CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals
A vital defect in the immune systems of HIV-infected individuals is the loss of CD4⁺ T cells, resulting in impaired immune responses. We hypothesized that there were CD4⁺ T cell–dependent and CD4⁺ T cell–independent alterations in the immune responses of HIV-1⁺ individuals. To test this, we analyzed...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
American Association for the Advancement of Science (AAAS)
2017
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| Online Access: | http://hdl.handle.net/1721.1/108235 https://orcid.org/0000-0001-7604-1333 https://orcid.org/0000-0003-1570-9445 |
| Summary: | A vital defect in the immune systems of HIV-infected individuals is the loss of CD4⁺ T cells, resulting in impaired immune responses. We hypothesized that there were CD4⁺ T cell–dependent and CD4⁺ T cell–independent alterations in the immune responses of HIV-1⁺ individuals. To test this, we analyzed the secretion of cytokines and chemokines from stimulated peripheral blood mononuclear cell (PBMC) populations from HIV+ donors, healthy donors, and healthy donors with CD4⁺ T cells experimentally depleted. Multivariate analyses of 16 cytokines and chemokines at 6 and 72 hours after three stimuli (antibody-coated beads to stimulate T cells and R848 or lipopolysaccharide to stimulate innate immune cells) enabled integrative analysis of secreted profiles. Two major effects in HIV⁺ PBMCs were not reproduced upon depletion of CD4⁺ T cells in healthy PBMCs: (i) HIV⁺ PBMCs maintained T cell–associated secreted profiles after T cell stimulation; (ii) HIV⁺ PBMCs showed impaired interferon-γ (IFN-γ) secretion early after innate stimulation. These changes arose from hyperactive T cells and debilitated natural killer (NK) cell, respectively. Modeling and experiments showed that early IFN-γ secretion predicted later differences in secreted profiles in vitro. This effect was recapitulated in healthy PBMCs by blocking the IFN-γ receptor. Thus, we identified a critical deficiency in NK cell responses of HIV-infected individuals, independent of CD4⁺ T cell depletion, which directs secreted profiles. Our findings illustrate a broad approach for identifying key disease-associated nodes in a multicellular, multivariate signaling network. |
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