Mouse Liver Sinusoidal Endothelium Eliminates HIV-Like Particles from Blood at a Rate of 100 Million per Minute by a Second-Order Kinetic Process

Jessica M Mates,Murugesan V S Rajaram,Latha P Ganesan,Alana M Cheplowitz,Ozan Suer,Zhili Yao,Gary S Phillips,Clark L Anderson,Jonghan Kim,Jesse J Kwiek,John M Robinson

doi:10.3389/fimmu.2017.00035

Abstract

We crafted human immunodeficiency virus (HIV)-like particles of diameter about 140 nm, which expressed two major HIV-1 proteins, namely, env and gag gene products, and used this reagent to simulate the rate of decay of HIV from the blood stream of BALB/c male mice. We found that most (~90%) of the particles were eliminated (cleared) from the blood by the liver sinusoidal endothelial cells (LSECs), the remainder from Kupffer cells; suggesting that LSECs are the major liver scavengers for HIV clearance from blood. Decay was rapid with kinetics suggesting second order with respect to particles, which infers dimerization of a putative receptor on LSEC. The number of HIV-like particles required for saturating the clearance mechanism was approximated. The capacity for elimination of blood-borne HIV-like particles by the sinusoid was 112 million particles per minute. Assuming that the sinusoid endothelial cells were about the size of glass-adherent macrophages, then elimination capacity was more than 540 particles per hour per endothelial cell.

Highlights

A readily apparent but poorly understood aspect of the innate immune response is the rapid and copious removal and subsequent degradation of blood-borne virus by the endothelium of the liver sinusoids (LSEC)
The molecular mechanism by which these small particles are cleared by liver sinusoidal endothelial cells (LSECs) is only beginning to be known: Fc receptors for IgG on LSEC are required, we have found, for the clearance from blood of small immune complexes [1, 3]
We engineered a small particle the size of a virus (HIV-like particle) that consisted of a viral membrane derived from cultured HEK-293 cells and expressed features of human immunodeficiency virus (HIV), namely, the HIV CXCR4 envelope protein and the gag protein p24, but lacked nucleic acid and accessory proteins required for replication (M&M)

Summary

Introduction

A readily apparent but poorly understood aspect of the innate immune response is the rapid and copious removal (or clearance) and subsequent degradation of blood-borne virus by the endothelium of the liver sinusoids (LSEC). This capacity of LSEC to remove virus is far more robust than like clearance by Kupffer cells (KC), which instead appear responsible mostly for the removal of larger particles such as bacteria and autologous cellular material [1]. The molecular mechanism by which these small particles are cleared by LSEC is only beginning to be known: Fc receptors for IgG on LSEC are required, we have found, for the clearance from blood of small immune complexes [1, 3].

Methods

Results

Conclusion