Genetic determinants in HIV-1 Gag and Env V3 are related to viral response to combination antiretroviral therapy with a protease inhibitor

Sarah K. Ho, Elena E. Perez, Stephanie L. Rose, Roxana M. Coman, Amanda C. Lowe, Wei Hou, Changxing Ma, Robert M. Lawrence, Ben M. Dunn, John W. Sleasman, Maureen M. Goodenow

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

OBJECTIVE: To identify novel viral determinants in HIV-1 protease, Gag, and envelope V3 that relate to outcomes to initial protease inhibitor-based antiretroviral therapy. DESIGN: A longitudinal cohort study of protease inhibitor-naive, HIV-infected individuals was designed to identify genetic variables in viral Gag and envelope sequences associated with response to antiretroviral therapy. METHODS: Genetic and statistical models, including amino acid profiles, phylogenetic analyses, receiver operating characteristic analyses, and covariation analyses, were used to evaluate viral sequences and clinical variables from individuals who developed immune reconstitution with or without suppression of viral replication. RESULTS: Pretherapy chemokine (C-X-C motif) receptor 4-using V3 regions had significant associations with viral failure (P = 0.04). Amino acid residues in protease covaried with Gag residues, particularly in p7, independent of cleavage sites. Pretherapy V3 charge combined with p6 and p2/p7 cleavage site genotypes produced the best three-variable model to predict viral suppression in 88% of individuals. Combinations of baseline CD4 cell percentage with genetic determinants in Gag-protease predicted viral fitness in 100% of individuals who failed to suppress viral replication. CONCLUSION: Baseline genetic determinants in Gag p6 and p2/p7, as well as envelope, provide novel combinations of biomarkers for predicting emergence of viral resistance to initial therapy regimens.

Original languageEnglish
Pages (from-to)1631-1640
Number of pages10
JournalAIDS
Volume23
Issue number13
DOIs
StatePublished - Aug 24 2009

Fingerprint

Protease Inhibitors
HIV-1
Peptide Hydrolases
CCR Receptors
HIV Protease Inhibitors
Amino Acids
Genetic Models
Statistical Models
ROC Curve
Longitudinal Studies
Cohort Studies
Therapeutics
Biomarkers
Genotype

Keywords

  • Antiretroviral therapy response
  • Coreceptors
  • HIV-1 Env V3
  • HIV-1 Gag
  • HIV-1 protease inhibitors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Ho, S. K., Perez, E. E., Rose, S. L., Coman, R. M., Lowe, A. C., Hou, W., ... Goodenow, M. M. (2009). Genetic determinants in HIV-1 Gag and Env V3 are related to viral response to combination antiretroviral therapy with a protease inhibitor. AIDS, 23(13), 1631-1640. https://doi.org/10.1097/QAD.0b013e32832e0599

Genetic determinants in HIV-1 Gag and Env V3 are related to viral response to combination antiretroviral therapy with a protease inhibitor. / Ho, Sarah K.; Perez, Elena E.; Rose, Stephanie L.; Coman, Roxana M.; Lowe, Amanda C.; Hou, Wei; Ma, Changxing; Lawrence, Robert M.; Dunn, Ben M.; Sleasman, John W.; Goodenow, Maureen M.

In: AIDS, Vol. 23, No. 13, 24.08.2009, p. 1631-1640.

Research output: Contribution to journalArticle

Ho, SK, Perez, EE, Rose, SL, Coman, RM, Lowe, AC, Hou, W, Ma, C, Lawrence, RM, Dunn, BM, Sleasman, JW & Goodenow, MM 2009, 'Genetic determinants in HIV-1 Gag and Env V3 are related to viral response to combination antiretroviral therapy with a protease inhibitor', AIDS, vol. 23, no. 13, pp. 1631-1640. https://doi.org/10.1097/QAD.0b013e32832e0599
Ho, Sarah K. ; Perez, Elena E. ; Rose, Stephanie L. ; Coman, Roxana M. ; Lowe, Amanda C. ; Hou, Wei ; Ma, Changxing ; Lawrence, Robert M. ; Dunn, Ben M. ; Sleasman, John W. ; Goodenow, Maureen M. / Genetic determinants in HIV-1 Gag and Env V3 are related to viral response to combination antiretroviral therapy with a protease inhibitor. In: AIDS. 2009 ; Vol. 23, No. 13. pp. 1631-1640.
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abstract = "OBJECTIVE: To identify novel viral determinants in HIV-1 protease, Gag, and envelope V3 that relate to outcomes to initial protease inhibitor-based antiretroviral therapy. DESIGN: A longitudinal cohort study of protease inhibitor-naive, HIV-infected individuals was designed to identify genetic variables in viral Gag and envelope sequences associated with response to antiretroviral therapy. METHODS: Genetic and statistical models, including amino acid profiles, phylogenetic analyses, receiver operating characteristic analyses, and covariation analyses, were used to evaluate viral sequences and clinical variables from individuals who developed immune reconstitution with or without suppression of viral replication. RESULTS: Pretherapy chemokine (C-X-C motif) receptor 4-using V3 regions had significant associations with viral failure (P = 0.04). Amino acid residues in protease covaried with Gag residues, particularly in p7, independent of cleavage sites. Pretherapy V3 charge combined with p6 and p2/p7 cleavage site genotypes produced the best three-variable model to predict viral suppression in 88{\%} of individuals. Combinations of baseline CD4 cell percentage with genetic determinants in Gag-protease predicted viral fitness in 100{\%} of individuals who failed to suppress viral replication. CONCLUSION: Baseline genetic determinants in Gag p6 and p2/p7, as well as envelope, provide novel combinations of biomarkers for predicting emergence of viral resistance to initial therapy regimens.",
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AU - Hou, Wei

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