HIV-1 imposes rigidity on blood and semen cytokine networks

Abstract

Problem: Although it is established that the levels of individual cytokines are altered by HIV-1 infection, the changes in cytokine interrelations that organize them into networks have been poorly studied. Here, we evaluated these networks in HIV-infected and HIV-uninfected individuals in fluid compartments that are critical for HIV-1 pathogenesis and transmission, namely blood and semen.

Method of study: In samples collected from therapy-naïve HIV-1-infected and HIV-1-uninfected individuals, we measured HIV-1-load, CD4 cell count, and levels of 21 cytokines using a multiplex bead assay.

Results: Cytokine networks in blood and semen were different for HIV-1-infected and HIV-1-uninfected individuals. In both compartments of HIV-1-infected individuals, the cytokine networks were more interlocked than in controls: HIV-1 infection resulted in the establishment of new correlations and in the strengthening of pre-existing correlations between different cytokines. In blood and semen of HIV-infected patients, there were, respectively, 68 and 72 statistically significant correlations between cytokines, while in uninfected individuals, there were 18 and 21 such correlations.

Conclusion: HIV-1 infection reorganizes the cytokine networks, establishing new strong correlations between various cytokines and thus imposes a high rigidity on the cytokine network. This rigidity may reflect the impairment of the ability of the immune system to respond to microbial challenges.

Figure 1. HIV-1 infection affects the cytokine networks in blood and seminal plasma

Correlations between cytokine concentrations in HIV-1-uninfected (a, c) and HIV-1-infected (b, d) individuals in blood (a, b) and seminal (c, d) plasmas. The levels of the following cytokines were measured: IL-1α, IL-1β, IL-2, IL-6, IL-7, CXCL8 (IL-8), IL-15, IL-16, CCL3 (MIP-1α), CCL4 (MIP-1β), CCL20 (MIP-3α), CCL5 (RANTES), CCL2 (MCP-1), CCL11(eotaxin-1), IFN-γ, CXCL9 (MIG), CXCL10 (IP-10), CXCL12b (SDF-1β), GM-CSF, TNF–α, and TGF-β. Neither IL-2 nor IFN-γ was found in seminal plasma. GM-CSF was not detected in any of the seminal plasma samples from HIV-1-uninfected individuals; therefore, correlations of the concentration of GM-CSF with that of other cytokines were not evaluated. Similarly, as GM-CSF was not detected in blood plasma samples from either HIV-1-infected or -uninfected individuals, correlations of its concentration with those of other cytokines in blood plasma were not evaluated. Because of the nonspecific spontaneous degranulation of CCL5 from platelets upon venipuncture, the measured levels of this cytokine were not included in the analysis of the blood plasma. Statistically significant correlations are presented as a heat map: different shades of red represent positive correlations of various strengths and different shades of blue represent negative correlations of various strengths. White cells in the matrix denote the absence of a statistically significant correlation between cytokines. Note that HIV-1 infection resulted in a dramatic increase of the number of correlations between different cytokines, thus making the cytokine network more interconnected.