CpG Frequency in the 5′ Third of the env Gene Determines Sensitivity of Primary HIV-1 Strains to the Zinc-Finger Antiviral Protein
| Autor: | Scott Sherrill-Mix, Beatrice H. Hahn, Konstantin M. J. Sparrer, Dorota Kmiec, Christina M. Stürzel, Daniel Sauter, Frank Kirchhoff, Elisabeth Braun, Marcos V. P. Gondim, Elena Heusinger, Rayhane Nchioua, Dominik Hotter |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Viral protein
viruses Antiviral protein zinc-finger antiviral protein chemical and pharmacologic phenomena Genome Viral Simian medicine.disease_cause Virus Replication Genome Microbiology envelope gene Host-Microbe Biology 03 medical and health sciences Virology medicine Humans Gene Immunodeficiency 030304 developmental biology 0303 health sciences biology human immunodeficiency virus 030306 microbiology env Gene Products Human Immunodeficiency Virus virus diseases RNA-Binding Proteins hemic and immune systems Simian immunodeficiency virus biology.organism_classification medicine.disease restriction factors QR1-502 3. Good health HEK293 Cells CpG site HIV-2 HIV-1 CpG Islands Simian Immunodeficiency Virus CpG dinucleotides Research Article |
| Zdroj: | mBio mBio, Vol 11, Iss 1, p e02903-19 (2020) mBio, Vol 11, Iss 1 (2020) |
| ISSN: | 2150-7511 |
| Popis: | Evasion of the zinc-finger antiviral protein (ZAP) may drive CpG dinucleotide suppression in HIV-1 and many other viral pathogens but the viral determinants of ZAP sensitivity are poorly defined. Here, we examined CpG suppression and ZAP sensitivity in a large number of primate lentiviruses and demonstrate that their genomic frequency of CpGs varies substantially and does not correlate with ZAP sensitivity. We further show that the number of CpG residues in a defined region at the 5′ end of the env gene together with structural features plays a key role in HIV-1 susceptibility to ZAP and correlates with differences in clinical progression rates in HIV-1-infected individuals. Our identification of a specific part of env as a major determinant of HIV-1 susceptibility to ZAP restriction provides a basis for future studies of the underlying inhibitory mechanisms and their potential relevance in the pathogenesis of AIDS. CpG dinucleotide suppression has been reported to allow HIV-1 to evade inhibition by the zinc-finger antiviral protein (ZAP). Here, we show that primate lentiviruses display marked differences in CpG frequencies across their genome, ranging from 0.44% in simian immunodeficiency virus SIVwrc from Western red colobus to 2.3% in SIVmon infecting mona monkeys. Moreover, functional analyses of a large panel of human and simian immunodeficiency viruses revealed that the magnitude of CpG suppression does not correlate with their susceptibility to ZAP. However, we found that the number of CpG dinucleotides within a region of ∼700 bases at the 5′ end of the env gene determines ZAP sensitivity of primary HIV-1 strains but not of HIV-2. Increased numbers of CpGs in this region were associated with reduced env mRNA expression and viral protein production. ZAP sensitivity profiles of chimeric simian-human immunodeficiency viruses (SHIVs) expressing different HIV-1 env genes were highly similar to those of the corresponding HIV-1 strains. The frequency of CpGs in the identified env region correlated with differences in clinical progression rates. Thus, the CpG frequency in a specific part of env, rather than the overall genomic CpG content, governs the susceptibility of HIV-1 to ZAP and might affect viral pathogenicity in vivo. |
| Databáze: | OpenAIRE |
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