Incidence of diabetes mellitus in a population-based cohort of HIV-infected and non-HIV-infected persons: the impact of clinical and therapeutic factors over time.

AIMS: To examine incidence density rate and correlates of incident diabetes mellitus in a cohort of HIV-infected individuals compared with matched non-HIV-infected persons. METHODS: Data were obtained from the South Carolina Medicaid system and the enhanced HIV/AIDS Reporting System surveillance database for persons ≥ 18 years of age who had been attended to during the period 1994 to 2011. Time-dependent proportional hazards analysis and marginal structural models were used to analyse the data. RESULTS: A total of 13 632 individuals (6816, 1:1 matched HIV-infected and non-HIV-infected persons; median age 39 years; 57% male) contributed 88 359 person-years of follow-up. Incidence rate of diabetes was higher in the non-HIV-infected group compared with the HIV-infected group (13.60 vs. 11.35 per 1000 person-years). Multivariable hazards analysis suggested a significantly lower risk of incident diabetes among HIV-infected persons treated with combination antiretroviral therapy compared with the matched non-HIV-infected persons (adjusted hazards ratio 0.55; 95% CI 0.46-0.65). Among HIV-infected persons, marginal structural modelling suggested a significantly higher risk of diabetes with cumulative exposure to protease inhibitors over the observation period (adjusted relative risk 1.35; 95% CI 1.03-1.78), but this association was not significant for exposure to non-nucleoside reverse transcriptase inhibitors. Overall, female gender, older age, non-white race/ethnicity, and pre-existing hypertension, dyslipidaemia, obesity and hepatitis C infection were associated with higher risk of diabetes incidence. CONCLUSIONS: HIV infection may not be independently associated with increased risk of diabetes. Among HIV-infected persons, exposure to protease inhibitor-based regimens may increase the risk of diabetes. Healthcare providers should make every effort to use combination antiretroviral therapy regimens with a better cardiometabolic profile.

Chronic herpes simplex virus type-2 infection and HIV viral load.

By December 2003, the estimated adult HIV/AIDS prevalence rate in sub-Saharan Africa was 7.5-8.5%, and rates of herpes simplex virus type-2 (HSV-2) infection among adults aged >30 years ranged from 60% to 82%. However, little is known about the natural history of HIV/HSV-2 co-infection in this population. We evaluated HIV viral load and CD4+ cell counts among persons with and without chronic HSV-2 co-infection in a cross-sectional study of HIV-infected persons not receiving antiretroviral therapy. HSV-2 and HIV co-infection was associated with a 0.3 log copies/mL higher HIV viral load compared with persons without HSV-2 infection (P=0.014). Chronic HSV-2 infection may have a negative effect on the clinical course of persons with HIV.

Effect of physician specialty on counseling practices and medical referral patterns among physicians caring for disadvantaged human immunodeficiency virus-infected populations.

Data regarding the care and management of human immunodeficiency virus (HIV)-infected patients provided by infectious diseases (ID)-trained physicians, compared with data for care and management provided by other specialists, are limited. Here, we report results of a self-administered survey sent to 317 physicians (response rate, 76%) in 4 metropolitan areas of the United States who were identified as providing care to disadvantaged HIV-infected patients. ID-trained physicians who responded that they strongly agreed or somewhat agreed that they had enough time to care for their HIV-infected patients were more likely than were non-ID-trained physicians to provide therapy-adherence counseling. Physicians with >or=50 patients in care and ID-trained physicians were less likely to always discuss condom use and risk reduction for HIV transmission. Factors significantly associated with referring rather than treating HIV-infected patients with hypertension or diabetes included having <50 patients in care, being an ID-trained physician, and practicing in a private practice. These results suggest the need for targeted physician training on the importance of HIV transmission prevention counseling, increasing the duration of patient visits, and improving strategies for generalist-specialist comanagement of HIV-infected patients.

Mechanisms of mutations inhibiting fusion and infection by Semliki Forest virus.

