Human Immunodeficiency Virus-1 Uses the Mannose-6-Phosphate Receptor to Cross the Blood-Brain Barrier

Shinya Dohgu,William A Banks,Jan S Ryerse,Sandra M Robinson,Maria A Deli

doi:10.1371/journal.pone.0039565

Abstract

HIV-1 circulates both as free virus and within immune cells, with the level of free virus being predictive of clinical course. Both forms of HIV-1 cross the blood-brain barrier (BBB) and much progress has been made in understanding the mechanisms by which infected immune cells cross the blood-brain barrier BBB. How HIV-1 as free virus crosses the BBB is less clear as brain endothelial cells are CD4 and galactosylceramide negative. Here, we found that HIV-1 can use the mannose-6 phosphate receptor (M6PR) to cross the BBB. Brain perfusion studies showed that HIV-1 crossed the BBB of all brain regions consistent with the uniform distribution of M6PR. Ultrastructural studies showed HIV-1 crossed by a transcytotic pathway consistent with transport by M6PR. An in vitro model of the BBB was used to show that transport of HIV-1 was inhibited by mannose, mannan, and mannose-6 phosphate and that enzymatic removal of high mannose oligosaccharide residues from HIV-1 reduced transport. Wheatgerm agglutinin and protamine sulfate, substances known to greatly increase transcytosis of HIV-1 across the BBB in vivo, were shown to be active in the in vitro model and to act through a mannose-dependent mechanism. Transport was also cAMP and calcium-dependent, the latter suggesting that the cation-dependent member of the M6PR family mediates HIV-1 transport across the BBB. We conclude that M6PR is an important receptor used by HIV-1 to cross the BBB.

Highlights

Human immunodeficiency virus-1 [1] crosses the blood-brain barrier (BBB) to infect the central nervous system (CNS)
In vivo and in vitro studies show that interactions between the HIV-1 viral coat glycoprotein gp120 and unknown glycoproteins on the cell membranes of brain endothelia interact to induce a type of vesicular transport termed adsorptive transcytosis [4,6,7], a transport that is enhanced by protamine sulfate, wheatgerm agglutinin, and heparan sulfate, all of which likely act by binding to the unknown glycoproteins [7,8,9]
[F(3,33) = 20.6, p,0.01] and Figure 4, panel D shows that mannan inhibited I-HIV transport [F(3,23) = 7.23, p,0.01]. These results show that a mannose binding site such as mannose-6 phosphate receptor (M6PR) is involved in HIV-1 transport across the BBB

Summary

Introduction

Human immunodeficiency virus-1 [1] crosses the blood-brain barrier (BBB) to infect the central nervous system (CNS). It crosses the BBB both within infected immune cells and as free virus [2,3,4]. High mannose glycans are one type of carbohydrate moiety found on gp120 [10]. By way of these mannose residues, gp120 can bind to and be internalized by macrophages through a CD4-independent, mannose-specific endocytic receptor pathway [11]; this is consistent with the high mannose sites being related to HIV-1 infectivity [12]

Methods

Results

Conclusion