Immunoregulatory cytokine changes result from HIV infection, with decreased type 1 cytokines that enhance cellular immunity (CI) and increased type 2 cytokines that augment humoral immunity (HI). IL-12 and IL-10 increase and decrease CI, respectively, and are produced by APC that are monocytes (MC) and dendritic cells (DC), important targets of HIV infection. MC from HIV+ patients produced reduced levels of IL- 12 and increased levels of IL-10, as did MC infected in vitro with HIV. In contrast, DC appeared to be resistant to HIV-induced cytokine changes. Therapeutic trials of pediatric AIDS patients with highly active anti-retroviral therapy (HAART) indicated that patients who presented with reduced viral loads and increased CD4 counts did not exhibit normalized IL-12 and IL-10 production. This finding suggests that multi-drug therapy-induced changes in CD4 count and viral load is not reflected in improved immune function. In vitro production of IL-12 by MC of HIV+ patients was restored by the synergistic effects of IFN- gamma and CD40 ligand, suggesting that this combination might be used in therapeutic trials. MC from uninfected newborns of HIV-infected mothers did not produce IL-12, in contrast to the MC of newborns of HIV uninfected mothers that did produce IL-12. Stimulation of PBMC with allogeneic leukocytes resulted in the production of IL-2, which was responsible for by-passing an induced defect in the CD80/86~CD28 costimulatory pathway. This defect is characteristic of immune dysregulation in HIV/AIDS. Stimulation of PBMC from HIV- control donors and some HIV+ patients with influenza A virus (Flu) results in the production of multiple anti-HIV factors that inhibit both CCR5- and CXCR4-using viral isolates at different points in the HIV replication cycle. These factors are produced by either CD4- or CD8-depleted PBMC cultures. Stimulation of PBMC with allogeneic leukocytes also results in the production of multiple anti-HIV factors. Efficient allo- stimulated anti-HIV factor production appears to be HLA associated, with the HLA-A2 allele conferring potent factor production. AZT was incorporated into the fetal cord blood leukocytes from a majority of women who received AZT during pregnancy. Based on experience from a murine model, this finding raises the possibility of long-term AZT- induced carcinogenesis in the offspring. Immunization of SIV-infected macaques with a poxvirus vector expressing SIV gag, pol and env genes protected against viral rebound when anti-retroviral therapy was withdrawn, and raised the possibility of this strategy for immune-based therapy. Mice transfected with the entire HIV-1 genome expressed virus in their monocytes but not in their T cells when infected with murine pathogens.AIDS Title: Immune Dysregulation In HIV/AIDS - AIDS, Cytokines, genes, HIV, T cells, HLA, antigen-presenting cells, - Human Tissues, Fluids, Cells, etc.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009267-17
Application #
6289245
Study Section
Special Emphasis Panel (EIB)
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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