Semliki Forest virus (SFV) infects cells by an acid-dependent membrane fusion reaction catalyzed by the virus spike protein, a complex containing E1 and E2 transmembrane subunits. E1 carries the putative virus fusion peptide, and mutations in this domain of the spike protein were previously shown to shift the pH threshold of cell-cell fusion (G91A), or block cell-cell fusion (G91D). We have used an SFV infectious clone to characterize virus particles containing these mutations. In keeping with the previous spike protein results, G91A virus showed limited secondary infection and an acid-shifted fusion threshold, while G91D virus was noninfectious and inactive in both cell-cell and virus-liposome fusion assays. During the low pH- induced SFV fusion reaction, the E1 subunit exposes new epitopes for monoclonal antibody (mAb) binding and forms an SDS-resistant homotrimer, the virus associates hydrophobically with the target membrane, and fusion of the virus and target membranes occurs. After low pH treatment, G91A spike proteins were shown to bind conformation-specific mAbs, associate with target liposome membranes, and form the E1 homotrimer. However, both G91A membrane association and homotrimer formation had an acid-shifted pH threshold and reduced efficiency compared to wt virus. In contrast, studies of the fusion-defective G91D mutant showed that the virus efficiently reacted with low pH as assayed by mAb binding and liposome association, but was essentially inactive in homotrimer formation. These results suggest that the G91D mutant is noninfectious due to a block in a late step in membrane fusion, separate from the initial reaction to low pH and interaction with the target membrane, and involving the lack of efficient formation of the E1 homotrimer.

Mutations in the putative fusion peptide of Semliki Forest virus affect spike protein oligomerization and virus assembly.

The two transmembrane spike protein subunits of Semliki Forest virus (SFV) form a heterodimeric complex in the rough endoplasmic reticulum. This complex is then transported to the plasma membrane, where spike-nucleocapsid binding and virus budding take place. By using an infectious SFV clone, we have characterized the effects of mutations within the putative fusion peptide of the E1 spike subunit on spike protein dimerization and virus assembly. These mutations were previously demonstrated to block spike protein membrane fusion activity (G91D) or cause an acid shift in the pH threshold of fusion (G91A). During infection of BHK cells at 37 degrees C, virus spike proteins containing either mutation were efficiently produced and transported to the plasma membrane, where they associated with the nucleocapsid. However, the assembly of mutant spike proteins into mature virions was severely impaired and a cleaved soluble fragment of E1 was released into the medium. In contrast, incubation of mutant-infected cells at reduced temperature (28 degrees C) dramatically decreased E1 cleavage and permitted assembly of morphologically normal virus particles. Pulse-labeling studies showed that the critical period for 28 degrees C incubation was during virus assembly, not spike protein synthesis. Thus, mutations in the putative fusion peptide of SFV confer a strong and thermoreversible budding defect. The dimerization of the E1 spike protein subunit with E2 was analyzed by using either cells infected with virus mutants or mutant virus particles assembled at 28 degrees C. The altered-assembly phenotype of the G91D and G91A mutants correlated with decreased stability of the E1-E2 dimer.

Characteristics of basal body cartwheel reassembly.

Cartwheel complexes reassembled in a fraction derived by treating isolated oral apparatuses from Tetrahymena with 1.0 M KCl for 12 h. Approximately 40% of the KCl-soluble protein reassembled into cartwheel complexes. The reassembly reaction was protein-concentration dependent, and reassembled cartwheels were stable at 3 degrees C. Sucrose gradient centrifugation resolved 3 high molecular mass protein complexes from the KCl-soluble fraction. Each of the 3 complexes has a different mass, but each contains the same 5 polypeptides, 2 of which are probably tubulins. When these complexes were removed from the KCl-soluble fraction by high speed centrifugation, cartwheel reassembly did not occur. The 5 polypeptides in the high molecular mass complexes were among several other polypeptides resolved from reassembled cartwheels by 2-dimensional gel electrophoresis. The high molecular mass complexes are probably essential for cartwheel formation. The electrophoretic data also show that several polypeptides in the KCL-soluble fraction do not appear to be incorporated into cartwheels. These polypeptides are probably non-essential for cartwheel formation.