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

Abstract

HIV infection is a risk factor for cardiovascular disease (CVD). This risk is accentuated by certain combination antiretroviral therapies (cARTs), independent of their effects on lipid metabolism and insulin sensitivity. We sought to define potential mechanisms for this association through systematic review of clinical and preclinical studies of CVD in the setting of HIV/cART from the English language literature from 1989 to March 2018. We used PubMed, Web of Knowledge and Google Scholar, and conference abstracts for the years 2015-March 2018. We uncovered three themes: (1) a critical role for the HIV protease inhibitor (PI) ritonavir and certain other PI-based regimens. (2) The importance of platelet activation. Virtually all PIs, and one nucleoside reverse transcriptase inhibitor, abacavir, activate platelets, but a role for this phenomenon in clinical CVD risk may require additional postactivation processes, including: release of platelet transforming growth factor-β1; induction of oxidative stress with production of reactive oxygen species from vascular cells; suppression of extracellular matrix autophagy; and/or sustained proinflammatory signalling, leading to cardiac fibrosis and dysfunction. Cardiac fibrosis may underlie an apparent shift in the character of HIV-linked CVD over the past decade from primarily left ventricular systolic to diastolic dysfunction, possibly driven by cART. (3) Recognition of the need for novel interventions. Switching from cART regimens based on PIs to contemporary antiretroviral agents such as the integrase strand transfer inhibitors, which have not been linked to clinical CVD, may not mitigate CVD risk assumed under prior cART. In conclusion, attention to the effects of specific antiretroviral drugs on platelet activation and related profibrotic signalling pathways should help: guide selection of appropriate anti-HIV therapy; assist in evaluation of CVD risk related to novel antiretrovirals; and direct appropriate interventions.

Keywords: HIV; cART; myocardial fibrosis; oxidative stress; platelet activation.

Figure 1

TGF-β1 regulates collagen synthesis and accumulation to maintain regulated extracellular matrix (ECM) production and deposition under physiological conditions. This involves positive signalling pathways initiating collagen synthesis mediated by the nuclear signalling adapter protein TRAF6 via Smad2,3 (canonical) and TAK1/MKK3/p38 (non-canonical) pathways. Mechanisms for collagen degradation via autophagy are linked to TAK1/MKK3/p38. TRAF6 is regulated via immunoproteasome degradation. TGF-β1, transforming growth factor β1; TRAF6, tumour necrosis factor receptor- associated factor 6.

Figure 2

HIV infection leads to increases in TGF-β1 levels, which may induce pathologic cardiac fibrosis. Active TGF-β1 upregulation can occur through various mechanisms, including direct binding of HIV envelope to platelets, induction of IL-6 and IL-8 and induction of tissue factor and reactive oxygen species (ROS). Other cells involved in this inflammatory milieu, may also contribute to TGF-β release. cART may mitigate, but not abolish, these perturbations. In addition, certain antiretroviral therapies, particularly those based on protease inhibitors, may accelerate cardiac fibrosis via direct activation of platelets. Metabolic disturbances linked to HIV and certain cART regimens may contribute to these pathological processes as, for example, cART-linked hyperlipidaemia can activate platelets. cART, combination antiretroviral therapy; TGF-β, transforming growth factor β.

Figure 3

Pathophysiology of CVD risk in association with cellular and metabolic pathways may be differentially affected by specific antiretroviral agents. Individuals drugs may be involved in pathways that primarily accelerate CVD risk, are neutral or decrease that risk. Certain antiretrovirals have positive and negative influences, thereby confounding attempts at prediction of impact on CVD risk. cART, combination antiretroviral therapy; CVD, cardiovascular disease; ECM, extracellular matrix; LV, left ventricle; ROS, reactive oxygen species; TGF-β1, transforming growth factor β1; TNF, tumour necrosis factor; TRAF6, TNF receptor-associated factor 6.

Figure 4

Pathways for intervention in HIV/cART-associated cardiac fibrosis in the platelet and the myofibroblast or other collagen-producing cells. Certain protease inhibitor therapies can activate platelets, induce ROS and suppress ECM autophagy. Positive feedback loops between ROS generation, platelet activation, M1 inflammatory macrophage subset polarisation and myofibroblast activity have been demonstrated. Oxidative stress characteristic of this milieu induces ROS, which may promote autophagy, and reactive nitrogen species (RNS) which can block it. Nrf2 activators may intervene in all of these pathways. ECM, extracellular matrix; Nrf2, nuclear factor erythroid 2-related factor 2; ROS, reactive nitrogen species; TGF-β1, transforming growth factor β1; TNF, tumour necrosis factor; TRAF6, TNF receptor-associated factor 6.