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Possible Biomarkers for the Early Detection of HIV-associated Heart Diseases: A Proteomics and Bioinformatics
Suraiya Rasheed1, Rahim Hashim1, Jasper S Yan1
1Laboratory of Viral Oncology and Proteomics Research, Keck School of Medicine, University of Southern California, Cancer Research Laboratory Building, 1303 North Mission Rd, Los Angeles, CA 90033, USA.
Insights
HIV infection in T-cells triggers novel proteins causing heart dysfunction. These include cardiac-specific Ca2+ kinase and myosin, leading to heart failure in HIV patients.
Area of Science:
- Immunology
- Cardiology
- Molecular Biology
Background:
- Cardiovascular disorders are rising in HIV-infected individuals despite effective antiretroviral therapies (ART).
- CD4+ T-cells play a crucial role in HIV replication and immune response, and their chronic infection may lead to cardiac issues.
- The specific mechanisms linking HIV infection to cardiac dysfunction, independent of co-infections, require elucidation.
Purpose of the Study:
- To identify novel proteins and molecular pathways induced by chronic HIV infection in CD4+ T-cells that contribute to cardiac dysfunction.
- To investigate the role of specific HIV-induced proteins in the pathogenesis of heart disease in HIV-infected individuals.
- To explore potential new biomarkers for early diagnosis and therapeutic targets for HIV-associated cardiomyopathy.
Main Methods:
- Genome-wide proteome analysis of CD4+ T-cell lines during different stages of HIV replication and after antiviral treatment (Zidovudine/AZT).
- Subtractive proteomic analysis to identify proteins differentially expressed in HIV-infected versus uninfected cells and in response to viral replication inhibition.
- Bioinformatics, functional categorization, and statistical analyses to predict the function and impact of identified proteins on cardiac function.
Main Results:
- A network of 12 soluble/diffusible proteins was identified in HIV-infected cells.
- Key identified proteins include cardiac-specific Ca2+ kinase and multiple Ca2+ release channels, leading to sustained intracellular Ca2+ overload in cardiac cells.
- These proteins induce fetal/cardiac myosin heavy chains (MYH6 and MYH7) and myosin light-chain kinase, implicated in cardiac stress, arrhythmia, and heart failure (p = 8 × 10^-11).
Conclusions:
- Chronic HIV infection of T-cells generates specific proteins that directly contribute to cardiac dysfunction and heart failure.
- The identified protein network, particularly involving Ca2+ regulation and myosin pathways, offers a novel mechanistic link between HIV and cardiomyopathy.
- These HIV-induced proteins represent potential biomarkers for early detection and novel therapeutic targets for heart disease in the HIV-infected population.
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.
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