Abstract
BackgroundExosomes are membranous nanovesicles secreted into the extracellular milieu by diverse cell types. Exosomes facilitate intercellular communication, modulate cellular pheno/genotype, and regulate microbial pathogenesis. Although human semen contains exosomes, their role in regulating infection with viruses that are sexually transmitted remains unknown. In this study, we used semen exosomes purified from healthy human donors to evaluate the role of exosomes on the infectivity of different strains of HIV-1 in a variety of cell lines.ResultsWe show that human semen contains a heterologous population of exosomes, enriched in mRNA encoding tetraspanin exosomal markers and various antiviral factors. Semen exosomes are internalized by recipient cells and upon internalization, inhibit replication of a broad array of HIV-1 strains. Remarkably, the anti-HIV-1 activity of semen exosomes is specific to retroviruses because semen exosomes blocked replication of the murine AIDS (mAIDS) virus complex (LP-BM5). However, exosomes from blood had no effect on HIV-1 or LP-BM5 replication. Additionally, semen and blood exosomes had no effect on replication of herpes simplex virus; types 1 and 2 (HSV1 and HSV2). Mechanistic studies indicate that semen exosomes exert a post-entry block on HIV-1 replication by orchestrating deleterious effects on particle-associated reverse transcriptase activity and infectivity.ConclusionsThese illuminating findings i) improve our knowledge of the cargo of semen exosomes, ii) reveal that semen exosomes possess anti-retroviral activity, and iii) suggest that semen exosome-mediated inhibition of HIV-1 replication may provide novel opportunities for the development of new therapeutics for HIV-1.
Highlights
Exosomes are membranous nanovesicles secreted into the extracellular milieu by diverse cell types
Human semen contains exosomes loaded with proteins and functional mRNA Fluorescence-activated cell sorting (FACS), Transmission electron microscopy (TEM), and immunoblot analysis revealed that semen exosomes (SE) is enriched in tetraspanin proteins CD63 and CD81, but devoid of contaminating endoplasmic reticulum-derived marker calnexin (Figure 1A, B and C), suggesting that we have pure populations of exosomes
The presence of host restriction factors (HRFs) mRNA, including Apobec3 (A3) and Bone marrow stromal cell antigen 2 (BST-2) in SE is intriguing since exosome-mediated transfer of Ribonucleic acid (RNA) from donor to recipient cells results in functional RNA-related biological effects in the recipient cells [15,31]
Summary
Exosomes are membranous nanovesicles secreted into the extracellular milieu by diverse cell types. Human semen contains exosomes, their role in regulating infection with viruses that are sexually transmitted remains unknown. Owing to the fact that these nanovesicles arise from diverse cell types within the MGT, it is more appropriate to refer to them as nanovesicles or exosomes. Due to their endosomal origin, exosomes are endowed with a repertoire of host proteins, including tetraspannins (CD9, CD63, and CD81) [11,12], miRNAs, and mRNAs [13]. The RNA “cargo” of exosomes may be significantly different from that of the originating parental cell content [14,15,16]
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