Possible Biomarkers for the Early Detection of HIV-associated Heart Diseases: A Proteomics and Bioinformatics Prediction

Abstract

The frequency of cardiovascular disorders is increasing in HIV-infected individuals despite a significant reduction in the viral load by antiretroviral therapies (ART). Since the CD4 + T-cells are responsible for the viral load as well as immunological responses, we hypothesized that chronic HIV-infection of T-cells produces novel proteins/enzymes that cause cardiac dysfunctions. To identify specific factors that might cause cardiac disorders without the influence of numerous cofactors produced by other pathogenic microorganisms that co-inhabit most HIV-infected individuals, we analyzed genome-wide proteomes of a CD4 + T-cell line at different stages of HIV replication and cell growth over > 6 months. Subtractive analyses of several hundred differentially regulated proteins from HIV-infected and uninfected counterpart cells and comparisons with proteins expressed from the same cells after treating with the antiviral drug Zidovudine/AZT and inhibiting virus replication, identified a well-coordinated network of 12 soluble/diffusible proteins in HIV-infected cells. Functional categorization, bioinformatics and statistical analyses of each protein predicted that the expression of cardiac-specific Ca2 + kinase together with multiple Ca2 + release channels causes a sustained overload of Ca2 + in the heart which induces fetal/cardiac myosin heavy chains (MYH6 and MYH7) and a myosin light-chain kinase. Each of these proteins has been shown to cause cardiac stress, arrhythmia, hypertrophic signaling, cardiomyopathy and heart failure (p = 8 × 10− 11). Translational studies using the newly discovered proteins produced by HIV infection alone would provide additional biomarkers that could be added to the conventional markers for an early diagnosis and/or development of specific therapeutic interventions for heart diseases in HIV-infected individuals.

Catalpol ameliorates doxorubicin‑induced inflammation and oxidative stress in H9C2 cells through PPAR‑γ activation

“…Drug-induced cardiomyopathy is a severe disease that occurs independent of other cardiovascular risk factors, but is a widespread side effect of a number of therapeutic agents, such as Daunorubicin, DOX and Paclitaxel ( 28-30 ). As it is difficult to identify symptoms and signs during the early stages of the disease, drug-induced cardiomyopathy often leads to refractory heart disease in the late stages, with increasing detrimental effects ( 31 , 32 ). DOX-induced cardiomyopathy is the most common type of drug-induced heart disease ( 33 ).…”

Cardiac MRI‐Based Assessment of Myocardial Injury in Asymptomatic People Living With Human Immunodeficiency Virus: Correlation With nadir CD4 Count

“…The exact mechanism is unclear, but a study shows that HIV-infected CD4 + T-cell are recruited to the heart through circulation, causing abnormal protein or enzyme expression and thus causing myocardial injury. 32 Moreover, lower nadir CD4 + T-cell count may cause myocardial steatosis, 28 which may lead to more serious myocardial injury. Therefore, lower nadir CD4 + T-cell count may be a risk factor for subclinical myocardial injury in PLWH.…”

“…In addition, △T1 mapping increased with the decrease of nadir CD4 + T‐cell count in PLWH with subclinical myocardial injury in the current study, suggesting that the severity of myocardial injury may be related to nadir CD4 + T‐cell count. The exact mechanism is unclear, but a study shows that HIV‐infected CD4 + T‐cell are recruited to the heart through circulation, causing abnormal protein or enzyme expression and thus causing myocardial injury 32 . Moreover, lower nadir CD4 + T‐cell count may cause myocardial steatosis, 28 which may lead to more serious myocardial injury.…”

HIV and Cardiovascular Disease: Update on Clinical Events, Special Populations, and Novel Biomarkers

“…These novel biomarkers span immunology, the intestinal microbiome [114, 115], red blood cells [116], and en-dothelial function [117]. The approaches being used are diverse and include imaging [118, 119], proteomics [120•], genomics [121, 122], metagenomics and metabolomics [123], and assessment of soluble and cellular proteins [124–130].…”