Genome-wide association study reveals genetic variants associated with HIV-1C infection in a Botswana study population.

Although there have been many studies of gene variant association with different stages of HIV/AIDS progression in United States and European cohorts, few gene-association studies have assessed genic determinants in sub-Saharan African populations, which have the highest density of HIV infections worldwide. We carried out genome-wide association studies on 766 study participants at risk for HIV-1 subtype C (HIV-1C) infection in Botswana. Three gene associations (AP3B1, PTPRA, and NEO1) were shown to have significant association with HIV-1C acquisition. Each gene association was replicated within Botswana or in the United States-African American or United States-European American AIDS cohorts or in both. Each associated gene has a prior reported influence on HIV/AIDS pathogenesis. Thirteen previously discovered AIDS restriction genes were further replicated in the Botswana cohorts, extending our confidence in these prior AIDS restriction gene reports. This work presents an early step toward the identification of genetic variants associated with and affecting HIV acquisition or AIDS progression in the understudied HIV-1C afflicted Botswana population.

Signal localization: a new approach in signal discovery.

A new approach for statistical association signal identification is developed in this paper. We consider a strategy for nonprecise signal identification by extending the well-known signal detection and signal identification methods applicable to the multiple testing problem. Collection of statistical instruments under the presented approach is much broader than under the traditional signal identification methods, allowing more efficient signal discovery. Further assessments of maximal value and average statistics in signal discovery are improved. While our method does not attempt to detect individual predictors, it instead detects sets of predictors that are jointly associated with the outcome. Therefore, an important application would be in genome wide association study (GWAS), where it can be used to detect genes which influence the phenotype but do not contain any individually significant single nucleotide polymorphism (SNP). We compare power of the signal identification method based on extremes of single p-values with the signal localization method based on average statistics for logarithms of p-values. A simulation analysis informs the application of signal localization using the average statistics for wide signals discovery in Gaussian white noise process. We apply average statistics and the localization method to GWAS to discover better gene influences of regulating loci in a Chinese cohort developed for risk of nasopharyngeal carcinoma (NPC).

A peer-educator network HIV prevention intervention among injection drug users: results of a randomized controlled trial in St. Petersburg, Russia.

We evaluated the efficacy of a peer-educator network intervention as a strategy to reduce HIV acquisition among injection drug users (IDUs) and their drug and/or sexual networks. A randomized controlled trial was conducted in St. Petersburg, Russia among IDU index participants and their risk network participants. Network units were randomized to the control or experimental intervention. Only the experimental index participants received training sessions to communicate risk reduction techniques to their network members. Analysis includes 76 index and 84 network participants who were HIV uninfected. The main outcome measure was HIV sero-conversion. The incidence rates in the control and experimental groups were 19.57 (95 % CI 10.74-35.65) and 7.76 (95 % CI 3.51-17.19) cases per 100 p/y, respectively. The IRR was 0.41 (95 % CI 0.15-1.08) without a statistically significant difference between the two groups (log rank test statistic X(2) = 2.73, permutation p value = 0.16). Retention rate was 67 % with a third of the loss due to incarceration or death. The results show a promising trend that this strategy would be successful in reducing the acquisition of HIV among IDUs.

Detection and estimation of multiple transient changes.

Change-point detection methods are proposed for the case of temporary failures, or transient changes, when an unexpected disorder is ultimately followed by a re-adjustment and return to the initial state. A base distribution of the 'in-control' state changes to an 'out-of-control' distribution for unknown periods of time. Likelihood based sequential and retrospective tools are proposed for the detection and estimation of each pair of change-points. The accuracy of the obtained change-point estimates is assessed. Proposed methods offer simultaneous control of the familywise false alarm and false re-adjustment rates at the pre-chosen levels.

Genome-Wide Analyses Reveal Gene Influence on HIV Disease Progression and HIV-1C Acquisition in Southern Africa.

Sub-Saharan Africans infected with HIV-1C make up the largest AIDS patient population in the world and exhibit large heterogeneity in disease progression before initiating antiretroviral therapy. To identify host variants associated with HIV disease progression, we performed genome-wide association studies on a total of 556 treatment-naive HIV-infected individuals in Botswana. We characterized the pattern of HIV disease progression using a novel functional principal component analysis, which can better capture longitudinal CD4 and viral load (VL) trajectories. Two single-nucleotide polymorphisms (SNPs) near HCG22 (chr6, peak variant rs2535307, combined p = 3.72 × 10-7, minor allele as risky allele) and CCNG1 (chr5, peak variant kgp22385164, combined p = 1.88 × 10-6, minor allele as risky allele) were significantly associated with CD4 and VL dynamics. Inspection of SNPs in these gene regions in a third Botswana cohort (using GWATCH) also revealed a strong association of HCG22 with HIV-1C acquisition, suggesting that this region is associated with infection as well as disease progression. Our study uncovered two genetic regions that are significant and have specific effects on HIV-1C acquisition or progression in sub-Saharan Africans, and the result suggested new potential targets for AIDS prevention and treatment. In addition, our results also indicate the possibility of using genetic markers as HIV disease progression indicators in sub-Saharan Africans to prioritize fast progressors for antiretroviral treatment.

HIV incidence and behavioral correlates of HIV acquisition in a cohort of injection drug users in St Petersburg, Russia.

The aim of the project was to study human immunodeficiency virus (HIV) incidence, sociodemographic and behavioral correlates of HIV acquisition among injection drug users (IDUs).A total of 717 IDUs were recruited, tested, and counseled for HIV-1; 466 HIV-negative participants were enrolled and followed-up at 6 and 12 months. Sociodemographic and behavioral data were collected during each study visit. The association of sociodemographic and behavioral factors to HIV-1 incidence was assessed.During the 9-month recruitment period, 717 IDUs were screened and 466 participants were enrolled. HIV-1 prevalence at baseline was 35%. Most enrolled subjects were young (median age 30), male (75%), injected heroin in the previous 3 months (86%), about 50% had shared syringes and other paraphernalia, and 44% had unprotected sex in the last month. The retention rate at the 12-month follow-up was 72% and the adjusted retention rate was 88%. The HIV incidence rate was 7.2/100 person-years. HIV incidence was significantly associated with specific drug risk behaviors, including injecting the mixture of heroin and psychostimulants, the frequency of injecting in groups with other people, and having more drug dealers.The St Petersburg IDUs cohort demonstrates one of the highest HIV incidence rates in the world. In 2004 to 2006, the HIV incidence was 4.5, in 2005 to 2007-19.6, and in 2008 to 2009-7.2/100 person-years. The peak of HIV epidemic among IDUs in St Petersburg, as determined by 3 independent cohort studies, was in 2006 to 2007. Interventions targeting IDUs with long experience of heroin injection and high levels of injection risk behaviors are urgently needed.