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.
Highlights
Acquired immune deficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV) and is one of the most important diseases threatening human health [1]
The HIV-1 gp41 6-HB core structure has been recognized as a critical structure in the viral fusion and entry process through the plasma membrane fusion or endocytosis pathways [17,18]
It is unclear whether the HIV-1 gp41 6-HB core can serve as a target for developing HIV fusion inhibitors since it is believed that 6-HB is a dead-end structure in the HIV fusion process
Summary
Acquired immune deficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV) and is one of the most important diseases threatening human health [1]. More than 30 anti-HIV drugs have been licensed for treatment of HIV infection, including twelve reverse transcriptase inhibitors (RTIs), ten protease inhibitors (PIs), one integrase inhibitor, two entry inhibitors, and five combinatorial drugs [2]. T20 (brand name: Fuzeon; generic name: Enfuvirtide) is the only HIV entry inhibitor targeting the HIV-1 envelope glycoprotein (Env) transmembrane subunit gp for treatment of HIV/AIDS patients who fail to respond to the RTIs and PIs [3,4]. Several new peptides derived from the gp CHR with improved efficacy and half-life have been identified. Administration of these peptides may lead to the production of antibodies against these peptides, which may attenuate their anti-HIV-1 activity [7]. One of the approaches is to identify human protein-derived antiviral agents
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