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HIV infection impairs more than just T cells
Infection with HIV, the virus that causes AIDS, results in substantial CD4+ T cell loss, which impairs immune responses to bacterial and fungal infections. To uncover changes in other immune cell types, Arnold et al. compared the pathogen-induced responses of peripheral blood mononuclear cells (PBMCs) from HIV-infected patients with the responses of PBMCs from healthy donors. They also analyzed the responses of healthy donor PBMCs that were experimentally depleted of CD4+ T cells to mimic the HIV-infected state. Mathematical analysis predicted and experiments showed that, independently from the loss of CD4+ T cells, the defective response of the immune cell network in HIV-infected patients to pathogens was associated with decreased production of interferon-γ by natural killer cells. Similar analysis of immune cells populations, rather than of purified subsets, may help to identify network-level effects in other diseases.
Abstract
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.
