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HIV infection of H9 lymphoblastoid cells chronically activates the inositol polyphosphate pathway
1Department of Immunology, St Mary's Hospital Medical School, London, UK.
Insights
HIV infection disrupts cellular signaling in CD4+ lymphocytes, causing chronic activation and impaired calcium responses. This study reveals how these signal transduction defects contribute to immune dysfunction in HIV.
Area of Science:
- Immunology
- Cell Biology
- Virology
Background:
- Human Immunodeficiency Virus (HIV) infection impairs CD4+ lymphocyte function.
- HIV leads to reduced CD4+ cell numbers and functional abnormalities in various cell types.
Purpose of the Study:
- To investigate the impact of HIV infection on signal transduction pathways in the H9 CD4+ lymphoblastoid cell line.
- To elucidate the mechanisms underlying CD4+ lymphocyte dysfunction in HIV.
Main Methods:
- Studied signal transduction in HIV-infected H9 cells.
- Measured inositol polyphosphate metabolites (InsP3, InsP4) and intracellular free calcium concentrations.
- Stimulated cells with phytohemagglutinin (PHA) and anti-CD3 antibody.
Main Results:
- Resting HIV-infected H9 cells exhibit chronic activation with elevated InsP3 and InsP4 levels, and increased intracellular calcium.
- PHA stimulation caused a decrease in InsP3 but an increase in InsP4.
- Both PHA and anti-CD3 antibody elicited an attenuated intracellular calcium rise in HIV-infected cells.
Conclusions:
- HIV infection alters inositol polyphosphate metabolism and calcium signaling in CD4+ cells.
- These signal transduction abnormalities provide a potential mechanism for CD4+ lymphocyte functional defects in HIV.
- The findings may also explain functional issues in other cell types affected by HIV.
Abstract:
Infection with HIV causes a reduction in the numbers and function of CD4+ lymphocytes and functional abnormalities of other cells. We have studied the effect of HIV infection on signal transduction in the H9 lymphoblastoid CD4+ cell line. Resting HIV-infected H9 cells show evidence of chronic activation with raised levels of InsP3 and InsP4, the active metabolites of the inositol polyphosphate pathway, and a consequently raised intracellular free calcium concentration. Stimulation of HIV-infected H9 cells with phytohemagglutinin (PHA) leads to a fall in the previously raised levels of InsP3 but a further rise in InsP4, whilst an attenuated intracellular calcium rise is seen with both PHA and anti-CD3 antibody. The observed effects of HIV infection on signal transduction provide a mechanism to explain the functional defects in CD4+ lymphocytes and, possibly, other cell types.