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Progressive impairment of monocytic function in HIV-1-infected human macrophage hybridomas
K Sperber1, G Hamrang, M J Louie
1Division of Clinical Immunology, Mount Sinai Medical Center, New York, New York 10029.
Abstract:
Using human macrophage hybridomas infected with HIV-1, we investigated monocyte function over a 5-week period after HIV-1 infection. Two clones, 63 and 30, were infected with HIV-1IIIB. Infection was documented by RT activity (15 x 10(6) cpm/ml), intracytoplasmic staining with an anti-p24 antibody, in situ hybridization with an HIV-1-specific riboprobe, and electron microscopy showing intracytoplasmic virus. Two weeks after infection, clones 63 and 30 lost expression of all class II antigens (DR, 81.7 vs. 0%; DQ, 15.6 vs. 0%; and DP, 76.9 vs. 0%) while retaining expression of class I (87.4 vs. 84.1%), LFA-1 (82.4 vs. 83.1%), and LFA-3 (79.1 vs. 74.7%) antigens when compared to uninfected cells. When tested for functional integrity, infected but not uninfected clone 63 cells failed to stimulate a tetanus-specific MHC-restricted T cell proliferative response 2 weeks after infection. Cytokine secretion and antigen processing were also perturbed as production of IL-1 was abolished 2 weeks after infection (although IL-6 secretion was augmented) and infected clone 63 cells failed to process exogenous antigen. Last, the viability of T cells cocultured with infected clone 63 was dramatically decreased 35 days after infection (85 vs. 15%). There was no evidence of transmission of HIV-1 to T cells, suggesting a toxic effect of infected clone 63. Taken together, these data suggest that altered macrophage function in our system occurs at multiple levels, which may account for the early immunological defects described in HIV-1 infection.
Insights
Human immunodeficiency virus (HIV-1) infection severely impairs macrophage function, leading to loss of class II antigens and reduced T cell stimulation. This study reveals multiple functional defects in HIV-1-infected macrophages, contributing to early immune system decline.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Human immunodeficiency virus (HIV-1) infection is known to cause immune system dysregulation.
- Macrophages play a critical role in immune responses and are targeted by HIV-1.
Purpose of the Study:
- To investigate the functional consequences of HIV-1 infection on human macrophage hybridomas over a 5-week period.
- To identify specific molecular and functional alterations in macrophages post-HIV-1 infection.
Main Methods:
- Infection of macrophage hybridoma clones (63 and 30) with HIV-1IIIB.
- Documentation of infection using reverse transcriptase (RT) activity, p24 antibody staining, in situ hybridization, and electron microscopy.
- Analysis of cell surface antigen expression (Class I, Class II, LFA-1, LFA-3) using flow cytometry.
- Assessment of T cell proliferative response, cytokine secretion (IL-1, IL-6), and antigen processing.
- Evaluation of T cell viability in co-culture with infected macrophages.
Main Results:
- HIV-1 infection led to a complete loss of class II antigen expression (DR, DQ, DP) on macrophages within 2 weeks, while Class I and adhesion molecule expression remained intact.
- Infected macrophages failed to stimulate T cell proliferation and exhibited impaired exogenous antigen processing.
- Production of IL-1 was abolished, while IL-6 secretion was augmented in infected macrophages.
- Co-culture with HIV-1-infected macrophages significantly decreased T cell viability, suggesting a cytotoxic effect.
Conclusions:
- HIV-1 infection profoundly alters macrophage function at multiple levels, including antigen presentation, cytokine production, and antigen processing.
- These functional deficits in macrophages may contribute to the early immunological defects observed in HIV-1 infection.
- The observed toxicity towards T cells highlights a potential mechanism for immune deterioration in HIV-1 pathogenesis.