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Surface Stability and Immunogenicity of the Human Immunodeficiency Virus Envelope Glycoprotein: Role of the Cytoplasmic Domain

Ling Ye,^1, Zhigao Bu,^2, Andrei Vzorov,¹ Dahnide Taylor,¹ Richard W. Compans,¹ and Chinglai Yang^1*

Department of Microbiology & Immunology and Vaccine Center, Emory University School of Medicine, Atlanta, Georgia,¹ National Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Harbin, People's Republic of China²

Received 12 April 2004/ Accepted 12 August 2004

The effects of two functional domains, the membrane-proximal YXX motif and the membrane-distal inhibitory sequence in the long cytoplasmic tail of the human immunodeficiency virus type 1 (HIV-1) envelope protein (Env), on immunogenicity of the envelope protein were investigated. Genes with codons optimized for mammalian expression were synthesized for the HIV 89.6 Env and a truncated Env with 50 amino acids in the cytoplasmic domain to delete the membrane distal inhibitory sequence for surface expression. Additional genes were generated in which the tyrosine residue in the YXX motif was changed into a serine. Pulse-chase radioactive labeling and immunoprecipitation studies indicated that both domains can mediate endocytosis of the HIV Env, and removal of both domains is required to enhance HIV Env protein surface stability. Analysis of immune responses induced by DNA immunization of mice showed that the DNA construct for the mutant Env exhibiting enhanced surface stability induced significantly higher levels of antibody responses against the HIV Env protein. Our results suggest that the HIV Env cytoplasmic domain may play important roles in virus infection and pathogenesis by modulating its immunogenicity.

L.Y. and Z.B. contributed equally to this work.

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