Apoptosis of Hepatocytes: Relevance for HIV-Infected Patients under Treatment

Abstract

Due to medical advances over the past few decades, human immunodeficiency virus (HIV) infection, once a devastatingly mortal pandemic, has become a manageable chronic condition. However, available antiretroviral treatments (cART) cannot fully restore immune health and, consequently, a number of inflammation-associated and/or immunodeficiency complications have manifested themselves in treated HIV-infected patients. Among these chronic, non-AIDS (acquired immune deficiency syndrome)-related conditions, liver disease is one of the deadliest, proving to be fatal for 15–17% of these individuals. Aside from the presence of liver-related comorbidities, including metabolic disturbances and co-infections, HIV itself and the adverse effects of cART are the main factors that contribute to hepatic cell injury, inflammation, and fibrosis. Among the molecular mechanisms that are activated in the liver during HIV infection, apoptotic cell death of hepatocytes stands out as a key pathogenic player. In this review, we will discuss the evidence and potential mechanisms involved in the apoptosis of hepatocytes induced by HIV, HIV-encoded proteins, or cART. Some antiretroviral drugs, especially the older generation, can induce apoptosis of hepatic cells, which occurs through a variety of mechanisms, such as mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR), all of which ultimately lead to caspase activation and cell death.

Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients – a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown

“…At the same time, HIV releases numerous profibrogenic, proinflammatory and proapoptotic signals in the liver parenchyma ( 178 ) which contribute to ROS generation ( 179 ), metabolic activation of CD4+T cells and immune stimulation ( 180 ). Consequently, HIV induces the cellular death by apoptosis or pyroptosis along with hepatocytes necrosis ( 181 ). Additionally, the activation of hepatic T and B lymphocytes during HIV infection and their ensuing apoptosis aggravates the inflammatory response and accelerates the fibrogenesis induced by HSCs ( 182 ) ( Figure 2 ).…”

The therapeutic effects of berberine against different diseases: A review on the involvement of the endoplasmic reticulum stress

“…Dyslipidemia and its complications, such as atherosclerosis and endothelial dysfunction, are the side effects of HIV protease inhibitors treatment (Nzuza & Owira, 2019). Multiple mechanisms are involved in complications associated with the HIV protease inhibitors, including apoptosis inflammation and ER stress (Gruevska et al, 2021; Nzuza & Owira, 2019). The inhibitory effect of BBR on HIV protease inhibitor‐induced inflammation in murine macrophages has been shown (Zha et al, 2010).…”

“…Multiple mechanisms are involved in complications associated with the HIV protease inhibitors, including apoptosis inflammation and ER stress (Gruevska et al, 2021;Nzuza & Owira, 2019). The inhibitory effect of BBR on HIV protease inhibitor-induced inflammation in murine macrophages has been shown (Zha et al, 2010).…”

Mathematical Analysis of the Role of HIV/HBV Latency in Hepatocytes

“…It is worth mentioning that in addition to CD4+ cells, HIV infects other body cells. There is still a debate on HIV infection in hepatocytes, despite evidence from research that HIV productively infects hepatocytes and other hepatoma cells in a CD4-independent way [6]. HIV has also a direct cytopathic effect on hepatocytes, primarily triggering apoptosis via the HIV gp120 proteinreceptor signalling pathway [7].…”