11th Conference on Retroviruses and Opportunistic Infections San Francisco, California - February 8 - 11, 2004

Conf Retrovir Opportunistic Infect 2004 Feb 8-11; 11:(abstract no. 28)

K Singh¹, R Ellis², J Marquie-Beck², S Letendre², R Heaton², I Grant², and S A Spector^1
1Univ. of California, San Diego, USA and ²HIV Neurobehavioral Res. Ctr., San Diego, CA, USA

BACKGROUND: Increasing evidence suggests that chemokine receptors, in addition to their role as HIV-1 co-receptors, also may affect HIV neuropathogenesis. However, limited data are available on the role of chemokine/chemokine receptor polymorphisms on HIV-related neuropsychological impairment. MCP-1, the ligand for CCR2, is associated with neuropsychological impairment. However, the importance of CCR2 in neuropsychological impairment is unknown. This research examined the effect of CCR2 polymorphisms on the development of HIV-related neuropsychological impairment.

METHODS: In a prospective study of the neurological complications of HIV-1, 279 HIV-1-infected adults aged 19 to 55 years were enrolled and studied. The CCR2-G/A (V64I) polymorphism was determined by real-time PCR. Neurocognitive status at baseline and follow-up was assessed by comprehensive neuropsychological testing. Subjects were classified as impaired or unimpaired using demographically corrected normative data. Kaplan-Meier analysis and Cox proportional hazards models were used to analyze the association of genotypes with incident neuropsychological impairment.

RESULTS: Among 121 subjects who underwent neuropsychological testing, 9 (7%) had CCR2-A/A, 31 (26%) had -G/A, and 81 (67%) had -G/G genotypes. In a Kaplan-Meier analysis of time until neuropsychological impairment from baseline visit, the median time for A/A homozygotes was 2.5 years versus 4.0 years for the remaining subjects (p = 0.01). Progression to neuropsychological impairment for heterozygotes was intermediate between that of the other 2 groups. In the subset of individuals with the CCR5-wt/wt genotype, the CCR2-A/A genotype was associated with more rapid progression to neuropsychological impairment (p = 0.056, n = 103). The results were similar when substituting estimated date of seroconversion for baseline: the CCR2-A/A genotype was associated with development of neuropsychological impairment, both in the cohort as a whole (p = 0.024, n = 119) and in the individuals with the CCR5-wt/wt genotype (p = 0.033, n = 109). The frequency of CCR2 genotypes did not differ by race/ethnicity. Of note, the CCR2 genotype showed no association with disease progression or with plasma or CSF HIV RNA levels.

CONCLUSIONS: A genetic variant of CCR2 (V64I), the principal receptor for the chemokine MCP-1, was associated with more rapid progression to neuropsychological impairment in this cohort of HIV-infected adults. The CCR2 polymorphism was not associated with increases in plasma or CSF viral load, suggesting that the impact of CCR2 on neuropathogenesis may involve alterations in host immune responses within the CNS rather than a direct impact on viral entry and replication.

040208
28

Copyright © 2004 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.