Vitamin D Levels and Markers of Inflammation and Metabolism in HIV-Infected Individuals on Suppressive Antiretroviral Therapy.

Data on vitamin D insufficiency as a cause of inflammation and metabolic dysfunction in HIV-infected individuals are conflicting. We examined the relationships between levels of 25-hydroxyvitamin D [25(OH)D] and biomarkers of inflammation and metabolism in stored blood samples from a prospective trial of vitamin D repletion. Blood samples from HIV-infected individuals on antiretroviral therapy (ART) with HIV-1 RNA <200 copies/ml enrolled in a prospective study were analyzed for 25(OH)D levels, a broad panel of cytokines, highly sensitive C-reactive protein, D-dimer, adiponectin, leptin, and insulin. Correlations between markers and 25(OH)D levels were determined. The Wilcoxon Rank Sum test was used to compare markers between individuals 25(OH)D insufficient and sufficient at baseline and before and after repletion among those who were insufficient and repleted to ≥30 ng/ml after 12 weeks. Of 106 subjects with stored plasma [66 with 25(OH)D <30 ng/ml and 40 ≥ 30 ng/ml], the median age was 50, the CD4 count was 515 cells/mm(3), 94% were male, and the median baseline 25(OH)D was 27 ng/ml. Higher 25(OH)D levels were associated with lower tumor necrosis factor (TNF)-α (r = -0.20, p = 0.04) and higher adiponectin levels (r = 0.30, p = 0.002). Following successful repletion to 25(OH)D ≥30 ng/ml there were no significant changes in inflammatory or metabolic parameters. Our study found associations between low 25(OH)D levels and TNF-α and adiponectin. Repletion did not result in changes in markers of inflammation or metabolism. These data support continued study of the relationship between vitamin D, inflammation, and metabolism in treated HIV infection.

Success of Standard Dose Vitamin D Supplementation in Treated Human Immunodeficiency Virus Infection.

Background. Vitamin D insufficiency is prevalent in human immunodeficiency virus-positive (HIV+) persons. Human immunodeficiency virus and antiretroviral therapy (ART) may create unique risk factors, and the optimal vitamin D repletion and maintenance regimen in HIV+ persons remains unclear. Methods. Human immunodeficiency virus-positive adults on suppressive ART underwent routine serum 25-hydroxyvitamin D (25OHD) screening. Persons with vitamin D insufficiency (25OHD <30 ng/mL) received open-label, oral vitamin D3 50 000 international units (IU) twice weekly for 5 weeks, then 2000 IU daily to complete 12 weeks. We predicted 70% (95% confidence interval, 60%-80%) repletion to 25OHD ≥30 ng/mL compared with 85% among historical HIV-negative controls. Eighty participants provided 91% power to detect this difference. Ability to maintain 25OHD ≥30 ng/mL after 24 weeks was also assessed. Results. Baseline characteristics were similar between the 82 vitamin D insufficient and 40 sufficient persons enrolled: 95% male, 60% white, 88% nonsmokers, median age 49 years, body mass index 26 kg/m(2), and CD4(+) T lymphocyte count 520 cells/mm(3). After 12 weeks, 81% (66 of 82) of insufficient persons achieved 25OHD ≥30 ng/mL (P = .32 vs historical controls), with only older age (odds ratio [OR] = 1.06; P = .06), higher baseline 25OHD (OR = 1.14; P < .01), white race (OR = 3.39; P = .04), and current smoking (OR = 0.25; P = .06) associated with successful repletion. After 24 weeks, 73% (48 of 66) maintained 25OHD ≥30 ng/mL, with tenofovir (OR = 5.00; P = .01) and abacavir use (OR = 0.23; P = .02) associated with success and failure, respectively, to maintain 25OHD levels. Conclusions. The 25OHD repletion rates were comparable between HIV+ adults on suppressive ART and historical HIV-negative controls, indicating that successful oral repletion can be achieved in this population.

RNAi-Mediated CCR5 Knockdown Provides HIV-1 Resistance to Memory T Cells in Humanized BLT Mice.

Transplantation of hematopoietic stem/progenitor cells (HSPC) modified with a lentiviral vector bearing a potent nontoxic short hairpin RNA (sh1005) directed to the HIV coreceptor CCR5 is capable of continuously producing CCR5 downregulated CD4+ T lymphocytes. Here, we characterized HIV-1 resistance of the sh1005-modified CD4+ T lymphocytes in vivo in humanized bone marrow/liver/thymus (hu BLT) mice. The sh1005-modified CD4+ T lymphocytes were positively selected in CCR5-tropic HIV-1-challenged mice. The sh1005-modified memory CD4+ T lymphocytes (the primary target of CCR5-tropic HIV-1) expressing sh1005 were maintained in lymphoid tissues in CCR5-tropic HIV-1-challenged mice. Frequencies of HIV-1 p24 expressing cells were significantly reduced in the sh1005-modified splenocytes by ex vivo cell stimulation confirming that CCR5 downregulated sh1005 modified cells are protected from viral infection. These results demonstrate that stable CCR5 downregulation through genetic modification of human HSPC by lentivirally delivered sh1005 is highly effective in providing HIV-1 resistance. Our results provide in vivo evidence in a relevant small animal model that sh1005 is a potent early-step anti-HIV reagent that has potential as a novel anti-HIV-1 HSPC gene therapeutic reagent for human applications.