The interdomain linker region of HIV-1 capsid protein is a critical determinant of proper core assembly and stability |
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| Authors: | Jiang Jiyang Ablan Sherimay D Derebail Suchitra Hercík Kamil Soheilian Ferri Thomas James A Tang Shixing Hewlett Indira Nagashima Kunio Gorelick Robert J Freed Eric O Levin Judith G |
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| Affiliation: | a Section on Viral Gene Regulation, Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health, National Institutes of Health, Building 6B, Room 216, 6 Center Drive, Bethesda, MD 20892-2780, USAb Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute Frederick, Frederick, MD 21702-1201, USAc Image Analysis Laboratory, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702-1201, USAd AIDS and Cancer Virus Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702-1201, USAe Laboratory of Molecular Virology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA |
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| Abstract: | The HIV-1 capsid protein consists of two independently folded domains connected by a flexible peptide linker (residues 146-150), the function of which remains to be defined. To investigate the role of this region in virus replication, we made alanine or leucine substitutions in each linker residue and two flanking residues. Three classes of mutants were identified: (i) S146A and T148A behave like wild type (WT); (ii) Y145A, I150A, and L151A are noninfectious, assemble unstable cores with aberrant morphology, and synthesize almost no viral DNA; and (iii) P147L and S149A display a poorly infectious, attenuated phenotype. Infectivity of P147L and S149A is rescued specifically by pseudotyping with vesicular stomatitis virus envelope glycoprotein. Moreover, despite having unstable cores, these mutants assemble WT-like structures and synthesize viral DNA, although less efficiently than WT. Collectively, these findings demonstrate that the linker region is essential for proper assembly and stability of cores and efficient replication. |
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