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Journal of Virology, June 2007, p. 6563-6572, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02546-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Variants Resistant to First- and Second-Version Fusion Inhibitors and Cytopathic in Ex Vivo Human Lymphoid Tissue{triangledown}

Raghavan Chinnadurai, Devi Rajan, Jan Münch, and Frank Kirchhoff*

Institute for Virology, University Clinic, Albert-Einstein-Allee 11, 89081 Ulm, Germany

Received 17 November 2006/ Accepted 30 March 2007

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.

* Corresponding author. Mailing address: Institute for Virology, University Clinic, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Phone: 49-731-500 65109. Fax: 49-731-500 65131. E-mail: frank.kirchhoff{at}uniklinik-ulm.de

{triangledown} Published ahead of print on 11 April 2007.

Journal of Virology, June 2007, p. 6563-6572, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02546-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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