Global Rescue of Defects in HIV-1 Envelope Glycoprotein Incorporation: Implications for Matrix Structure

PLoS Pathogens

Eric O. Freed¹  Sherimay D. Ablan¹  Philip R. Tedbury¹ 

[1] Virus-Cell Interaction Section, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America

关键词: Viral replication;    Crystal structure;    HIV-1;    Virions;    Point mutation;    Molecular cloning;    293T cells;    Viral structure;   

DOI  :  10.1371/journal.ppat.1003739

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The matrix (MA) domain of HIV-1 Gag plays key roles in membrane targeting of Gag, and envelope (Env) glycoprotein incorporation into virions. Although a trimeric MA structure has been available since 1996, evidence for functional MA trimers has been elusive. The mechanism of HIV-1 Env recruitment into virions likewise remains unclear. Here, we identify a point mutation in MA that rescues the Env incorporation defects imposed by an extensive panel of MA and Env mutations. Mapping the mutations onto the putative MA trimer reveals that the incorporation-defective mutations cluster at the tips of the trimer, around the perimeter of a putative gap in the MA lattice into which the cytoplasmic tail of gp41 could insert. By contrast, the rescue mutation is located at the trimer interface, suggesting that it may confer rescue of Env incorporation via modification of MA trimer interactions, a hypothesis consistent with additional mutational analysis. These data strongly support the existence of MA trimers in the immature Gag lattice and demonstrate that rescue of Env incorporation defects is mediated by modified interactions at the MA trimer interface. The data support the hypothesis that mutations in MA that block Env incorporation do so by imposing a steric clash with the gp41 cytoplasmic tail, rather than by disrupting a specific MA-gp41 interaction. The importance of the trimer interface in rescuing Env incorporation suggests that the trimeric arrangement of MA may be a critical factor in permitting incorporation of Env into the Gag lattice.

【 授权许可】

CC BY