cholecalciferol and Acquired-Immunodeficiency-Syndrome

Autophagy is a self-digestion pathway essential for maintaining cellular homeostasis and cell survival and for degrading intracellular pathogens. Human immunodeficiency virus-1 (HIV-1) may utilize autophagy for replication as the autophagy-related protein-7 (ATG-7), microtubule-associated protein 1 light chain 3, ATG-12, and ATG-16L2 are required for productive HIV-1 infection; however, the effects of autophagy induction on HIV-1 infection are unknown. HIV-1-infected individuals have lower levels of 1α,25-dihydroxycholecalciferol, the hormonally active form of vitamin D, than uninfected individuals. with the lowest concentrations found in persons with AIDS. Using human macrophages and RNA interference for ATG-5 and Beclin-1 and chemical inhibition of phosphatidylinositol 3-kinase, we have found that physiologically relevant concentrations of 1α,25-dihydroxycholecalciferol induce autophagy in human macrophages through a phosphatidylinositol 3-kinase-, ATG-5-, and Beclin-1-dependent mechanism that significantly inhibits HIV-1 replication in a dose-dependent manner. We also show that the inhibition of basal autophagy inhibits HIV-1 replication. Furthermore, although 1α,25-dihydroxycholecalciferol induces the secretion of human cathelicidin, at the concentrations produced in vitro, cathelicidin does not trigger autophagy. Our findings support an important role for autophagy during HIV-1 infection and provide new insights into novel approaches to prevent and treat HIV-1 infection and related opportunistic infections.

Topics: Acquired Immunodeficiency Syndrome; Antimicrobial Cationic Peptides; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 12; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Beclin-1; Cathelicidins; Cholecalciferol; Dose-Response Relationship, Drug; HIV-1; Humans; Macrophages; Membrane Proteins; Microtubule-Associated Proteins; Phosphatidylinositol 3-Kinases; RNA Interference; Small Ubiquitin-Related Modifier Proteins; Ubiquitin-Activating Enzymes; Virus Replication; Vitamins

Tenofovir-containing antiviral therapy might result in acute renal failure and is able to induce tubular dysfunction with hypocalcemia. On the other hand, hypercalcemia induced by intoxication with colecalciferol has been described to induce renal failure in HIV-positive individuals as well. Here, the authors describe the unusual case of reversible renal failure due to hypercalcemia in a patient with low-dose colecalciferol substitution treated with tenofovir.. A 31-year-old HIV-positive female, CDC stage C3, was admitted to the authors' hospital with progressive renal failure and hypercalcemia. Antiretroviral therapy consisted of tenofovir and emtricitabine in combination with efavirenz. Additionally, she was on low-dose vitamin D(3) substitution (25 microg/d) and calcium supplementation (500 mg/d) due to systemic steroid treatment.. Additionally to regular control of renal function, serologic level of calcium should be supervised in patients concomitantly treated with tenofovir and colecalciferol.

Topics: Acquired Immunodeficiency Syndrome; Acute Kidney Injury; Adenine; Adrenal Cortex Hormones; Adult; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Calcium; Cholecalciferol; Cyclopropanes; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; Female; Humans; Hypercalcemia; Immune Reconstitution Inflammatory Syndrome; Kidney Function Tests; Mycobacterium avium-intracellulare Infection; Organophosphonates; Osteoporosis; Tenofovir