Pharmacogenomics of HIV Therapy: Summary of a Workshop Sponsored by the National Institute of Allergy and Infectious Diseases

Approximately 1 million people in the United States and over 30 million worldwide are living with human immunodeficiency virus type 1 (HIV-1). While mortality from untreated infection approaches 100%, survival improves markedly with use of contemporary antiretroviral therapies (ART). In the United States, 25 drugs are approved for treating HIV-1, and increasing numbers are available in resource-limited countries. Safe and effective ART is a cornerstone in the global struggle against the acquired immunodeficiency syndrome. Variable responses to ART are due at least in part to human genetic variants that affect drug metabolism, drug disposition, and off-site drug targets. Defining effects of human genetic variants on HIV treatment toxicity, efficacy, and pharmacokinetics has far-reaching implications. In 2010, the National Institute of Allergy and Infectious Diseases sponsored a workshop entitled, Pharmacogenomics A Path Towards Personalized HIV Care. This article summarizes workshop objectives, presentations, discussions, and recommendations derived from this meeting.

HIV disclosure and nondisclosure among migrant women from sub-Saharan Africa living in Switzerland.

No study to date has focused specifically on the reasons for and against disclosure of HIV-positive status among sub-Saharan migrant women. Thirty HIV-positive women from 11 sub-Saharan countries living in French-speaking Switzerland participated in semi-structured individual interviews. The reasons women reported for disclosure or nondisclosure of their HIV serostatus were classified into three categories: social, medical, and ethical. The women identified the stigma associated with HIV as a major social reason for nondisclosure. However, this study identifies new trends related to disclosure for medical and ethical reasons. Being undetectable played an important role in the life of sub-Saharan migrant women, and analysis revealed their medical reasons for both disclosure and nondisclosure. Disclosure to new sexual partners occurred when women had a more positive perception about HIV and when they believed themselves to be in a long-term relationship. Women reported nondisclosure to family members when they did not need help outside the support provided by the medical and social fields. The results on ethical reasons suggested that challenging stigma was a reason for disclosure. Since the women' perceptions on HIV changed when they came to see it as a chronic disease, disclosure occurred in an attempt to normalize life with HIV in their communities in migration and to challenge racism and discrimination. Our findings can help health providers better understand the communication needs of sub-Saharan migrant women with respect to HIV/AIDS and sexuality and offer them adequate disclosure advice that takes into account migration and gender issues.

Williams-Beuren syndrome TRIM50 encodes an E3 ubiquitin ligase.

Williams-Beuren syndrome (WBS) is a neurodevelopmental and multisystemic disease that results from hemizygosity of approximately 25 genes mapping to chromosomal region 7q11.23. We report here the preliminary description of eight novel genes mapping within the WBS critical region and/or its syntenic mouse region. Three of these genes, TRIM50, TRIM73 and TRIM74, belong to the TRIpartite motif gene family, members of which were shown to be associated to several human genetic diseases. We describe the preliminary functional characterization of these genes and show that Trim50 encodes an E3 ubiquitin ligase, opening the interesting hypothesis that the ubiquitin-mediated proteasome pathway might be involved in the WBS phenotype.

Parents living with HIV in a high-income country: do patients need specific support?

The number of HIV-infected persons with children and caregiving duties is likely to increase. From this statement, the present study was designed to establish how HIV infected caregivers organise their parenting routines and to determine their support needs. A further aim was to ascertain caregivers' perception of conspicuous behaviours displayed by their children. Finally, it sought to determine the extent to which the caregivers' assessment of their parenting activity is influenced by the required support and their children's perceived conspicuous behaviours. The study design was observational and cross-sectional. Sampling was based on the 7 HIV Outpatient Clinics associated with the national population-based Swiss HIV Cohort Study. It focused on persons living with HIV who are responsible for raising children below the age of 18. A total of 520 caregivers were approached and 261 participated. An anonymous, standardised, self-administered questionnaire was used for data collection. The data were analysed using descriptive statistical procedures and backward elimination multiple regression analysis. The 261 respondents cared for 406 children and adolescents under 18 years of age; the median age was 10 years. The caregivers' material resources were low. 70% had a net family income in a range below the median of Swiss net family income and 30% were dependent on welfare assistance. 73% were undergoing treatment with 86% reporting no physical impairments. The proportion of single caregivers was 34%. 92% of the children were living with their HIV infected caregivers. 80% of the children attended an institution such as a school or kindergarten during the day. 89% of the caregivers had access to social networks providing support. Nevertheless, caregivers required additional support in performing their parenting duties and indicated a need for assistance on the material level, in connection with legal problems and with participation in the labour market. 46% of the caregivers had observed one or more conspicuous behaviours displayed by their children, which indicates a challenging situation. However, most of these caregivers assessed their parenting activity very favourably. Backward elimination multiple regression analysis indicated that a smaller number of support needs, younger age of the eldest child and fewer physical impairments on the part of the caregiver enhance the caregivers' assessment of their parenting activity. Physicians should speak to caregivers living with HIV about their parenting responsibilities and provide the necessary scope for this subject in their consultation sessions. Physicians are in a position to draw their patients' attention to the services available to them.

Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.

BACKGROUND: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). OBJECTIVE: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. METHODS: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. RESULTS: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1. CONCLUSION: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family.

HDLs, diabetes, and metabolic syndrome.

The prevalence of type 2 diabetes mellitus and of the metabolic syndrome is rising worldwide and reaching epidemic proportions. These pathologies are associated with significant morbidity and mortality, in particular with an excess of cardiovascular deaths. Type 2 diabetes mellitus and the cluster of pathologies including insulin resistance, central obesity, high blood pressure, and hypertriglyceridemia that constitute the metabolic syndrome are associated with low levels of HDL cholesterol and the presence of dysfunctional HDLs. We here review the epidemiological evidence and the potential underlying mechanisms of this association. We first discuss the well-established association of type 2 diabetes mellitus and insulin resistance with alterations of lipid metabolism and how these alterations may lead to low levels of HDL cholesterol and the occurrence of dysfunctional HDLs. We then present and discuss the evidence showing that HDL modulates insulin sensitivity, insulin-independent glucose uptake, insulin secretion, and beta cell survival. A dysfunction in these actions could play a direct role in the pathogenesis of type 2 diabetes mellitus.