Exosomes Derived from HIV-1 Infected DCs Mediate Viral trans-Infection via Fibronectin and Galectin-3

Rutuja Kulkarni,Anil Prasad

doi:10.1038/s41598-017-14817-8

Rutuja Kulkarni, Anil Prasad

Open Access

https://doi.org/10.1038/s41598-017-14817-8

Copy DOI

Abstract

Exosomes are membrane enclosed nano-sized vesicles actively released into the extracellular milieu that can harbor genomic, proteomic and lipid cargos. Functionally, they are shown to regulate cell-cell communication and transmission of pathogens. Though studies have implicated a role for exosomes in HIV-1 pathogenesis, their mechanisms are not well defined. Here, we characterized exosomes derived from uninfected or HIV-1 infected T-cells and DCs. We demonstrate substantial differences in morphological, molecular and biogenesis machinery between exosomes derived from these two immune cell types. In addition, exosomes derived from HIV-1 infected DCs were 4 fold more infective than either cell free HIV-1 or exosomes derived from T-cells. Molecular analysis of exosomes detected the presence of fibronectin and galectin-3 in those derived from DCs, whereas T-cell exosomes lacked these molecules. Addition of anti-fibronectin antibody and β-lactose, a galectin-3 antagonist, significantly blocked DC exosome-mediated HIV-1 infection of T-cells. We also observed increased gene expression of the pro-inflammatory cytokines IFN-γ, TNF-α, IL-1β and RANTES and activation of p38/Stat pathways in T-cells exposed to exosomes derived from HIV-1 infected DCs. Our study provides insight into the role of exosomes in HIV pathogenesis and suggests they can be a target in development of novel therapeutic strategies against viral infection.

Highlights

CD4+ T cells, making them permissive for HIV-1 infected (HIV)-1 infection, and may trigger apoptosis[38]
We did not observe significant differences in the expression pattern of these markers between exosomes derived from HIV-1 infected DCs compared to those derived from uninfected cells except HSP70, with markedly increased expression in exosomes derived from virus infected DCs (Fig. 1A and C)
Analysis of molecules involved in multivesicular endosome biogenesis revealed the expression of TSG101 and Alix in exosomes derived from DCs; expression of TSG101 markedly increased in exosomes derived from HIV-1 infected DCs compared to those from uninfected DCs

Summary

Introduction

CD4+ T cells, making them permissive for HIV-1 infection, and may trigger apoptosis[38]. Exosomes may prevent viral infection by activating immune cells and inducing anti-viral adaptive immune responses[11,18,39]. In this context, exosomes can transfer intrinsic resistance factors such as APOBEC3G from cell to cell and enhance resistance to HIV-1 infection[40]. We show that such exosomes can induce production of pro-inflammatory cytokines. These novel observations provide insights into how virus may modulate host immune responses via exosomes to the benefit of the pathogen

Methods

Results

Conclusion