title: Identification of a human protein-derived HIV-1 fusion inhibitor targeting the gp41 fusion core structure.
abstract: The HIV-1 envelope glycoprotein (Env) gp41 plays a crucial role in the viral fusion process. The peptides derived from the C-terminal heptad repeat (CHR) of gp41 are potent HIV fusion inhibitors. However, the activity of these anti-HIV-1 peptides in vivo may be attenuated by their induction of anti-gp41 antibodies. Thus, it is essential to identify antiviral peptides or proteins with low, or no, immunogenicity to humans. Here, we found that the C-terminal fragment (aa 462-521) of the human POB1 (the partner of RalBP1), designated C60, is an HIV-1 fusion inhibitor. It bound to N36, the peptide derived from the N-terminal heptad repeat (NHR) of gp41, and to the six-helix bundle (6-HB) formed by N36 and C34, a CHR-peptide, but it did not bind to C34. Unlike the CHR-peptides, C60 did not block gp41 6-HB formation. Rather, results suggest that C60 inhibits HIV-1 fusion by binding to the 6-HB, in particular, the residues in the gp41 NHR domain that are exposed on the surface of 6-HB. Since 6-HB plays a crucial role in the late stage of fusion between the viral envelope and endosomal membrane during the endocytic process of HIV-1, C60 may serve as a host restriction factor to suppress HIV-1 entry into CD4+ T lymphocytes. Taken together, it can be concluded from these results that C60 can be used as a lead for the development of anti-HIV-1 therapeutics or microbicides for the treatment and prevention of HIV-1 infection, as well as a molecular probe to study the fusogenic mechanism of HIV-1.
authors.affiliation: Laboratory of Immunology, School of Life Sciences, Tsinghua University, Beijing Key Laboratory for Protein Therapeutics, Protein Science Laboratory of the Ministry of Education, Beijing, P. R. China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Chao
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Hengwen
authors.initials: H
authors.lastname: Yang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Yu
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Chen
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism; D016466:CHO Cells; D002135:Calcium-Binding Proteins; D002462:Cell Membrane / Q000378:metabolism; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015726:Giant Cells / Q000187:drug effects; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding
chemical_list: D015704:CD4 Antigens; D002135:Calcium-Binding Proteins; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C489722:REPS2 protein, human