Publications

BACKGROUND

Although the rate of mother-to-child transmission of hepatitis C virus (HCV) is low, the effect of HCV exposure in utero on the fetal immune system is unknown.

METHODS

Umbilical cord blood was obtained from 7 neonates born to HCV-seropositive, HCV RNA-positive women and 8 neonates born to HCV-seronegative women. Cord blood mononuclear cells were analyzed by immunophenotyping and by intracellular cytokine staining after HCV-specific and polyclonal stimulation. Plasma was analyzed for anti-HCV immunoglobulin M (IgM), cytokine/granzyme concentrations, and indoleamine 2,3-dioxygenase (IDO) activity.

RESULTS

HCV-exposed neonates had significantly lower levels of regulatory T cells expressing HLA-DR, lower CD4(+) and CD8(+) T cell activation, and lower plasma levels of pro-inflammatory markers than did controls. However, CD4(+) and CD8(+) T cells from HCV-exposed neonates had higher IFN-γ production in response to polyclonal stimulation than did T cells from controls. IDO activity was similar between groups. No HCV-specific T cell responses or anti-HCV IgM were detected in any neonates.

CONCLUSIONS

HCV-exposed neonates showed a relative suppression of immune activation and pro-inflammatory markers, which was counterbalanced by an increased production capacity for IFN-γ. These results suggest that HCV encounters the fetal immune system in utero, and alters the balance between suppressive and pro-inflammatory responses.

Men who have sex with men (MSM) continue to be disproportionately affected by human immunodeficiency virus (HIV) infection. While the MSM population does better than other HIV infection risk groups with regard to linkage to and retention in care, little is known about engagement in care outcomes for important subpopulations of MSM. There is also a dearth of research on engagement in care strategies specific to the MSM population. Key MSM subpopulations in the United States on which to focus future research efforts include racial/ethnic minority, young, and substance-using MSM. Health care systems navigation may offer a promising engagement in care strategy for MSM and should be further evaluated. As is the case for HIV-infected populations in general, future research should also focus on identifying the best metrics for measuring engagement in care.

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.