Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication

• Authors: Jonathan MO Rawson, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USA; Olga A Nikolaitchik, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USA; Jennifer A Yoo, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USA; Xayathed Somoulay, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USA; Matthew A Brown, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USA; Franck Mbuntcha Bogni, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USA; Vinay K Pathak, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USA; Ferri Soheilian, Leidos Biomedical Research, Inc; Ryan L Slack, Emory University; Stefan Sarafianos, Emory University; Wei-Shau Hu, HIV Dynamics and Replication Program, NCI, Frederick, Maryland, USA
• Journal Title: MBIO
• Volume: Volume 13, Number 5
• Publisher: AMER SOC MICROBIOLOGY | 2022-08-29, Pages e0222022-e0222022
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1128/mbio.02220-22
• Subjects: Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Microbiology; Gag; HIV-1; HIV-2; RNA packaging; adaptation; chimeric virus; evolution; lentivirus; nucleocapsid; recombination; replication; zinc finger; IMMUNODEFICIENCY-VIRUS TYPE-1; DEPENDENT DNA-POLYMERASE; FUSION INHIBITOR T-20; MURINE LEUKEMIA-VIRUS; NUCLEOCAPSID PROTEIN; REVERSE TRANSCRIPTION; GENETIC-RECOMBINATION; RNA; GAG

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.