An Omics Approach to Extracellular Vesicles from HIV-1 Infected Cells

Abstract

Human Immunodeficiency Virus-1 (HIV-1) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), infecting nearly 37 million people worldwide. Currently, there is no definitive cure, mainly due to HIV-1′s ability to enact latency. Our previous work has shown that exosomes, a small extracellular vesicle, from uninfected cells can activate HIV-1 in latent cells, leading to increased mostly short and some long HIV-1 RNA transcripts. This is consistent with the notion that none of the FDA-approved antiretroviral drugs used today in the clinic are transcription inhibitors. Furthermore, these HIV-1 transcripts can be packaged into exosomes and released from the infected cell. Here, we examined the differences in protein and nucleic acid content between exosomes from uninfected and HIV-1-infected cells. We found increased cyclin-dependent kinases, among other kinases, in exosomes from infected T-cells while other kinases were present in exosomes from infected monocytes. Additionally, we found a series of short antisense HIV-1 RNA from the 3′ LTR that appears heavily mutated in exosomes from HIV-1-infected cells along with the presence of cellular noncoding RNAs and cellular miRNAs. Both physical and functional validations were performed on some of the key findings. Collectively, our data indicate distinct differences in protein and RNA content between exosomes from uninfected and HIV-1-infected cells, which can lead to different functional outcomes in recipient cells.

Characterizing Extracellular Vesicles and Their Diverse RNA Contents

“…We therefore advocate, as others have, for a holistic study of EVs (Soekmadji et al, 2018 ). We propose, due to significant advancements in omics technologies (both hardware and software pipelines), a greater implementation of existing multi-omics strategies (Chen et al, 2012 ; Vallabhaneni et al, 2015 ; Barclay et al, 2019 ; Eylem et al, 2020 ) to characterize EVs in a detailed and integrative fashion (Domanskyi et al, 2019 ). Omics technologies are continuing to uncover and describe distinct EV subtypes in specialized biological contexts.…”

“…EVs from HIV-infected cells were also shown to initiate DNA replication in recipient cells and bring infected cells out of latency. A multi-omic analysis of these EVs found a number of cyclin-dependent and receptor tyrosine kinases that could be responsible for the effects (Barclay et al, 2019 ). A small subset of HIV-infected individuals, called elite controllers, can control the viral load without antiretroviral drug regimens.…”

Retroviral Infection of Human Neurospheres and Use of Stem Cell EVs to Repair Cellular Damage

“…Exposure to IR is known to initiate cell cycle arrest; moreover, we have recently published data using IR to activate transcription of HTLV-1 in HUT 102 cells [66,67,68,128]. Therefore, we rationalized that co-culturing of In recent years our laboratory has also focused extensively on EVs and considerable efforts have been made in the characterization of EVs from both infected and non-infected cells [68,72,105,106,107,129,130,131].…”

Long Non-coding RNAs Mechanisms of Action in HIV-1 Modulation and the Identification of Novel Therapeutic Targets

“…The interaction of viruses and host factors has been well documented in the literature [10,[40][41][42][43][44]. Recently, we have started to expand upon our understanding of host-virus interactions to include non-coding RNAs [21,[45][46][47]. In particular, how viruses are able to dysregulate immune function has been a focal point.…”