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Correlation between high level gp160 expression and reduced CD4 biosynthesis in clonal derivatives of human
R Geleziunas1, S Bour, M A Wainberg
1McGill AIDS Centre, Lady Davis Institute-Jewish General Hospital, Montreal, Canada.
Abstract:
We have compared cytoplasmic CD4 mRNA accumulation, CD4 biosynthesis and steady-state levels of both CD4 protein and mRNA in a variety of clonal derivatives of U-937 cells, chronically infected with human immunodeficiency virus type 1 IIIB (HIV-1), that express various cellular and viral phenotypes. These phenotypes included defective processing of either gp160 or Gag-Pol, viruses with severely limited host-range, and inability to generate viral products. All clones, with the exception of the one that failed to generate viral mRNA and proteins, did not express cell surface CD4. Furthermore, each of these clones had steady-state levels of CD4 mRNA which were either equivalent to or higher than those of the parental U-937 cell line. Patterns of cytoplasmic CD4 mRNA levels resembled those of total RNA, suggesting that CD4 mRNA transport from the nucleus to the cytoplasm was unaffected by HIV-1 infection. Profiles of steady-state levels of the CD4 protein resembled those of CD4 mRNA in the UHC clones, but CD4 biosynthesis was reduced in all clones with the exception of that which failed to express viral products. This report is the first demonstration that steady-state CD4 biosynthesis is reduced in HIV-1-infected cells. In general, there was a good correlation between high levels of expression of gp160 and reduced CD4 biosynthesis. These results suggest that HIV-1 env gene products may contribute to the observed reduction in levels of CD4 biosynthesis.
Insights
Human immunodeficiency virus type 1 (HIV-1) infection reduces CD4 protein biosynthesis in U-937 cells. HIV-1 env gene products may contribute to this reduction, impacting CD4 protein levels.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Human immunodeficiency virus type 1 (HIV-1) infects CD4+ T cells, crucial for immune function.
- CD4 protein and mRNA levels are critical for HIV-1 pathogenesis and viral replication.
- Understanding CD4 regulation during chronic HIV-1 infection is vital for therapeutic strategies.
Purpose of the Study:
- To investigate the impact of chronic HIV-1 infection on CD4 mRNA and protein levels in U-937 cell derivatives.
- To determine the relationship between viral phenotypes and CD4 expression.
- To identify mechanisms underlying CD4 downregulation during HIV-1 infection.
Main Methods:
- Comparison of cytoplasmic CD4 mRNA accumulation, CD4 biosynthesis, and steady-state levels of CD4 protein and mRNA.
- Analysis of U-937 cell clones with varying HIV-1-induced phenotypes (e.g., defective gp160 processing, limited host-range).
- Assessment of viral mRNA and protein production in infected cell lines.
Main Results:
- Most HIV-1 infected U-937 clones failed to express cell surface CD4, despite normal or elevated CD4 mRNA levels.
- Cytoplasmic CD4 mRNA levels were unaffected, indicating intact nuclear export.
- CD4 protein biosynthesis was reduced in most infected clones, correlating with high gp160 expression.
Conclusions:
- HIV-1 infection significantly reduces CD4 protein biosynthesis, independent of CD4 mRNA levels.
- HIV-1 env gene products are implicated in the observed reduction of CD4 biosynthesis.
- This study provides the first evidence of reduced steady-state CD4 biosynthesis in HIV-1-infected cells.