Elevated CD4 + T-cell glucose metabolism in HIV+ women with diabetes mellitus.

OBJECTIVE: Immune dysfunction and chronic inflammation are characteristic of HIV infection and diabetes mellitus, with CD4 + T-cell metabolism implicated in the pathogenesis of each disease. However, there is limited information on CD4 + T-cell metabolism in HIV+ persons with diabetes mellitus. We examined CD4 + T-cell glucose metabolism in HIV+ women with and without diabetes mellitus. DESIGN: A case-control study was used to compare CD4 + T-cell glucose metabolism in women with HIV with or without diabetes mellitus. METHODS: Nondiabetic (HIV+DM-, N = 20) or type 2 diabetic HIV+ women with (HIV+DM+, N  = 16) or without (HIV+DMTx+, N  = 18) antidiabetic treatment were identified from the WIHS and matched for age, race/ethnicity, smoking status and CD4 + cell count. CD4 + T-cell immunometabolism was examined by flow cytometry, microfluidic qRT-PCR of metabolic genes, and Seahorse extracellular flux analysis of stimulated CD4 + T cells. RESULTS: HIV+DM+ displayed a significantly elevated proportion of CD4 + T cells expressing the immunometabolic marker GLUT1 compared with HIV+DMTx+ and HIV+DM- ( P  = 0.04 and P  = 0.01, respectively). Relative expression of genes encoding key enzymes for glucose metabolism pathways were elevated in CD4 + T cells of HIV+DM+ compared with HIV+DMTx+ and HIV+DM-. T-cell receptor (TCR)-activated CD4 + T cells from HIV+DM+ showed elevated glycolysis and oxidative phosphorylation compared with HIV+DM-. CONCLUSION: CD4 + T cells from HIV+DM+ have elevated glucose metabolism. Treatment of diabetes mellitus among women with HIV may partially correct CD4 + T-cell metabolic dysfunction.

Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS).

Cardiovascular disease (CVD) is a major comorbidity among HIV-infected individuals. Common carotid artery intima-media thickness (cCIMT) is a valid and reliable subclinical measure of atherosclerosis and is known to predict CVD. We performed genome-wide association (GWA) and admixture analysis among 682 HIV-positive and 288 HIV-negative Black, non-Hispanic women from the Women's Interagency HIV study (WIHS) cohort using a combined and stratified analysis approach. We found some suggestive associations but none of the SNPs reached genome-wide statistical significance in our GWAS analysis. The top GWAS SNPs were rs2280828 in the region intergenic to mediator complex subunit 30 and exostosin glycosyltransferase 1 (MED30 | EXT1) among all women, rs2907092 in the catenin delta 2 (CTNND2) gene among HIV-positive women, and rs7529733 in the region intergenic to family with sequence similarity 5, member C and regulator of G-protein signaling 18 (FAM5C | RGS18) genes among HIV-negative women. The most significant local European ancestry associations were in the region intergenic to the zinc finger and SCAN domain containing 5D gene and NADH: ubiquinone oxidoreductase complex assembly factor 1 (ZSCAN5D | NDUF1) pseudogene on chromosome 19 among all women, in the region intergenic to vomeronasal 1 receptor 6 pseudogene and zinc finger protein 845 (VN1R6P | ZNF845) gene on chromosome 19 among HIV-positive women, and in the region intergenic to the SEC23-interacting protein and phosphatidic acid phosphatase type 2 domain containing 1A (SEC23IP | PPAPDC1A) genes located on chromosome 10 among HIV-negative women. A number of previously identified SNP associations with cCIMT were also observed and included rs2572204 in the ryanodine receptor 3 (RYR3) and an admixture region in the secretion-regulating guanine nucleotide exchange factor (SERGEF) gene. We report several SNPs and gene regions in the GWAS and admixture analysis, some of which are common across HIV-positive and HIV-negative women as demonstrated using meta-analysis, and also across the two analytic approaches (i.e., GWA and admixture). These findings suggest that local European ancestry plays an important role in genetic associations of cCIMT among black women from WIHS along with other environmental factors that are related to CVD and may also be triggered by HIV. These findings warrant confirmation in independent samples.

Increased glucose transporter-1 expression on intermediate monocytes from HIV-infected women with subclinical cardiovascular disease.

