Exploring the impact of TGF-β superfamily cytokines on HIV-1 replication

Thesis

The transforming growth factor (TGF)-β superfamily comprises evolutionarily conserved cytokines including TGF-β isoforms, activins and bone morphogenetic proteins (BMPs). Recent work has shown that TGF-β superfamily cytokines elicit transcriptional changes overlapping with those of type I interferons (IFNs) in hepatoma and epithelial cells and control the replication of several viruses by IFN-dependent and -independent mechanisms. Type I IFNs play a complex role in HIV-1 infection, restricting virus replication and transmission but also driving immune activation and apoptosis. However, the roles of TGF-β superfamily cytokines in HIV-1 infection are less well understood. In this thesis, both the induction of TGF-β superfamily cytokines during HIV-1 infection and their putative roles in HIV-1 control and pathogenesis were explored.

TGF-β1 was found to be systemically induced very early in acute HIV-1 infection (prior to the innate cytokine “storm”), likely due to release from platelets; remaining upregulated throughout infection. In contrast, activins A and B, and BMP-2 were not found to be significantly perturbed during acute or chronic infection. TGF-β1 inhibited HIV-1 replication in primary, activated CD4⁺ T cells in vitro, but had no effect on HIV-1 replication in less activated cells or in macrophages. Other TGF-β superfamily cytokines did not inhibit HIV-1 replication in any of the cell types tested. Neither TGF-β₁, activin A nor BMP-2 upregulated antiviral genes or modulated type I IFN signalling genes in activated CD4+ T cells. Further investigation of how TGF-β₁ restricts HIV-1 replication suggested that TGF-β₁ may reduce the proportion of Th17 cells in activated PBMC cultures. Most notably, TGF-β₁ reduced cell activation status and proliferation; and diminished transcriptional activity from the HIV-1 promoter. This study gives insight into the utility of harnessing TGF-β1 activity for HIV-1 prophylaxis or therapy, and provides broader insight into an apparent cell type-dependent nature of innate antiviral activity of TGF-β superfamily cytokines.

Authors: Dickinson, M

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: innate immunity; BMP; transforming growth factor beta; TGF beta; HIV; cytokine; activin; bone morphogenetic protein
• Subjects: Virology; Immunology