Research ArticleImmunology

CD4+ T cell–dependent and CD4+ T cell–independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals

See allHide authors and affiliations

Sci. Signal.  20 Oct 2015:
Vol. 8, Issue 399, pp. ra104
DOI: 10.1126/scisignal.aab0808

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

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.

View Full Text