Rapid and Efficient Clearance of Blood-borne Virus by Liver Sinusoidal Endothelium

Abstract

The liver removes quickly the great bulk of virus circulating in blood, leaving only a small fraction to infect the host, in a manner characteristic of each virus. The scavenger cells of the liver sinusoids are implicated, but the mechanism is entirely unknown. Here we show, borrowing a mouse model of adenovirus clearance, that nearly all infused adenovirus is cleared by the liver sinusoidal endothelial cell (LSEC). Using refined immunofluorescence microscopy techniques for distinguishing macrophages and endothelial cells in fixed liver, and identifying virus by two distinct physicochemical methods, we localized adenovirus 1 minute after infusion mainly to the LSEC (∼90%), finding ∼10% with Kupffer cells (KC) and none with hepatocytes. Electron microscopy confirmed our results. In contrast with much prior work claiming the main scavenger to be the KC, our results locate the clearance mechanism to the LSEC and identify this cell as a key site of antiviral activity.

Nipah Virus Envelope-Pseudotyped Lentiviruses Efficiently Target ephrinB2-Positive Stem Cell Populations In Vitro and Bypass the Liver Sink When Administered In Vivo

“…3), prompted us to examine the transduction efficiency of NiVpp in vivo, especially when NiVpp were administered intravenously and therefore subjected not only to dilution into the blood and tissue volume but also to the problem of hepatic clearance, a critical barrier for in vivo virusbased gene therapy (23,24,62). Interestingly, when VSVpp and NiVpp carrying a luciferase reporter gene were injected intravenously into mice and subsequently subjected to whole-animal and -organ imaging for D-luciferin-induced bioluminescence signals, T5F⌬N3/wt G NiVpp demonstrated an enhanced signal in the spleen and lungs compared to T5F/wt G NiVpp (Fig.…”

“…Biodistribution studies quantifying genome-integrated vector copy numbers in various tissues confirmed these observations. Bypassing the liver sink is a critical barrier for targeted gene therapy (23,24), suggesting that the extraordinary specificity of NiV-G for ephrinB2 may allow for targeting of specific ephrinB2 ϩ populations in vivo or in vitro, without the need for prior cell purification.…”

Gene Therapy for the Nervous System: Challenges and New Strategies

“…The systemic delivery route for gene delivery vehicles is very promising, but has major caveats. On the one hand, the vasculature has the potential to be a conduit to the entire CNS (every cell in the brain is a maximum distance of 40 μm from an endothelial cell [22]), while on the other hand the BBB blocks transport of most delivery vehicles (see section below on Blood-Brain Barrier), and the filtration systems of the spleen and liver are efficient at removal of viruses and virus vectors from the circulation before they can reach the brain [23][24][25][26]. Other non-target organs, such as muscle and heart, will also be transduced with potential off-target toxicities.…”

Emerging concepts in immunity to hepatitis C virus infection

“…Expression of the C-type lectin L-SIGN by LSECs was postulated to mediate capture of HCV particles and transcytosis of the virus across the endothelial barrier, thereby concentrating infectious particles and facilitating their direct contact with hepatocytes (102). Moreover, LSECs are highly efficient scavengers that pinocytose particles less than 0.2 μm in size, which typically encompasses virus-sized particles (103). The recent demonstration that LSECs, rather than KCs, clear the bulk of blood-borne human adenovirus underscores their importance during the viremic phase of any natural viral infection (103).…”

“…Moreover, LSECs are highly efficient scavengers that pinocytose particles less than 0.2 μm in size, which typically encompasses virus-sized particles (103). The recent demonstration that LSECs, rather than KCs, clear the bulk of blood-borne human adenovirus underscores their importance during the viremic phase of any natural viral infection (103). Even if LSECs do not sustain active replication, viral sensing and its downstream effector responses, including exosomal transfer of ISG products (ref.…”