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 p7NC, independent of cleavage sites. Pretherapy V3 charge combined with p6Pol and p2/p7NC 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 p6Pol and p2/p7NC, as well as envelope, provide novel combinations of biomarkers for predicting emergence of viral resistance to initial therapy regimens.
aDepartment of Pathology, Immunology, and Laboratory Medicine, USA
bDepartment of Biochemistry and Molecular Biology, USA
cDepartment of Pediatrics, Division of Rheumatology and Infectious Diseases, USA
dDepartment of Epidemiology and Health Policy Research, University of Florida College of Medicine, Gainesville, USA
eDepartment of Pediatrics, Division of Allergy, Immunology, and Rheumatology, College of Medicine, University of South Florida, and All Children's Hospital, St. Petersburg, Florida, USA
fDepartment of Biostatistics, University at Buffalo, The State University of New York, Buffalo, New York, USA.
Received 6 January, 2009
Revised 1 May, 2009
Accepted 7 May, 2009
Correspondence to Maureen M. Goodenow, PhD, Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, 1376 Mowry Road, PO Box 103633, Gainesville, FL 32610, USA. Tel: +1 352 273 8288; fax: +1 352 273 8284; e-mail: firstname.lastname@example.org