Genetic and molecular epidemiology studies of HIV susceptibility and needle sharing among injection drug users in Baltimore

Background. Injection drug users (IDUs) are at high risk of acquiring infectious diseases. Most studies examining the behavioral risk factors for various diseases have relied on self-reports which are not valid and reliable. Even with known risk factors, differential responses to equivalent levels of exposure to diseases have been observed in various studies suggesting the role of host genetics.; Objectives. This dissertation consisted of two major objectives: (1) to genotypically determine the true level of needle sharing among IDUs, and (2) to examine the association of candidate genes with HIV susceptibility.; Methods. We used molecular methods based on biomarkers---short tandem repeats (STRs) as gold standard to examine and differentiate multi-person versus single-person use of syringes. Exudates from 2512 syringes exchanged at Baltimore needle exchange program by 315 ALIVE participants between 1995--1996 were analyzed and the results compared to the self-reports. We also conducted a nested case-control study within the ALIVE cohort to examine the association of 43 single nucleotide polymorphisms (SNPs) in 8 candidate genes (CCR2/ CCR5, RANTES, MIP1alpha, MCP2, IL10, IFNG, MCSF, and IL2 ) with HIV susceptibility. We estimated the cumulative risk exposure based on self-reported risk behaviors for each individual and accounted for the differential propensity in the analyses of genetic components.; Results. STR-based analysis showed that 56% of the syringes had evidence of multi-person use of syringes. Sharing cotton, exchanging low volume syringes and exchanging secondary syringes were found to be independent predictors of multi-person use of syringes. In the second study, four SNPs (CCR2-64I, CCR5-2459, MIP1alpha+ 954, and IL2+3896) and haplotypes in the CCR2/CCR5 and IL2 regions were significantly associated with HIV susceptibility after adjusting for the cumulative risk exposure and age.; Conclusion. The high prevalence of multi-person use of syringes found in our study suggests that more syringes that are sterile need to be available to the IDU community, especially to those who cannot or will not cease drug injection. Syringes are contaminated by both direct and indirect sharing and have tremendous public health burden in the community. The involvement of host genetics in HIV susceptibility could have enormous therapeutical implications in HIV prevention. Future studies include examination of additional SNPs around the significant regions in our study and replication of the results in other cohorts.