Suppressor of cytokine signaling (SOCS) is a family of proteins upregulated rapidly in response to stimulation by Toll-like receptors, cytokines, grow factors and hormones that provide a negative feedback to the stimulation that triggered them by inhibiting the JAK-STAT signaling pathway. SOCS proteins, in particular SOCS3, have also been described as having a central role in metabolic syndrome, diabetes and atherosclerosis. In vivo data for SOCS levels in HIV-infected patients are very limited.
Using intracellular staining (ICS) and flow cytometric analyses, we evaluated the expression kinetics of SOCS1 and SOCS3 proteins and their activity by measuring the percentages and the accumulation level, estimated via MFI, of SOCS1, SOCS3, TLRs, IFNs and other JAK-STAT signaling pathway-related proteins in individual subpopulations of blood and lymph node MNC, harvested at day 0, peak of infection, and week 20, and 60 from SIV-infected Rhesus macaques left untreated, treated with ART or ART+p38MAPK inhibitor. Boolean data analysis permitted the evaluation of co-expression of the above proteins.
In the context of untreated or treated chronic HIV or SIV infection, a persistent but aberrant activation of SOCS proteins and their targets is an important feature of the dysfunctional TLR-IFN-SOCS pathway. The percentage of SOCS+ cells remains higher than at peak viremia after 54-59 weeks of ART despite virus suppression and its expression does not correlate with viral loads. SOCS1 and SOCS3 expression is elevated in virtually all mononuclear cell subpopulations yet the inhibition of their targets JAK and STAT is not complete and markers of innate immunity that should be impacted by SOCS activity remain elevated.
Persistent SOCS protein expression during suppressed SIV infection supports the existence of additional stimulation that maintains their expression and/or dysregulation of their negative feedback. Incomplete JAK-STAT pathway suppression by SOCS proteins is consistent with residual activation of innate immunity pathways and dysregulation of antiviral immunity. Given the association of their expression with metabolic conditions, SOCS protein chronic activation could be also relevant to the metabolic complications observed in ART patients.