Specific Enfuvirtide‐Associated Mutational Pathways in HIV‐1 Gp41 Are Significantly Correlated With an Increase in CD4+ Cell Count, Despite Virological Failure
1Department of Experimental Medicine, University of “Tor Vergata” Rome, 2National Institute of Infectious Diseases (INMI) “L. Spallanzani”, Rome, 3Department of Pharmaco‐Biology, University of Calabria, Rende (CS), 4University of Catanzaro, 5Clinic of Infectious Diseases, University of Turin, Hospital “Amedeo di Savoia”, Turin, and 6SM Annunziata Hospital, Florence, Italy
Background.
Human immunodeficiency virus type 1 (HIV‐1) gp41 is a crucial determinant for HIV‐1 pathogenicity. We investigated the correlation of enfuvirtide (ENF)‐associated gp41 mutational clusters with viroimmunological parameters, as well as the potential underlying mechanisms.
Methods.A total of 172 gp41 sequences and clinical follow‐up data from 73 ENF‐treated patients were analyzed monthly, from baseline to week 48.
Results.There were 7 novel gp41 mutations positively associated with ENF treatment and correlated with classic ENF mutations. The ENF‐associated clusters 
and 
significantly correlated with an increase in CD4 cell count at week 48 ( an increase from baseline of 112 and 209 cells/μL, respectively), whereas 
significantly correlated with a decrease in CD4 cell count (−53 cells/μL), without a change in the level of viremia. Residues 38 and 18 are located complementarily to each other in the Rev‐responsive element, whereas analysis of molecular dynamics showed that the copresence of 
abolishes the interaction between residue 38 and 145 important for stabilization of the 6‐helix bundle. In contrast, T268A localizes in the gp41 calmodulin‐binding domain responsible for gp41‐induced CD4+ T lymphocyte apoptosis.
Conclusion.Specific gp41 mutational clusters associated with ENF treatment significantly correlate with increases in CD4+ cell count. Structural analysis suggests that this immunological gain is associated with mechanisms that act at both the protein level and the RNA level (even under conditions of virological failure). This result may help in the selection of patients who can benefit most from ENF treatment and represents a driving force for the design of the next generation of entry inhibitors.
Received 17 August 2007; accepted 16 November 2007; electronically published 15 April 2008.
Cited by
Online publication date: 1-Aug-2009.
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Online publication date: 1-Apr-2009.
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Online publication date: 1-Dec-2008.
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Online publication date: 1-Oct-2008.
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Presented in part: 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, California, 25–28 February, 2007 (abstract 621); XX Conference on Antiviral Research, Palm Spring, California, 29 April 29–3 May, 2007 (abstract 5); XVI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications, Barbados, 13–17 June, 2007 (abstract 104).
Potential conflicts of interest: none reported.
Financial support: Italian National Institute of Health; the Ministry of University and Scientific Research (grant ISS20G.16); Current and Finalized Research of the Italian Ministry of Health (grant PRIN2006067294_003); the European Community (grant QLK2‐CT‐2000‐00291 and the Descartes Prize [HPAW‐90001]). Computational work was supported by the LNF‐INFN AMICO project coordinated by Dr. Vitaliano Chiarella (Laboratori Nazionali di Frascati‐ Istituto Nazionale di Fisica Nucleare, Frascati, Rome, Italy).
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V. S. and S. A. contributed equally to the work.
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For the INMI‐Collaborative Group for Clinical Use of HIV Genotype Resistance Test. Members of the group are listed at the end of the text.