Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment.

OBJECTIVES To investigate gp41 variability and correlation with viro-immunological parameters in 54 HIV-1-infected patients receiving enfuvirtide added as single active drug to a failing regimen. METHODS One hundred and two HIV-1 gp41 sequences and clinical follow-up from 54 enfuvirtide-treated patients were analysed from baseline to week 36 of treatment. The association of mutations with viraemia/CD4 count was assessed by Mann-Whitney test. RESULTS The addition of enfuvirtide to the failing regimen induced at week 4 a viraemia decrease from 5.1 to 4.3 log(10)/mL (P = 0.0002) and a CD4 increase from 48 to 106 cells/mm(3) (P = 0.008). While viraemia rebounded to 4.8 and 4.6 log(10)/mL at week 12 and 36, respectively, CD4 continued to increase to 136 cells/mm(3) at week 36. Enfuvirtide resistance mutations, rarely found at baseline, occurred in 45/54 (83.3%) enfuvirtide-treated patients. V38A/E were the most represented mutations at all time-points. The presence of V38A/E was significantly associated with a 4.5-fold CD4 increase from baseline to week 24 and with a 6-fold increase at week 36 (P = 0.004 and 0.02 compared without V38A/E, respectively), without significant correlation with viraemia. In contrast, Q40H + L45M (present in six enfuvirtide-treated patients at week 36) correlated with CD4 loss from baseline to week 36 (P = 0.02), without significant correlation with viraemia. Mutation N126K (observed in six enfuvirtide-treated patients, never found at baseline) abrogates the fourth gp41 glycosylation site and correlates with a 2.1-fold CD4 increase at week 24. CONCLUSIONS Specific enfuvirtide resistance mutations (V38A/E) are associated with a sustained CD4 increase, without remarkable effects upon viraemia. This CD4 recovery, due to virus- and immune-mediated mechanisms most probably not applicable to protease/reverse transcriptase inhibitors, is important for innovative therapeutic strategies.

[1]  Cassandra B. Jabara,et al.  Enfuvirtide Resistance Mutations: Impact on Human Immunodeficiency Virus Envelope Function, Entry Inhibitor Sensitivity, and Virus Neutralization , 2005, Journal of Virology.

[2]  D. Pillay,et al.  Emergence and Evolution of Enfuvirtide Resistance following Long-Term Therapy Involves Heptad Repeat 2 Mutations within gp41 , 2005, Antimicrobial Agents and Chemotherapy.

[3]  P. Narciso,et al.  Variable prediction of antiretroviral treatment outcome by different systems for interpreting genotypic human immunodeficiency virus type 1 drug resistance. , 2003, The Journal of infectious diseases.

[4]  J. Sodroski,et al.  The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. , 1998, Science.

[5]  R. Lal,et al.  Resistance mutation in HIV entry inhibitors , 2002 .

[6]  Li Xu,et al.  Minimal variation in T-20 binding domain of different HIV-1 subtypes from antiretroviral-naive and -experienced patients. , 2002, AIDS.

[7]  W. Cleveland.  Robust Locally Weighted Regression and Smoothing Scatterplots , 1979 .

[8]  G. Shaw,et al.  Sensitivity of Human Immunodeficiency Virus Type 1 to Fusion Inhibitors Targeted to the gp41 First Heptad Repeat Involves Distinct Regions of gp41 and Is Consistently Modulated by gp120 Interactions with the Coreceptor , 2001, Journal of Virology.

[9]  J. Erickson,et al.  Impact of Human Immunodeficiency Virus Type 1 gp41 Amino Acid Substitutions Selected during Enfuvirtide Treatment on gp41 Binding and Antiviral Potency of Enfuvirtide In Vitro , 2005, Journal of Virology.

[10]  M. Peeters,et al.  Enfuvirtide binding domain is highly conserved in non-B HIV type 1 strains from Cameroon, West Central Africa. , 2005, AIDS research and human retroviruses.

