Elevated Abundance, Size, and MicroRNA Content of Plasma Extracellular Vesicles in Viremic HIV-1+ Patients

Abstract

Background:Because of factors only partly understood, the generalized elevated immune activation and inflammation characterizing HIV-1–infected patients are corrected incompletely with antiretroviral therapy (ART). Extracellular vesicles (EVs) including exosomes and microvesicles released by several cell types may contribute to immune activation and dysfunction. EV size, abundance, and content appear to differ according to infection phase, disease progression, and ART.Methods:We examined whether the size of EVs and the abundance of exosomes in plasma are associated with cell and tissue activation as well as with viral production. Acetylcholinesterase-bearing (AChE+) exosomes in plasma were quantified using an AChE assay. EV size was analyzed using dynamic light scattering. Proteins and microRNAs present in EVs were detected by Western blot and real-time polymerase chain reaction, respectively.Results:Exosomes were found more abundant in the plasma of ART-naive patients. EV size was larger in ART-naive than in ART-suppressed patients, elite controllers, or healthy control subjects. Both exosome abundance and EV sizes were inversely correlated with CD4/CD8 T-cell ratio and neutrophil, platelet, and CD4 T-cell counts and positively correlated with CD8 T-cell counts. A negative correlation was found between CD4 T-cell nadir and exosome abundance, but not EV size. Levels of miR-155 and miR-223 but not miR-92 were strongly correlated negatively with EV abundance and size in ART-naive patients.Conclusions:Monitoring of circulating EVs and EV-borne microRNA is possible and may provide new insight into HIV-1 pathogenesis, disease progression, and the associated inflammatory state, as well as the efficacy of ART and the treatments intended to reduce immune activation.

Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology

“…This phenomenon is not limited to HBMEC as it was shown that monocyte-derived macrophages infected with HIV-1 also secreted ECV in a larger amount (Kadiu et al 2012). These findings were also confirmed in human samples where both ECV number and size were increased in the plasma of HIV-1 positive ART-naive patients when compared to ART-suppressed patients, elite controllers, or healthy control subjects (Hubert et al 2015). The mechanism of increased ECV release by HIV-1 may be related to blocking the vesicle tethering by the protein tetherin, a process that can result in the facilitation of vesicle release.…”

Serum extracellular vesicle depletion processes affect release and infectivity of HIV-1 in culture

“…However, EVs produced by HIV-1-infected cells contain fragments of viral RNA [7] and viral proteins such as Nef [8] and Gag [9] (although another study did not find Nef to be associated with EVs [10]). HIV infection may alter the number and size of EVs as well as the host microRNA and proteins contained in EVs, which in turn may have implications for immune activation and HIV-1 pathogenesis [11][12][13][14]. In the setting of HIV-1 infection, EVs containing viral or host components may contribute to or exacerbate other conditions, such as HIV-1-or opiate-mediated neuron damage [15,16].…”

MicroRNA and HIV

“…The knowledge about miRNAs, and particularly their relation with HIV, is growing and may provide future new tools for HIV-infected patients manage. For instance, some studies point to the possible usefulness of some miRNAs as biomarkers of disease progression, inflammatory state, and response to therapy [1,4,13]. Moreover, the use of some of them as antiviral treatment is studied.…”

“…During this process microvesicles are released into the extracellular compartment transmitting pro-inflammatory signals to other cells [18]. Their mRNA and miRNA content is associated with the cells activation state as well as their origin [13]. miRNAs have been related to the production of interleukins (IL-10/Let-7; IL-6/miR-21, miR-122, miR-200a; IL-21/miRNA-29, miR-146a, miR-155) [4,5,12].…”

“…[3][4][5][6]8,10,[13][14][15][16][17][18] For instance, miR-155 regulates T cell differentiation as well as contributes to Treg development [15]. miR-223 has a role during infection, inflammation as well as hematopoietic cell differentiation [16].…”