Role of membrane alterations in HIV-1 infection
Description
Acquired immunodeficiency syndrome (AIDS) is characterized by the depletion of CD4 positive T-lymphocytes, and the development of opportunistic infections as well as rare cancers. Human immunodeficiency virus (HIV), the etiologic agent of AIDS, infects and is proficient at killing CD4$\sp+$ T-cells. Plasma membrane alterations and intracellular ionic changes are implicated in HIV-1 induced cytopathogenicity. The HIV-1 envelope glycoproteins (Env) gp120 and gp41 are localized to cell membranes and may play a role in cytopathogenesis. The expression of envelope glycoproteins (HIV-1 strains JRCSF and HXB2) in Xenopus lavius oocytes caused an outward current, indicating membrane disturbances. Utilizing the tetracycline inducible expression system, expression of HIV-1 Env (strain HXB2) in the CD4$\sp+$ T-cell line Jurkat caused single cell death. Cell death is preceded by decreases in cytoplasmic and mitochondrial membrane potentials, and a decline in ATP levels. These results suggest HIV-1 Env induced modification of target cell membranes may impart contribute to HIV-1 cytopathogenesis The modified plasma membrane can be targeted by toxic compounds normally impermeable to uninfected cells. Hygromycin B, a low molecular weight (MW 527) aminoglycoside protein synthesis inhibitor, that is normally impermeable to mammalian cells at micromolar concentrations, selectively inhibits HIV expression and cytopathogenesis. Hygromycin B inhibited HIV-1 production in a dose-dependent manner during acute infection of peripheral blood mononuclear cells (PBMC) and CD4$\sp+$ T lymphoblastoid cells (H9). G418, a larger and more hydrophobic aminoglycoside (MW 692), did not display the same selective inhibition of HIV-1 production as hygromycin B. Relative to mock-infected cells protein synthesis in infected H9 cells was selectively inhibited by hygromycin B. PCR analysis demonstrated that hygromycin B did not inhibit HIV-1 reverse transcription These results suggest that HIV-1 Env induces alterations in plasma membrane permeability, and that the modified cell membrane may be a target for antiviral intervention and chemotherapy