Publications

Recent evidence suggests that transmembrane domain (TMD) interactions are essential for HIV-1 Vpu-mediated antagonism of the restriction factor BST-2/tetherin. We made Vpu TMD mutants to study the mechanism of BST-2 antagonism. Vpu-I17A, -A18F, -W22L, and -S23L co-localized with BST-2 within endosomal membranes while effectively enhancing virion release and down-regulating surface BST-2. However, Vpu-A18H was confined to an endoplasmic reticulum (ER)-like distribution, resulting in impaired down-regulation of BST-2 and reduced virion release. Brefeldin A confined wild type Vpu to the ER, resulting in a similarly impaired phenotype, as did the addition of a C-terminal ER-retention signal to Vpu. We determined the half-life of cell-surface BST-2 to be ~8 hours, whereas Vpu mediated an ~80% reduction of surface BST-2 within 6 hours, suggesting that TMD interactions between Vpu and BST-2 occur within post-ER membranes to directly and rapidly remove BST-2 from the cell surface and relieve restricted virion release.

BACKGROUND

A common variant of the UMOD gene was linked with prevalent chronic kidney disease (CKD) in large, genomics consortia. One community-based study found that urine concentrations of the uromodulin protein forecast risk of incident CKD. This study within persons with known coronary artery disease (CAD) evaluated whether uromodulin concentrations could distinguish CKD risk.

METHODS

In the Heart and Soul Study, the UMOD snp (12917707) was genotyped in 879 individuals with baseline creatinine clearance (CrCl) measured from a 24-hour urine collection. Uromodulin protein was measured from stored urine specimens among a subset of 120 participants, balanced by genotype. Incident CKD cases (N = 102) were defined by an initial CrCl > 70 ml/min and a 5-year follow-up CrCl <60 ml/min; controls (N = 94) were matched on age, sex, and race.

RESULTS

Among 527 self-described White participants with DNA, 373 (71%) were homozygous for the dominant allele (G/G), 133 (25%) were heterozygous (G/T) and only 21 (4%) were homozygous for the minor allele (T/T). The T/T genotype had an approximately 11 ml/min higher CrCl than the other 2 groups, but this difference did not reach statistical significance (p = 0.20). The T/T genotype had significantly lower uromodulin levels than the common G/G genotype, and the G/T genotype had intermediate levels. However, uromodulin concentrations were similar between cases and controls (44 vs. 48 mg/dL, p = 0.88).

CONCLUSIONS

This study among a cohort of persons with established CAD found no association between urine uromodulin and incident CKD, although UMOD genotype was associated with urine uromodulin concentrations.

OBJECTIVE

to assess the associations between nucleoside reverse transcriptase inhibitors (NRTIs) and change in lipid levels among a large cohort of HIV-infected patients in routine clinical care initiating their first potent antiretroviral regimen.

DESIGN

longitudinal observational cohort study from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort.

METHODS

we used generalized estimating equations to examine the association between NRTIs and lipids accounting for within-patient correlations between repeated measures and key clinical and demographic characteristics including other antiretroviral medications.

RESULTS

among 2267 individuals who started their first antiretroviral regimen, tenofovir with emtricitabine or lamivudine was associated with lower levels for total cholesterol, low-density lipoprotein (LDL), triglycerides, non-high-density lipoprotein (HDL), and HDL, compared with other NRTI pairs in adjusted analyses. LDL levels were highest among patients receiving didanosine/lamivudine. Triglyceride levels were highest in stavudine/lamivudine users. HDL levels were highest among patients receiving didanosine/stavudine. Hepatitis C infection and younger age were also associated with lower lipid levels.

CONCLUSION

we found clinically important heterogeneity within the NRTI class of antiretroviral medications regarding their effect on lipid levels over time. Although the lipid profile of tenofovir with emtricitabine or lamivudine appeared to be less pro-atherogenic in this large longitudinal study of HIV-infected patients in routine clinical care, there was no association with beneficial HDL levels. In general, the change in lipid levels associated with most antiretroviral agents, particularly those NRTI combinations currently in common use, are relatively modest. Additional studies are needed to understand the long-term implications of these findings on cardiovascular disease risk.

CONTEXT

The literature predominately describes hospice utilization among Medicare recipients, with a limited number of reports describing use among all age groups.

OBJECTIVES

This study aimed to describe and compare patterns of hospice use among decedents of all ages in Alabama using a population-based approach.

METHODS

We obtained death certificates for Alabama residents who died from January 1, 2002 to December 31, 2005 (n=178,420). To ascertain hospice use, we linked death certificates to the hospice administering care using state-mandated listings of deaths reported by hospices. Additionally, each decedent's residence at death was geocoded and area-level socioeconomic status (SES) measures were added.

RESULTS

From 2002 to 2005, a total of 43,638 Alabamians died while under hospice care, representing a quarter (24.5%) of all deaths in the state. During this four-year span, the rate of hospice use increased by nearly 15% (22.2%-25.6%). As expected, rates of hospice use increased with age at death. For the SES indicators for poverty, education, and income, rates of hospice use increased as SES improved. However, this pattern was found to vary by race and metro/nonmetro status.

CONCLUSIONS

In addition to revealing racial, geographic, and other disparities in hospice care across Alabama, our results indicate usage rates in Alabama trail behind those observed nationally. We also identified previously unreported interactions between race, urbanization level, and poverty classification. Future studies should explore whether such relationships exist elsewhere and the rationale for their occurrence.