Roles of intracellular ions in human immunodeficiency virus production and cytopathic effects
Description
Infection by cytolytic viruses can result in alteration of the plasma membrane and changes in the intracellular content of ions and other small molecules. A variety of steps in viral replication proceed more efficiently in the altered intracellular ionic environment present in the infected cells. Acute infection of CD4+ lymphoid cells by human immunodeficiency virus type 1 (HIV-1) induces an increase in the intracellular concentration of potassium (K+). Media containing reduced or elevated concentrations of K+ was used to investigate the role of this ion in HIV-1 production and cytopathology. Incubation of CD4+ T-lymphoblastoid cells acutely-infected by HIV-1 (strain LAI) in low K+ medium resulted in a decrease in HIV-1 production and markedly diminished HIV-1 induced cytopathic effects (CPE) relative to cells incubated in medium containing a normal K+ concentration (approximately 5 mM). Incubation of HIV-1 infected cells in media containing elevated concentrations of K+ increased HIV-1 production over the amount produced in cells incubated in normal K+ medium. Cells incubated in high K+ media also displayed enhanced HIV-1-induced cytopathology. The decrease in HIV-1 production by low K+ medium and increase by high K+ media could not be accounted for by effects on HIV-1 reverse transcription. However, low K+ medium inhibited HIV-1 protein synthesis and high K+ media increased HIV-1 protein synthesis. These results suggest that the HIV-1 induced increase in intracellular K+ concentration is required for efficient viral replication and to induce cytopathology. A possible role of alteration of intracellular K+ concentration in HIV-infected cell killing is based on the assumption that K+ homeostasis in HIV-infected cells differs from normal cells Several HIV-1 proteins have been shown to perturb ionic permeability of the plasma membrane. The studies presented here suggested that HIV-1 Nef proteins are capable of inducing alterations in the intracellular potassium concentration but not the intracellular pH in CD4+ lymphocytes. These results provide further support possible dysregulation of K+ transport in HIV-mediated cytopathogenesis. Nef proteins did not form ion channel-like pores in Xenopus oocytes, however, this HIV-1 protein may alter intracellular potassium concentration by acting as ion channel or interacting with monovalent ion channels such as K+ channels in CD4+ lymphocytes The CXCR4 is a member of the G-protein-coupled chemokine receptor family with seven membrane-spanning domains and is required along with CD4 for entry into the cell by syncytium-inducing (SI) HIV-1 strains. Acute cytopathic infection of human T-lymphoid cell line H9 with HIV-1 resulted in an extensive downregulation of cell surface CXCR4 expression. Surface CXCR4 receptor decline was concomitant with the increase in HIV-1 antigen expression. However, HIV-1 infection did not alter the cell surface level of CD3. CXCR4 is internalized from the cell surface and concentrated in intracellular compartments in H9 cells after HIV-1 infection. Both CXCR4 and HIV-1 proteins are colocalized in HIV infected cells. Downregulation of HIV-1 coreceptor, CXCR4 following productive infection may render infected cells refractory to superinfection by viruses that use the same receptor