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Epidemiology of HIV-1 Co-Receptor Usage: Association of CXCR4 Use with CD4 Count, CCR5 d32 Genotype and HIV V3 Sequence in Antiretroviral-naive Individuals
Zabrina Brumme*1, J Goodrich2, C Brumme1, B Henrick1, B Wynhoven1, P Cheung1, J Asselin1, R Hogg1, J Montaner1, and P Harrigan1
1British Columbia Ctr for Excellence in HIV and 2Pfizer Inc, New York, NY, USA
Background:
CXCR4-using HIV variants may emerge
over the natural history of HIV-1 infection and are associated with accelerated
disease progression and differential susceptibility to co-receptor inhibitors. We
wished to characterize the epidemiology and clinical correlates of CXCR4-using
HIV in a cross-sectional analysis of a cohort of HIV-infected,
antiretroviral naïve individuals.
Methods: HIV co-receptor
usage (Virologic Phenosense Assay) was determined in
the last pretherapy plasma sample from 1191 antiretroviral
naïve individuals initiating triple therapy in British
Columbia, Canada.
Baseline variables investigated for association with HIV co-receptor usage
included sociodemographic characteristics, plasma viral load (pVL), CD4 count,
AIDS diagnosis, HIV envelope V3 loop sequence, and the human CCR5 ∆32 genotype.
Results: Individuals
harboring CXCR4-using HIV ('X4 variants') (n = 178 of 979 successfully
phenotyped samples; 18.2%) displayed a poorer baseline clinical profile (median
pVL 175,000 vs 120,000 [p = 0.006]; median CD4 count 110 vs 290 [p < 0.0001]) than individuals
harboring exclusively CCR5-using
HIV. Individuals heterozygous for the CCR5
∆32 deletion (n = 134 of 958, 14.0%) were at 2.2 times increased risk of
harboring X4 variants when compared to CCR5
wt/wt individuals (multivariate p =
0.002). The presence of basic amino acids at codons 11 and/or 25 of the HIV V3
loop (n = 109 of 955; 11.4%) was associated with 9.3 times increased risk of
harboring X4 variants (multivariate p
< 0.0001), regardless of ∆32 genotype. In multivariate analyses
adjusting for baseline parameters including CCR5
∆32 genotype, HIV co-receptor usage was not a significant predictor of
survival or treatment response after initiating triple therapy.
Conclusion: Baseline CD4 count, pVL, HIV V3 sequence, and CCR5
∆32 genotype were the strongest determinants of CXCR4-using HIV in this
population. The association between CCR5
∆32 and CXCR4 use suggests that decreased target cell availability of CCR5 may select for X4 variants. These observations
may be of relevance to the use of CCR5
antagonists as antiretroviral agents.
Keywords: HIV; co-receptor ; epidemiology
