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SELECTBIO Conferences Extracellular Vesicles (EV)-Exosomes: Diagnostics, Delivery and Therapeutics

Fatah Kashanchi's Biography

Fatah Kashanchi, Professor, George Mason University

Dr. Kashanchi received his Ph.D. in 1990 under the supervision of Dr. Charles Wood who also worked with the Nobel Laureate, Dr. Susumu Tonegawa at MIT. He then moved to National Cancer Institute at NIH’s intramural program and continued his work on RNA viral infections. He is currently a Tenured Faculty in the department of Systems Biology at the Prince William Campus of George Mason University. He has obtained independent funding of more than $15.6 M in funding (NIH, DOD, DOE, and Keck) since his departure from NIH in 2000. He has published 236 peer-reviewed manuscripts (h index = 63), and served as an editorial board and reviewer for number of journal including Cell, Molecular Cell, Nature, Nature Medicine, Science Translational Medicine, Retrovirology, JBC, J. Virol, Virology, NAR, and 4 PLoS journals. He is a regular NIH study section member and has served on 153 panels and chaired 17 since 2000.

For the past eighteen years Kashanchi lab has been interested in understanding the mechanism of viral gene expression in human viruses and how the virus and the host control the dynamics of fundamental machineries needed for viral replication and/or host survival. They also have ample experience with biochemical pathways that leads to transcription and chromatin remolding using in vitro reconstituted machineries. These complexes with epigenetic modifications utilize host signaling events and therapeutic targets that control viral replication. In recent years, they have also started focusing on Extracellular vesicles (i.e., exosomes) mainly from latent virally infected cells. These cells remain in the body for a long period of time can be extended to the life of a person (i.e., CNS cells). These latent cells produce exosomes that carry markers of the infection including RNA and protein sequences specific to a given virus.

The Kashanchi lab, for the first time, showed that viral release and exosome release have overlapping biogenesis in the ESCRT pathway. For instance, HIV-1 latent cells utilize ESCRT-I for viral release, and ESCRT-II for exosomal release. Using in vitro and in vivo (both patient samples and animal models), the lab has found that exosomes from HIV-1 infected cells carry short non-coding RNAs (i.e., TAR) which regulate TLR3 and other pathways in the recipient cells. This data also implies that endogenous retroviruses may have a similar mode of action in their gene expression by expressing short non-coding RNAs that no only regulate the donor cells, but also the recipient cells through the exosomes transfer pathway. The infected cells (in presence of antiretroviral drugs or innate immune molecules) still secret exosomes that contain viral products including TAR, TAR-Gag RNA, and Nef protein1-7.

Similar results were also observed from other neuro-tropic RNA viral infections including HTLV-1, Ebola, RVFV, and Zika infection. More recently data from HTLV-1 infected HAM/TSP patient showed that exosomes isolated from patient PBMCs (25/35) in ex vivo cultures were Tax positive and patient CSF (7/11) contained Tax+ exosomes but not in HTLV-1 seronegative MS donors (0/5), despite the absence of viral detection in the CSF supernatant. Furthermore, exosomes cultivated from HAM/TSP PBMCs were capable of sensitizing target cells for HTLV-1 specific CTL lysis8.

Collectively, data from Kashanchi lab on exosomes both latent and persistent viral infections (5 RNA viruses tested so far), indicate secretion of exosomes that contain various viral components (RNA and/or proteins), all of which affect the immune cells by either destroying or activating T-cells. Broader implications of these findings in the context of diagnostic and vaccine development are currently under development in the lab.

Fatah Kashanchi Image

Exosomes and Viruses: A Tale of Two Overlapping Worlds

Friday, 26 February 2021 at 08:00

Add to Calendar ▼2021-02-26 08:00:002021-02-26 09:00:00Europe/LondonExosomes and Viruses: A Tale of Two Overlapping WorldsExtracellular Vesicles (EV)-Exosomes: Diagnostics, Delivery and Therapeutics in Virtual ConferenceVirtual

Extracellular vesicles (EVs) play a significant role in intercellular communication by serving as a carrier for the transfer of membrane and cytosolic proteins, lipids, and RNA between cells.  In recent years, using state of art technologies such as RNA seq, RPMA, and single cell omics, we have found that virally infected cells including HIV-1, HTLV-1, Rift Valley Fever, Zika, Ebola, and Coronavirus infected cells secret exosomes that contain biomarker of these infections in urine, saliva, CSF, and blood. We have been able to separate and characterize EVs from several different viruses including HIV-1.  These EVs are not infectious and have a different density than infectious virions using gradients.  They contain various viral RNAs including TAR (non-coding RNA), Nef, gp120/160 and Tat.  The origin of these EVs are infected cells, especially when treated with cART or Interferons.  They are present in patient samples tested (plasma and CSF, 33%-95%) to date (4 cohorts of 5-20 patients each). The EVs contribute to pro-inflammatory signals in the naïve recipient cells using TLR3 signaling.  Recently, we have asked about the timing difference between EV and virus release from infected cells using serum starvation experiments from cells followed by release. Results from supernatants of uninfected cells showed a peak of tetraspanin proteins (CD63, CD81, and CD9) at 6 hours and a gradual decrease of all EV associated proteins by 24 hours. However, the EV from HIV-1 infected cells showed all three tetraspanins present at 3 hours and expression gradually increased up to 24 hours. HIV-1 viral proteins (p24, gp120, Nef) expression was present at 6 hours and continued to increase and peaked at 24 hours.  HIV-1 supernatant 6- hour sample was found not to be infectious. However, infectious HIV-1 was successfully rescued from 24-hour sample.

Our data indicates that EV release may occur prior to viral release in infected cells, thereby implicating a potentially significant effect of EVs on uninfected recipient cells prior to subsequent viral infection.

Add to Calendar ▼2021-02-25 00:00:002021-02-26 00:00:00Europe/LondonExtracellular Vesicles (EV)-Exosomes: Diagnostics, Delivery and TherapeuticsExtracellular Vesicles (EV)-Exosomes: Diagnostics, Delivery and Therapeutics in Virtual ConferenceVirtual