Human Immunodeficiency Virus (HIV) Infection and Use of Illicit Substances Promote Secretion of Semen Exosomes that Enhance Monocyte Adhesion and Induce Actin Reorganization and Chemotactic Migration.

Lyu Lyu,Kim Kim,Martinez-Maza Martinez-Maza,Panzner Panzner,Kaddour Kaddour,Kopcho Kopcho,Shouman Shouman,Martinson Martinson,Mckay Mckay,Margolick Margolick,Okeoma Okeoma,Stapleton Stapleton

doi:10.3390/cells8091027

Abstract

Semen exosomes (SE) from HIV-uninfected (HIV−) individuals potently inhibit HIV infection in vitro. However, morphological changes in target cells in response to SE have not been characterized or have the effect of HIV infection or the use of illicit substances, specifically psychostimulants, on the function of SE been elucidated. The objective of this study was to evaluate the effect of HIV infection, psychostimulant use, and both together on SE-mediated regulation of monocyte function. SE were isolated from semen of HIV− and HIV-infected (HIV+) antiretroviral therapy (ART)-naive participants who reported either using or not using psychostimulants. The SE samples were thus designated as HIV−Drug−, HIV−Drug+, HIV+Drug−, and HIV+Drug+. U937 monocytes were treated with different SEs and analyzed for changes in transcriptome, morphometrics, actin reorganization, adhesion, and chemotaxis. HIV infection and/or use of psychostimulants had minimal effects on the physical characteristics of SE. However, different SEs had diverse effects on the messenger RNA signature of monocytes and rapidly induced monocyte adhesion and spreading. SE from HIV infected or psychostimulants users but not HIV−Drug− SE, stimulated actin reorganization, leading to the formation of filopodia-like structures and membrane ruffles containing F-actin and vinculin that in some cases were colocalized. All SE stimulated monocyte chemotaxis to HIV secretome and activated the secretion of matrix metalloproteinases, a phenotype exacerbated by HIV infection and psychostimulant use. SE-directed regulation of cellular morphometrics and chemotaxis depended on the donor clinical status because HIV infection and psychostimulant use altered SE function. Although our inclusion criteria specified the use of cocaine, humans are poly-drug and alcohol users and our study participants used psychostimulants, marijuana, opiates, and alcohol. Thus, it is possible that the effects observed in this study may be due to one of these other substances or due to an interaction between different substances.

Highlights

HIV encodes pathogenic proteins, such as gp120, Nef, and Tat, that modulate cellular architecture and behavior. Such modulations are implicated in HIV-induced pathological processes, including immune activation that persist during combination antiretroviral therapy and contribute to serious non-AIDS events
Ultraviolet–visible spectroscopy (UV–Vis) analysis of semen exosomes (SE) profiles indicated that the fractions eluted in the void peak were enriched in vesicles, whereas the vesicle-free proteins eluted in the latter peak (Figure 1A)
Since the electrical properties of the exosomal surface measured as ζ-potential is determined by the surface molecules on exosome membranes, we examined the effect of HIV infection and psychostimulant use on the ζ-potential of SE

Summary

Introduction

HIV encodes pathogenic proteins, such as gp120, Nef, and Tat, that modulate cellular architecture and behavior. CART has dramatically reduced HIV/AIDS-related pathologies and mortality [1], use of illicit substances (mostly psychostimulants) is a major barrier to combating the HIV pandemic [2,3,4,5]. Psychostimulants such as cocaine have been linked to exacerbated HIV disease progression and HIV-associated disorders [6,7,8,9,10,11,12,13]. The risk of exacerbated HIV disease progression and/or HIV-associated disorders among those who use psychostimulants and who are infected with HIV is present in those adherent to cART [16,17,18]

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