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Amino acid substitutions at the HIV-1 transframe region significantly impair virus infectivity.

ABSTRACT: A transframe region within HIV-1 Gag-Pol (referred to as p6* or p6pol), directly linked to the protease (PR) N-terminus, plays a pivotal role in modulating PR activation. To identify specific p6* residues involved in PR activation, we created a series of p6* mutants by making substitutions for conserved p6* residues. Our results indicate that some p6* mutants were defective in terms of virus infectivity, despite displaying a wild-type virus particle processing pattern. Mutations at p6* F8 reduced virus infectivity associated with insufficient virus processing, due in part to impaired PR maturation and RT packaging. Our data strongly suggest that conserved Phe (F) residues at position 8 of p6* are involved in the PR maturation process.

SUBMITTER: Yu FH

PROVIDER: S-EPMC8794111 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Amino acid substitutions at the HIV-1 transframe region significantly impair virus infectivity.

Yu Fu-Hsien FH Huang Kuo-Jung KJ Wang Chin-Tien CT

PloS one 20220127 1

A transframe region within HIV-1 Gag-Pol (referred to as p6* or p6pol), directly linked to the protease (PR) N-terminus, plays a pivotal role in modulating PR activation. To identify specific p6* residues involved in PR activation, we created a series of p6* mutants by making substitutions for conserved p6* residues. Our results indicate that some p6* mutants were defective in terms of virus infectivity, despite displaying a wild-type virus particle processing pattern. Mutations at p6* F8 reduce ...[more]

PMID: 35085286

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Project description:UnlabelledStreptolysin O is a potent pore-forming toxin produced by group A Streptococcus. The aims of the present study were to dissect the relative contributions of different structural domains of the protein to hemolytic activity, to obtain a detoxified form of streptolysin O amenable to human vaccine formulation, and to investigate the role of streptolysin O-specific antibodies in protection against group A Streptococcus infection. On the basis of in silico structural predictions, we introduced two amino acid substitutions, one in the proline-rich domain 1 and the other in the conserved undecapeptide loop in domain 4. The resulting streptolysin O derivative showed no toxicity, was highly impaired in binding to eukaryotic cells, and was unable to form organized oligomeric structures on the cell surface. However, it was fully capable of conferring consistent protection in a murine model of group A Streptococcus infection. When we engineered a streptococcal strain to express the double-mutated streptolysin O, a drastic reduction in virulence as well as a diminished capacity to kill immune cells recruited at the infection site was observed. Furthermore, when mice immunized with the toxoid were challenged with the wild-type and mutant strains, protection only against the wild-type strain, not against the strain expressing the double-mutated streptolysin O, was obtained. We conclude that protection occurs by antibody-mediated neutralization of active toxin.ImportanceWe present a novel example of structural design of a vaccine antigen optimized for human vaccine use. Having previously demonstrated that immunization of mice with streptolysin O elicits a protective immune response against infection with group A Streptococcus strains of different serotypes, we developed in this study a double-mutated nontoxic derivative that represents a novel tool for the development of protective vaccine formulations against this important human pathogen. Furthermore, the innovative construction of an isogenic strain expressing a functionally inactive toxin and its use in infection and opsonophagocytosis experiments allowed us to investigate the mechanism by which streptolysin O mediates protection against group A Streptococcus. Finally, the ability of this toxin to directly attack and kill host immune cells during infection was studied in an air pouch model, which allowed parallel quantification of cellular recruitment, vitality, and cytokine release at the infection site.

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Amino acid substitutions at the HIV-1 transframe region significantly impair virus infectivity.

Publications

Amino acid substitutions at the HIV-1 transframe region significantly impair virus infectivity.

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