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 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.Ragon Institute of MGH, MIT and HarvardNational Institutes of Health (U.S.) (AI6922694)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award #F32-CA180586)National Institutes of Health (U.S.) (U19-AI6922694)National Cancer Institute (U.S.) (David H. Koch Center for Integrative Cancer Research. Support (Core) Grant P30-CA14051