Dynamics of Transforming Growth Factor (TGF)-β Superfamily Cytokine Induction During HIV-1 Infection Are Distinct From Other Innate Cytokines

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection triggers rapid induction of multiple innate cytokines including type I interferons, which play important roles in viral control and disease pathogenesis. The transforming growth factor (TGF)-β superfamily is a pleiotropic innate cytokine family, some members of which (activins and bone morphogenetic proteins (BMPs)) were recently demonstrated to exert antiviral activity against Zika and hepatitis B and C viruses but are poorly studied in HIV-1 infection. Here, we show that TGF-β1 is systemically induced with very rapid kinetics (as early as 1–4 days after viremic spread begins) in acute HIV-1 infection, likely due to release from platelets, and remains upregulated throughout infection. Contrastingly, no substantial systemic upregulation of activins A and B or BMP-2 was observed during acute infection, although plasma activin levels trended to be elevated during chronic infection. HIV-1 triggered production of type I interferons but not TGF-β superfamily cytokines from plasmacytoid dendritic cells (DCs) in vitro, putatively explaining their differing in vivo induction; whilst lipopolysaccharide (but not HIV-1) elicited activin A production from myeloid DCs. These findings underscore the need for better definition of the protective and pathogenic capacity of TGF-β superfamily cytokines, to enable appropriate modulation for therapeutic purposes.

CD160 Promotes NK Cell Functions by Upregulating Glucose Metabolism and Negatively Correlates With HIV Disease Progression

“…According to our findings, CD160 + NK cells also exhibited increasing levels of CD69 and Ki67, as well as producing more TNF-a and IFN-g, and CD160 expression was strongly associated with Ki67, TNFa, and IFN-g production, revealing that CD160 may improve NK cell activation, proliferation, and cytokine production. NK cells from CD160-deficient mice produced reduced levels of IFN-g and TNF-a, and formed larger tumors than wildtype controls (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). We also found that expression of CD160 on total NK cells was positively and negatively correlated with CD4 + T cell counts and HIV viral load, respectively, possibly because cells that do not express CD160 have diminished effector functions, leading to an increase in HIV viral load and a decrease in CD4 + T cells.…”

“…Little is known about the mechanism involved in downregulation of CD160 in HIV-infected individuals. TGF-b1 is systemically elevated as early as 1-4 days after viremic dissemination begins in acute HIV-1 infection and remains raised throughout infection (37). TGF-b1 is an immunosuppressive cytokine that negatively regulates IFN-g production and expression of the activating receptors NKG2D and NKp30, reducing NK cell cytotoxicity and affecting antitumor activity (47).…”

“…As a multipotent immunosuppressive cytokine, transforming growth factor beta (TGF-b) is systemically induced during acute HIV infection, and levels are sustained throughout infection (37). We hypothesized that TGF-b may inhibit CD160 expression on total NK cells; therefore, we assessed plasma TGF-b levels in the HIV-infected group and NC group, and found that levels were higher during HIV infection (Figure 6A).…”

The Role of Neuroinflammatory Mediators in the Pathogenesis of Traumatic Brain Injury: A Narrative Review

“…TGF-β, a pleiotropic cytokine, was believe to be involved in the intercellular communication pathways of growth, differentiation, morphogenesis, apoptosis, and immune response in different cell types of the body. − TGF-β was found to be expressed in almost all CNS cells . TGF-β may also inhibit the activation, migration, and proliferation of immune cells, while aiding nerve regeneration by stimulating the NGF production in the CNS, and controlling astrocyte proliferation as well as scar tissue formation .…”

Caracterização genética e funcional do NLRP3 em linfócitos e monócitos de indivíduos cronicamente infectados por HIV-1

“…A contínua estimulação com fatores pró-inflamatórios induz também a ativação de vias de regulação negativas, como as SOCS (Do inglês: Suppressor of Cytokine Signaling), que inibem as vias de ativação mediadas pelos PRRs (Baetz et al, 2004;Huang et al, 2020), a ubiquitinação de proteínas de sinalização dos PRRs e do próprio NLRP3 (Kattah et al, 2017;Lopez et al, 2020), e a produção de citocinas anti-inflamatórias como IL-10 e TGF-β, cujos níveis são descritos aumentados em pacientes HIV (Dickinson et al, 2020).…”