RESUMEN
Several groups have shown that peripheral CD8+ lymphocytes can be infected with human immunodeficiency virus type 1 (HIV-1), resulting in noncytopathic infection and persistent production of viral particles. We studied the ability of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI) to inhibit the establishment of HIV-1 infection in CD8+ cells that were derived from cultures of peripheral blood lymphocytes exposed to both virus and drug. In situ infection of CD8+ cells was demonstrated by double flow cytometry analysis by using both anti-glycoprotein 120 (anti-gp120) and anti-CD8 monoclonal antibodies. At higher concentrations of drug (e.g., 0.4 microM AZT), the production of viral particles was inhibited for over 2 months, as assessed by p24 antigen levels in the culture medium. We also performed a time course experiment to determine whether HIV-1 infection of CD8+ cells would be affected by treatment of peripheral blood lymphocytes with AZT or ddI for different intervals following exposure to virus. Quantitative PCR revealed that 0.4 microM AZT, added as late as 24 h after infection, interfered with the formation of proviral DNA in CD8+ cells. Both HIV-1 load and the production of progeny virions by CD8+ cells, as monitored by reverse transcriptase activity in culture fluids, were inhibited by both AZT and ddI in a dose-dependent manner.
Asunto(s)
Antígenos CD8/inmunología , Didanosina/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Linfocitos/microbiología , Zidovudina/farmacología , Anticuerpos Monoclonales/inmunología , Secuencia de Bases , Células Cultivadas , Sondas de ADN , ADN Viral/análisis , Citometría de Flujo , Infecciones por VIH/microbiología , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Datos de Secuencia MolecularRESUMEN
The effects of phosphorus depletion on cardiac muscle function in six awake dogs were evaluated with surgically implanted transducers to serially measure ascending aortic root blood flow and high fidelity left ventricular pressure. After the animals recovered from surgery, phosphorus depletion was induced by feeding them a synthetic phosphorus-deficient diet plus aluminum carbonate gel for 35 days, followed by the same diet with phosphorus supplementation for 21 days. In addition to the cardiac studies, sequential measurements of phosphorus content in skeletal muscle and phosphorus in serum were obtained to ascertain the level of phosphorus depletion. Serum inorganic phosphorus concentration (mg/100 ml) decreased from 5.1 +/- 0.1 on day 0 to 0.9 +/- 0.1 on day 35 (P less than 0.01), and total muscle phosphorus (content mmul/100 g fat-free dry weight) decreased from 28.0 +/- on day 0 to 22.6 +/- 0.5 on day 35 (P less than 0.01). During the period of phosphorus depletion, there was no significant change in heart rate; however, stroke volume (milliliter) and peak blood flow velocity (centimeter per second) declined from 24 +/- 2 to 17 +/- 2 (P less than 0.01) and 121 +/- 12 to 98 +/- 7 (P less than 0.01), respectively. Maximum ascending aortic blood flow acceleration (centimeter per second square) and maximum left ventricular time rate of change of pressure (mm Hg per second) also decreased from 4,630 +/- 313 to 3,817 +/0 346 (P less than 0.01) and 2,582 +/- 347 to 2,120 +/- 297 (P less than 0.01) during phosphorus depletion. After repletion all values returned to control values. These results indicate that moderate diet-induced phosphorus depletion can depress myocardial performance. With repletion of phosphorus, myocardial performance improves.