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


METHODS
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(NC), independent of cleavage sites. Pretherapy V3 charge combined with p6(Pol) and p2/p7(NC) 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.


CONCLUSIONS
Baseline genetic determinants in Gag p6(Pol) and p2/p7(NC), as well as envelope, provide novel combinations of biomarkers for predicting emergence of viral resistance to initial therapy regimens.
Ho
Sarah K
SK
Department of Pathology, Immunology, and Laboratory Medicine, University at Buffalo, University of Florida College of Medicine,Gainesville, USA.
Perez
Elena E
EE
Rose
Stephanie L
SL
Coman
Roxana M
RM
Lowe
Amanda C
AC
Hou
Wei
W
Ma
Changxing
C
Lawrence
Robert M
RM
Dunn
Ben M
BM
Sleasman
John W
JW
Goodenow
Maureen M
MM
D000293:Adolescent; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics; D005819:Genetic Markers; D014644:Genetic Variation; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D010446:Peptide Fragments / Q000235:genetics*; D010802:Phylogeny; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome; D019562:Viral Load; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
D005819:Genetic Markers; D015699:HIV Envelope Protein gp120; D017320:HIV Protease Inhibitors; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D054301:gag Gene Products, Human Immunodeficiency Virus