human Immunodeficiency Virus Type 1 Variants Resistant to First- and Second-Version Fusion Inhibitors and Cytopathic in Ex Vivo Human Lymphoid Tissue
- 15 June 2007
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 81 (12), 6563-6572
- https://doi.org/10.1128/jvi.02546-06
Abstract
Human immunodeficiency virus type 1 (HIV-1) fusion inhibitors blocking viral entry by binding the gp41 heptad repeat 1 (HR1) region offer great promise for antiretroviral therapy, and the first of these inhibitors, T20 (Fuzeon; enfuvirtide), is successfully used in the clinic. It has been reported previously that changes in the 3-amino-acid GIV motif at positions 36 to 38 of gp41 HR1 mediate resistance to T20 but usually not to second-version fusion inhibitors, such as T1249, which target an overlapping but distinct region in HR1 including a conserved hydrophobic pocket (HP). Based on the common lack of cross-resistance and the difficulty of selecting T1249-resistant HIV-1 variants, it has been suggested that the determinants of resistance to first- and second-version fusion inhibitors may be different. To further assess HIV-1 resistance to fusion inhibitors and to analyze where changes in HR1 are tolerated, we randomized 16 codons in the HR1 region, including those making contact with HR2 codons and/or encoding residues in the GIV motif and the HP. We found that changes only at positions 37I, 38V, and 40Q near the N terminus of HR1 were tolerated. The propagation of randomly gp41-mutated HIV-1 variants in the presence of T1249 allowed the effective selection of highly resistant forms, all containing changes in the IV residues. Overall, the extent of T1249 resistance was inversely correlated to viral fitness and cytopathicity. Notably, one HIV-1 mutant showing ∼10-fold-reduced susceptibility to T1249 inhibition replicated with wild type-like kinetics and caused substantial CD4 + -T-cell depletion in ex vivo-infected human lymphoid tissue in the presence and absence of an inhibitor. Taken together, our results show that the GIV motif also plays a key role in resistance to second-version fusion inhibitors and suggest that some resistant HIV-1 variants may be pathogenic in vivo.Keywords
This publication has 56 references indexed in Scilit:
- Update on HAART in HIVJournal of Hepatology, 2005
- Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: a case reportThe Lancet, 2005
- HIV Drug ResistanceNew England Journal of Medicine, 2004
- Novel Therapies Based on Mechanisms of HIV-1 Cell EntryNew England Journal of Medicine, 2003
- The Hydrophobic Pocket Contributes to the Structural Stability of the N-Terminal Coiled Coil of HIV gp41 but Is Not Required for Six-Helix Bundle FormationBiochemistry, 2003
- Genetic Evidence that Interhelical Packing Interactions in the gp41 Core Are Critical for Transition of the Human Immunodeficiency Virus Type 1 Envelope Glycoprotein to the Fusion-Active StateJournal of Virology, 2002
- Structure-Based Identification of Small Molecule Antiviral Compounds Targeted to the gp41 Core Structure of the Human Immunodeficiency Virus Type 1Journal of Medicinal Chemistry, 1999
- Experimental HIV Infection of Human Lymphoid Tissue: Correlation of CD4+T Cell Depletion and Virus Syncytium-Inducing/Non-Syncytium-Inducing Phenotype in Histocultures Inoculated with Laboratory Strains and Patient Isolates of HIV Type 1AIDS Research and Human Retroviruses, 1997
- Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection.Proceedings of the National Academy of Sciences, 1994
- A Synthetic Peptide from HIV-1 gp41 Is a Potent Inhibitor of Virus-Mediated Cell—Cell FusionAIDS Research and Human Retroviruses, 1993