Immunomodulation of the antiviral response of macrophages of newborns by type I interferon adjuvants

Newborns (NBs) are more susceptible to infections due to the relative immaturity of innate and adaptive immune responses. In this scenario, immunological modulation has been investigated as a strategy to increase protection against infections. Macrophages play a role on both innate and adaptive immunity, being potential targets for stimulating the neonatal immune response. In HIV infection, macrophages act as viral reservoirs contributing to viral replication for long periods of time. Toll-like receptor agonists can control HIV-1 replication in adult macrophages in vitro but the impact of such molecules on macrophages of NBs has not yet been verified. Therefore, the aim of this study was to evaluate the immunomodulatory and antiviral effects of type I interferon adjuvants on macrophages of neonates and adults. For this, macrophages were generated from monocytes isolated from umbilical cord blood and peripheral blood from adults. It was observed that the macrophages of NBs have an anti-inflammatory profile with IL-10 production. The findings also show that neonatal macrophages are similar to adult macrophages regarding the gene expression of innate immunity components. However, neonatal cells show increased viral replication when infected with HIV-1 in vitro. It has also been found that the treatment with TLR7/TLR8 (CL097), STING (cGAMP) and TLR3/RIG-I/MDA-5 (Poly-I:C) agonists induces the expression of IFN-&#223 and the antiviral factor MxA in macrophages of NBs and adults, however CL097 is more effective in promoting the expression of cytosolic sensors, especially RIG-I and cGAS, in addition to inhibit the expression of TREX-1. This agonist also promotes the induction of inflammatory cytokines and &#223-chemokines, as well as the regulatory cytokine IL-10. The results further indicate that CL097 inhibits HIV-1 replication in macrophages of NBs and adults, and this effect does not seem to be dependent on NF-&#967B activation. Therefore, CL097 shows a relevant therapeutic potential as adjuvant of the neonatal response, being able to induce antiviral factors that inhibit HIV-1 replication. (AU)