Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication
ABSTRACT Frequent recombination is a hallmark of retrovirus replication. In rare cases, recombination occurs between distantly related retroviruses, generating novel viruses that may significantly impact viral evolution and public health. These recombinants may initially have substantial replication...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-10-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02220-22 |
| _version_ | 1797989777114398720 |
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| author | Jonathan M. O. Rawson Olga A. Nikolaitchik Jennifer A. Yoo Xayathed Somoulay Matthew A. Brown Franck S. Mbuntcha Bogni Vinay K. Pathak Ferri Soheilian Ryan L. Slack Stefan G. Sarafianos Wei-Shau Hu |
| author_facet | Jonathan M. O. Rawson Olga A. Nikolaitchik Jennifer A. Yoo Xayathed Somoulay Matthew A. Brown Franck S. Mbuntcha Bogni Vinay K. Pathak Ferri Soheilian Ryan L. Slack Stefan G. Sarafianos Wei-Shau Hu |
| author_sort | Jonathan M. O. Rawson |
| collection | DOAJ |
| description | ABSTRACT Frequent recombination is a hallmark of retrovirus replication. In rare cases, recombination occurs between distantly related retroviruses, generating novel viruses that may significantly impact viral evolution and public health. These recombinants may initially have substantial replication defects due to impaired interactions between proteins and/or nucleic acids from the two parental viruses. However, given the high mutation rates of retroviruses, these recombinants may be able to evolve improved compatibility of these viral elements. To test this hypothesis, we examined the adaptation of chimeras between two distantly related human pathogens: HIV-1 and HIV-2. We constructed HIV-1-based chimeras containing the HIV-2 nucleocapsid (NC) domain of Gag or the two zinc fingers of HIV-2 NC, which are critical for specific recognition of viral RNA. These chimeras exhibited significant defects in RNA genome packaging and replication kinetics in T cells. However, in some experiments, the chimeric viruses replicated with faster kinetics when repassaged, indicating that viral adaptation had occurred. Sequence analysis revealed the acquisition of a single amino acid substitution, S18L, in the first zinc finger of HIV-2 NC. This substitution, which represents a switch from a conserved HIV-2 residue to a conserved HIV-1 residue at this position, partially rescued RNA packaging and replication kinetics. Further analysis revealed that the combination of two substitutions in HIV-2 NC, W10F and S18L, almost completely restored RNA packaging and replication kinetics. Our study demonstrates that chimeras of distantly related retroviruses can adapt and significantly enhance their replication by acquiring a single substitution. IMPORTANCE Novel retroviruses can emerge from recombination between distantly related retroviruses. Most notably, HIV-1 originated from zoonotic transmission of a novel recombinant (SIVcpz) into humans. Newly generated recombinants may initially have significant replication defects due to impaired interactions between viral proteins and/or nucleic acids, such as between cis- and trans-acting elements from the two parental viruses. However, provided that the recombinants retain some ability to replicate, they may be able to adapt and repair the defective interactions. Here, we used HIV-1 and HIV-2 Gag chimeras as a model system for studying the adaptation of recombinant viruses. We found that only two substitutions in the HIV-2 NC domain, W10F and S18L, were required to almost fully restore RNA genome packaging and replication kinetics. These results illustrate the extremely flexible nature of retroviruses and highlight the possible emergence of novel recombinants in the future that could pose a significant threat to public health. |
| first_indexed | 2024-04-11T08:25:50Z |
| format | Article |
| id | doaj.art-86bec7df75394f38ab143fb2a046a35d |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-11T08:25:50Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-86bec7df75394f38ab143fb2a046a35d2022-12-22T04:34:47ZengAmerican Society for MicrobiologymBio2150-75112022-10-0113510.1128/mbio.02220-22Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral ReplicationJonathan M. O. Rawson0Olga A. Nikolaitchik1Jennifer A. Yoo2Xayathed Somoulay3Matthew A. Brown4Franck S. Mbuntcha Bogni5Vinay K. Pathak6Ferri Soheilian7Ryan L. Slack8Stefan G. Sarafianos9Wei-Shau Hu10Viral Recombination Section, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USAViral Recombination Section, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USAViral Recombination Section, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USAViral Recombination Section, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USAViral Recombination Section, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USAViral Recombination Section, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USAViral Mutation Section, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USAElectron Microscopy Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USALaboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USALaboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USAViral Recombination Section, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USAABSTRACT Frequent recombination is a hallmark of retrovirus replication. In rare cases, recombination occurs between distantly related retroviruses, generating novel viruses that may significantly impact viral evolution and public health. These recombinants may initially have substantial replication defects due to impaired interactions between proteins and/or nucleic acids from the two parental viruses. However, given the high mutation rates of retroviruses, these recombinants may be able to evolve improved compatibility of these viral elements. To test this hypothesis, we examined the adaptation of chimeras between two distantly related human pathogens: HIV-1 and HIV-2. We constructed HIV-1-based chimeras containing the HIV-2 nucleocapsid (NC) domain of Gag or the two zinc fingers of HIV-2 NC, which are critical for specific recognition of viral RNA. These chimeras exhibited significant defects in RNA genome packaging and replication kinetics in T cells. However, in some experiments, the chimeric viruses replicated with faster kinetics when repassaged, indicating that viral adaptation had occurred. Sequence analysis revealed the acquisition of a single amino acid substitution, S18L, in the first zinc finger of HIV-2 NC. This substitution, which represents a switch from a conserved HIV-2 residue to a conserved HIV-1 residue at this position, partially rescued RNA packaging and replication kinetics. Further analysis revealed that the combination of two substitutions in HIV-2 NC, W10F and S18L, almost completely restored RNA packaging and replication kinetics. Our study demonstrates that chimeras of distantly related retroviruses can adapt and significantly enhance their replication by acquiring a single substitution. IMPORTANCE Novel retroviruses can emerge from recombination between distantly related retroviruses. Most notably, HIV-1 originated from zoonotic transmission of a novel recombinant (SIVcpz) into humans. Newly generated recombinants may initially have significant replication defects due to impaired interactions between viral proteins and/or nucleic acids, such as between cis- and trans-acting elements from the two parental viruses. However, provided that the recombinants retain some ability to replicate, they may be able to adapt and repair the defective interactions. Here, we used HIV-1 and HIV-2 Gag chimeras as a model system for studying the adaptation of recombinant viruses. We found that only two substitutions in the HIV-2 NC domain, W10F and S18L, were required to almost fully restore RNA genome packaging and replication kinetics. These results illustrate the extremely flexible nature of retroviruses and highlight the possible emergence of novel recombinants in the future that could pose a significant threat to public health.https://journals.asm.org/doi/10.1128/mbio.02220-22GagHIV-1HIV-2RNA packagingadaptationchimeric virus |
| spellingShingle | Jonathan M. O. Rawson Olga A. Nikolaitchik Jennifer A. Yoo Xayathed Somoulay Matthew A. Brown Franck S. Mbuntcha Bogni Vinay K. Pathak Ferri Soheilian Ryan L. Slack Stefan G. Sarafianos Wei-Shau Hu Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication mBio Gag HIV-1 HIV-2 RNA packaging adaptation chimeric virus |
| title | Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication |
| title_full | Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication |
| title_fullStr | Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication |
| title_full_unstemmed | Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication |
| title_short | Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication |
| title_sort | adaptation of hiv 1 hiv 2 chimeras with defects in genome packaging and viral replication |
| topic | Gag HIV-1 HIV-2 RNA packaging adaptation chimeric virus |
| url | https://journals.asm.org/doi/10.1128/mbio.02220-22 |
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