The Role of Exosomes and Exosomal RNAs as Biomarkers and Mediators for HIV-Associated Atherosclerosis

Project: Research projectExploratory/Developmental Grants

Description

Human deficiency virus-1 (HIV) infection increases the risk of atherosclerosis even in the absence of detectable viral load. Thus, the latent HIV reservoir established during early infection may impact host cells through epigenetic interactions. Furthermore, antiretroviral therapy (ART) may also affect the host cells via epigenetic mechanisms. Exosomes are nanovesicles that are formed by the fusion of an intracellular multivesicular body with the cell membrane. They are widely distributed in serum, urine, and other biological fluids. As important transfer vehicles for intercellular communication, exosomes can stimulate target cells via the transfer of various bioactive molecules, such as RNAs, including mRNAs and microRNAs, proteins, and lipids, to exert their biological functions. This mechanism of cell-cell communication is more important than direct cell-cell contact as it allows for communication to a large number of cells either locally or at dispersed sites, such as endothelial progenitor cells (EPCs) residing in the bone marrow, affecting their functions. Dysfunctional EPCs are deficient in vascular repair and are associated with atherosclerosis development. We and others have shown that HIV-infected individuals have decreased circulating EPC levels. We have also demonstrated that these EPCs exhibit a senescent phenotype with impaired repair capability, relative to the same cells from HIV seronegative subjects. Our goal for this proposal is to understand how HIV affects EPCs and atherogenesis when the viruses are below the level of detection by standard assays, thus establishing the missing link between latent HIV infection (residual low-level viremia) and the EPC changes observed in previous studies. Our central hypotheses are that the persistent residual low-level viremia detected only by ultrasensitive RT-PCR assays in most patients treated with ART affects the physical characteristics and quantity of exosomes, as well as their exosomal RNA (ex-RNA) contents in blood and urine, which may in turn serve as biomarkers for EPC dysfunction and atherosclerosis, and that some of the candidate ex-RNAs from blood may mediate the effects of HIV on EPC senescence, resulting in accelerated atherosclerosis. We will test these hypotheses in two Aims. Aim 1 will test the hypothesis that HIV infection significantly alters the quantity and physical characteristics of serum and urine exosomes and their ex-RNA content, which in turn may serve as biomarkers for EPC dysfunction and atherosclerosis. Aim 2 will test the hypothesis that candidate ex-RNAs derived from serum exosomes mediate HIV infection-induced EPC senescence and that modification of these ex-RNAs will abrogate HIV infection-associated EPC senescence and functional impairment.
StatusActive
Effective start/end date6/7/185/31/20

Funding

  • National Institutes of Health: $230,250.00

Fingerprint

Exosome Multienzyme Ribonuclease Complex
Atherosclerosis
Biomarkers
Viruses
Exosomes
Virus Diseases
RNA
Cell Aging
Viremia
Urine
Epigenomics
Endothelial Progenitor Cells
Serum
Multivesicular Bodies
Viral Load
MicroRNAs
Cell Communication