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Sci Rep. 2019 Jul 8;9(1):9806. doi: 10.1038/s41598-019-46082-2.

Amino-acid inserts of HIV-1 capsid (CA) induce CA degradation and abrogate viral infectivity: Insights for the dynamics and mechanisms of HIV-1 CA decomposition.

Author information

1
Department of Hematology, Rheumatology, and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan.
2
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
3
Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, Tokyo, 162-8655, Japan.
4
Department of Hematology, Rheumatology, and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan. mitsuyah@nih.gov.
5
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. mitsuyah@nih.gov.
6
Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, Tokyo, 162-8655, Japan. mitsuyah@nih.gov.

Abstract

Accumulation of amino acid (AA) insertions/substitutions are observed in the Gag-protein of HIV-1 variants resistant to HIV-1 protease inhibitors. Here, we found that HIV-1 carrying AA insertions in capsid protein (CA) undergoes aberrant CA degradation. When we generated recombinant HIV-1s (rHIV-1s) containing 19-AAs in Gag, such insertions caused significant CA degradation, which initiated in CA's C-terminal. Such rHIV-1s had remarkable morphological abnormality, decreased infectivity, and no replicative ability, which correlated with levels of CA degradation. The CA degradation observed was energy-independent and had no association with cellular/viral proteolytic mechanisms, suggesting that the CA degradation occurs due to conformational/structural incompatibility caused by the 19-AA insertions. The incorporation of degradation-prone CA into the wild-type CA resulted in significant disruption of replication competence in "chimeric" virions. The data should allow better understanding of the dynamics and mechanisms of CA decomposition/degradation and retroviral uncoating, which may lead to new approach for antiretroviral modalities.

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