The Role of Transforming Growth Factor Beta-1 in the Progression of HIV/AIDS and Development of Non-AIDS-Defining Fibrotic Disorders

Abstract

Even after attainment of sustained viral suppression following implementation of highly active antiretroviral therapy, HIV-infected persons continue to experience persistent, low-grade, systemic inflammation. Among other mechanisms, this appears to result from ongoing microbial translocation from a damaged gastrointestinal tract. This HIV-related chronic inflammatory response is paralleled by counteracting, but only partially effective, biological anti-inflammatory processes. Paradoxically, however, this anti-inflammatory response not only exacerbates immunosuppression but also predisposes for development of non-AIDS-related, non-communicable disorders. With respect to the pathogenesis of both sustained immunosuppression and the increased frequency of non-AIDS-related disorders, the anti-inflammatory/profibrotic cytokine, transforming growth factor-β1 (TGF-β1), which remains persistently elevated in both untreated and virally suppressed HIV-infected persons, may provide a common link. In this context, the current review is focused on two different, albeit related, harmful activities of TGF-β1 in HIV infection. First, on the spectrum of anti-inflammatory/immunosuppressive activities of TGF-β1 and the involvement of this cytokine, derived predominantly from T regulatory cells, in driving disease progression in HIV-infected persons via both non-fibrotic and profibrotic mechanisms. Second, the possible involvement of sustained elevations in circulating and tissue TGF-β1 in the pathogenesis of non-AIDS-defining cardiovascular, hepatic, pulmonary and renal disorders, together with a brief comment on potential TGF-β1-targeted therapeutic strategies.

HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies

“…Simian immunodeficiency virus-infected macaques show cardiac dysfunction similar to that of HIV infection, in association with interstitial and vascular fibrosis and infiltration of cardiac tissue with proinflammatory macrophages 63 64The role of TGF-β1 in development of CVD and other non-AIDS defining fibrotic disorders in the setting of HIV/cART is of increasing interest 55 65 66. Aortic arterial fibrosis is prominent in HIV-infected individuals versus controls and is not suppressed by cART 32.…”

“…The role of TGF-β1 in development of CVD and other non-AIDS defining fibrotic disorders in the setting of HIV/cART is of increasing interest 55 65 66. Aortic arterial fibrosis is prominent in HIV-infected individuals versus controls and is not suppressed by cART 32.…”

Extracellular Vesicles in Smoking-Mediated HIV Pathogenesis and their Potential Role in Biomarker Discovery and Therapeutic Interventions

“…The potential of EVs is already under investigation in terms of biomarker identification, diagnosis, and prognosis of various conditions, and as therapeutic carriers of drugs in the periphery as well as in the CNS. Our studies and others have postulated the prospect of IL-6, RANTES, soluble CD14, and properdin being potential biomarkers for tobacco-enhanced HIV-pathogenesis [37,49,128,129,[131][132][133][134]. Whether they could be used in actual therapeutic settings will require further study.…”

“…Soluble CD14 is a biomarker for monocyte activation, which is also associated with cardiovascular disease [132]. On the other hand, TGF-β1 has a crucial role in regulating cells of immune system, in which increasing TGF-β1 was correlated to a defective T cell proliferation in an HIV-infected population [133]. Among these two, TGF-β1 is reported to be in EVs, however confirming its potential as a biomarker for smoking-mediated HIV progression warrants further investigation [134].…”

“…In addition, a few possible markers, IL-6, RANTES, soluble CD14, and properdin have been identified within EVs isolated from the plasma of HIV smokers [37,49,128,129,[131][132][133][134]. However, further studies are warranted to establish their true potential as biomarkers of smoking-induced HIV pathogenesis.…”