The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9.
Adeno-associated virus serotype 8 (AAV8) is currently emerging as a powerful gene transfer vector, owing to its capability to efficiently transduce many different tissues in vivo. While this is believed to be in part due to its ability to uncoat more readily than other AAV serotypes such as AAV2, understanding all the processes behind AAV8 transduction is important for its application and optimal use in human gene therapy. Here, we provide the first report of a cellular receptor for AAV8, the 37/67-kDa laminin receptor (LamR). We document binding of LamR to AAV8 capsid proteins and intact virions in vitro and demonstrate its contribution to AAV8 transduction of cultured cells and mouse liver in vivo. We also show that LamR plays a role in transduction by three other closely related serotypes (AAV2, -3, and -9). Sequence and deletion analysis allowed us to map LamR binding to two protein subdomains predicted to be exposed on the AAV capsid exterior. Use of LamR, which is constitutively expressed in many clinically relevant tissues and is overexpressed in numerous cancers, provides a molecular explanation for AAV8's broad tissue tropism. Along with its robust transduction efficiency, our findings support the continued development of AAV8-based vectors for clinical applications in humans, especially for tumor gene therapy.
Akache
Bassel
B
Stanford University, Department of Pediatrics, 300 Pasteur Drive, Room G305, Stanford, CA 94305-5208, USA.
Grimm
Dirk
D
Pandey
Kusum
K
Yant
Stephen R
SR
Xu
Hui
H
Kay
Mark A
MA
D000818:Animals; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002459:Cell Fusion; D002460:Cell Line; D000229:Dependovirus / Q000145:classification / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008970:Molecular Weight; D010322:Parvoviridae Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D034622:RNA Interference; D017474:Receptors, Laminin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D036022:Capsid Proteins; D017474:Receptors, Laminin