OBJECTIVE: People living with HIV (PLWH) have chronic immune activation and increased cardiovascular disease (CVD) risk. Activation of monocytes and T lymphocytes causes upregulation of glucose transporter-1 (GLUT1) for efficient function. PLWH have an increased percentage of GLUT1-expressing monocytes and T lymphocytes, but it is unclear if these cells are associated with CVD. We evaluated the expression of GLUT1 and CD38 on monocyte and T lymphocyte populations from HIV-infected women with subclinical CVD. METHODS: Participants with more than 75th percentile (n = 15) and less than 25th percentile (n = 15) age-adjusted intima-media thickness (IMT) at the right common carotid artery and bifurcation were identified from the Women's Interagency HIV Study. Groups were matched by age, race/ethnicity, smoking status, and CD4 cell count. All women were receiving suppressive antiretroviral therapy except for one high and one low IMT participant. Monocyte and T lymphocyte populations were evaluated for GLUT1 and CD38 expression using flow cytometry. RESULTS: Intermediate monocytes from high IMT women had significantly increased expression of GLUT1 (310 MFI vs. 210 MFI, P = 0.024) (66.4% vs. 48.5%, P = 0.031) and CD38 (339 MFI vs. 211 MFI, P = 0.002) (10.5% vs. 3.8%, P = 0.0002) compared with women with low IMT. High and low IMT participants showed no differences in GLUT1 or CD38 expression on classical monocytes, nonclassical monocytes, CD4 and CD8 T lymphocytes. CONCLUSION: GLUT1-expressing intermediate monocytes are elevated in HIV-infected women with subclinical CVD. These cells may contribute to development of CVD in PLWH and could be a novel target to limit inflammation.

Antiretroviral activity and safety of once-daily etravirine in treatment-naive HIV-infected adults: 48-week results.

BACKGROUND: Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor approved for 200 mg twice-daily dosing in conjunction with other antiretrovirals (ARVs), has pharmacokinetic properties which support once-daily dosing. METHODS: In this single-arm, open-label study, 79 treatment-naive HIV-infected adults were assigned to receive ETR 400 mg plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) 300/200 mg once daily to assess antiviral activity, safety and tolerability. ARV activity at 48 weeks was determined by proportion of subjects with HIV-1 RNA<50 copies/ml (intention-to-treat, missing = failure). RESULTS: Of 79 eligible subjects, 90% were men, 62% African-American and 29% Caucasian. At baseline, median (Q1, Q3) age was 29 years (23, 44) and HIV-1 RNA 4.52 log10 copies/ml (4.07, 5.04). A total of 69 (87%) completed a week 48 visit and 61 (77%, 95% CI 66%, 86%) achieved HIV-1 RNA<50 copies/ml at week 48. At time of virological failure, genotypic resistance-associated mutations were detected in three participants, two with E138K (one alone and one with additional mutations). Median (95% CI) CD4(+) cell count increase was 163 (136, 203) cells/µl. Fifteen (19.0%) participants reported a new sign/symptom or lab abnormality ≥ Grade 3 and three participants (3.8%) permanently discontinued ETR due to toxicity. Two participants had psychiatric symptoms of any grade. There were no deaths. CONCLUSIONS: In this study of ARV-naive HIV-positive adults, once-daily ETR with TDF/FTC had acceptable antiviral activity and was well-tolerated. Once-daily ETR may be a plausible option as part of a combination ARV regimen for treatment-naive individuals. ClinicalTrials.gov NCT00959894.

Ending the epidemic of heterosexual HIV transmission among African Americans.

This article examines factors responsible for the stark racial disparities in HIV infection in the U.S. and the now concentrated epidemic among African Americans. Sexual network patterns characterized by concurrency and mixing among different subpopulations, together with high rates of other sexually transmitted infections, facilitate dissemination of HIV among African Americans. The social and economic environment in which many African Americans live shapes sexual network patterns and increases personal infection risk almost independently of personal behavior. The African-American HIV epidemic constitutes a national crisis whose successful resolution will require modifying the social and economic systems, structures, and processes that facilitate HIV transmission in this population.

Adverse reactions to trimethoprim/sulfamethoxazole in AIDS.

OBJECTIVE: To report the case of a woman with AIDS who developed tremor, acute pancreatitis, and elevated serum creatinine levels while receiving trimethoprim/sulfamethoxazole (TMP/SMX). CASE SUMMARY: A 37-year-old Puerto Rican woman with AIDS, HIV nephropathy, and a recent history of disseminated histoplasmosis presented with fever, nonproductive cough, pancytopenia, and elevated transaminase and alkaline phosphatase levels. Serum creatinine was near her baseline level of 2.9 mg/dL. Treatment was started with amphotericin B lipid complex for histoplasmosis and intravenous TMP/SMX for presumed Pneumocystis carinii pneumonia. Two days later, the patient developed a high-frequency tremor and severe abdominal pain, and serum creatinine increased to 5.6 mg/dL. TMP/SMX was discontinued, after which the patient's symptoms resolved within 72 hours and serum creatinine returned to baseline levels. DISCUSSION: A high incidence of adverse reactions to TMP/SMX has been reported among HIV-infected persons. Toxic sulfamethoxazole metabolites may elicit hypersensitivity reactions. Trimethoprim can inhibit renal creatinine secretion, leading to high serum creatinine levels. Trimethoprim also inhibits dihydrofolate reductase, causing decreased dopamine production, which may lead to parkinsonian symptoms. Use of the Naranjo probability scale indicated a probable relationship between the adverse effect and TMP/SMX. CONCLUSIONS: The high frequency and wide range of potential adverse effects associated with the use of TMP/SMX in HIV-infected persons require that clinicians consider drug toxicity as a cause of new symptoms in patients receiving this medication.