[11]  Carlos Toro,et al.  Evolution of genotypic and phenotypic resistance to Enfuvirtide in HIV‐infected patients experiencing prolonged virologic failure , 2004, Journal of medical virology.

[12]  J. Montaner,et al.  Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. , 2003, The New England journal of medicine.

[13]  L. Pérez-Alvárez,et al.  Natural resistance-associated mutations to Enfuvirtide (T20) and polymorphisms in the gp41 region of different HIV-1 genetic forms from T20 naive patients. , 2005, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[14]  A. Debnath,et al.  Peptide and non-peptide HIV fusion inhibitors. , 2002, Current pharmaceutical design.

[15]  Robert Blumenthal,et al.  Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  D. Hazuda,et al.  HIV resistance to the fusion inhibitor enfuvirtide: mechanisms and clinical implications. , 2004, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[17]  J. Kappes,et al.  Emergence of Resistant Human Immunodeficiency Virus Type 1 in Patients Receiving Fusion Inhibitor (T-20) Monotherapy , 2002, Antimicrobial Agents and Chemotherapy.

[18]  R. Garry,et al.  A general model for the transmembrane proteins of HIV and other retroviruses. , 1989, AIDS research and human retroviruses.

[19]  Susan Zolla-Pazner,et al.  Identifying epitopes of HIV-1 that induce protective antibodies , 2004, Nature Reviews Immunology.

[20]  P. S. Kim,et al.  HIV Entry and Its Inhibition , 1998, Cell.

[21]  Michael Greenberg,et al.  Relative Replicative Fitness of Human Immunodeficiency Virus Type 1 Mutants Resistant to Enfuvirtide (T-20) , 2004, Journal of Virology.

[22]  M. Greenberg,et al.  HIV fusion and its inhibition in antiretroviral therapy , 2004, Reviews in medical virology.

[23]  H. Garg,et al.  HIV gp41‐induced apoptosis is mediated by caspase‐3‐dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir , 2006, Journal of leukocyte biology.

[24]  D. Lambert,et al.  Peptides from conserved regions of paramyxovirus fusion (F) proteins are potent inhibitors of viral fusion. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[25]  E. Delwart,et al.  Retroviral envelope glycoproteins contain a "leucine zipper"-like repeat. , 1990, AIDS research and human retroviruses.

[26]  R. Lal,et al.  Variability of critical epitopes within HIV-1 heptad repeat domains for selected entry inhibitors in HIV-infected populations worldwide [corrected]. , 2002, AIDS.

[27]  Christine Katlama,et al.  Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. , 2003, The New England journal of medicine.

[28]  W. Gallaher,et al.  Detection of a fusion peptide sequence in the transmembrane protein of human immunodeficiency virus , 1987, Cell.

[29]  M. Matsuoka,et al.  Mutations Conferring Resistance to Human Immunodeficiency Virus Type 1 Fusion Inhibitors Are Restricted by gp41 and Rev-Responsive Element Functions , 2005, Journal of Virology.

[30]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[31]  S. Hammer,et al.  The Relation between Baseline HIV Drug Resistance and Response to Antiretroviral Therapy: Re-Analysis of Retrospective and Prospective Studies Using a Standardized Data Analysis Plan , 2000, Antiviral therapy.

[32]  W. Cleveland.  LOWESS: A Program for Smoothing Scatterplots by Robust Locally Weighted Regression , 1981 .

[33]  R. Laufs,et al.  Primary genotypic resistance of HIV-1 to the fusion inhibitor T-20 in long-term infected patients. , 2001, AIDS.

[34]  V. Arendt,et al.  Uncommon mutations at residue positions critical for enfuvirtide (T-20) resistance in enfuvirtide-naive patients infected with subtype B and non-B HIV-1 strains. , 2003, Journal of acquired immune deficiency syndromes.

[35]  L. Pérez-Alvárez,et al.  Primary resistance mutations to fusion inhibitors and polymorphisms in gp41 sequences of HIV-1 non-B subtypes and recombinants. , 2003, AIDS.