Clinical and immunological impact of HIV envelope V3 sequence variation after starting initial triple antiretroviral therapy.
BACKGROUND
The HIV-1 envelope third variable loop (V3 loop) is an important determinant of viral phenotype and co-receptor usage. We wished to determine the impact of specific V3 genotypes associated with viral phenotype and co-receptor usage on response to initial triple antiretroviral therapy.


METHODS
Pre-therapy plasma samples from the HOMER cohort of 1191 antiretroviral-naive, HIV-infected adults who initiated triple therapy in British Columbia, Canada between August 1996 and September 1999 were genotyped for V3 loop sequence. V3 sequences were dichotomized by the presence or absence of positively charged residues at codons 11 and/or 25 (an '11/25' genotype). Neural network (NN) and Position Specific Scoring Matrix (PSSM) approaches were used as alternative V3 sequence interpretation methods. The association of V3 genotypes with clinical endpoints was assessed over a median of 43 months of follow up.


RESULTS
One-hundred and eighteen (10.9%) of the 1085 isolates successfully genotyped for V3 displayed the 11/25 genotype. In multivariate analyses, this genotype was associated with a more rapid CD4 decline [risk ratio, (RR), 1.38; P = 0.012] and earlier mortality (RR, 1.70; P = 0.027), despite comparable viral load suppression below 500 HIV RNA copies/ml. We observed no influence of the 11/25 genotype on time to viral rebound or the development of drug resistance. PSSM-based sequence categories were similarly predictive of outcomes. NN sequence categories were not associated with any endpoints.


CONCLUSIONS
The 11/25 genotype of the HIV V3 loop is an independent predictor of poor immunological response and more rapid mortality even after starting triple antiretroviral therapy. These results may prove to be useful for the clinical management of HIV-infected individuals.
Brumme
Zabrina L
ZL
BC Centre for Excellence in HIV/AIDS, St. Paul's Hospital, the Faculty of Medicine, University of British Columbia, 603-1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6.
Dong
Winnie W Y
WW
Yip
Benita
B
Wynhoven
Brian
B
Hoffman
Noah G
NG
Swanstrom
Ronald
R
Jensen
Mark A
MA
Mullins
James I
JI
Hogg
Robert S
RS
Montaner
Julio S G
JS
Harrigan
P Richard
PR
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D016571:Neural Networks, Computer; D010446:Peptide Fragments / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome; D019562:Viral Load
D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments