A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing

Viruses

Tomozumi Imamichi¹  Ming Hao¹  Suranjana Goswami¹  Brad T. Sherman¹  Jun Yang¹  Qian Chen¹  Weizhong Chang¹  Catherine A. Rehm²  Helene C. Highbarger³  Robin L. Dewar³  Muhammad A. Khan³  Muhammad T. Rehman³ 

[1] Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory, Frederick, MD 21702, USA;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA;Virus Isolation and Serology Laboratory, Frederick National Laboratory, Frederick, MD 21702, USA;

关键词: polymorphisms;    integrase;    M50I;    V151I;    autoprocessing;    maturation;   

DOI  :  10.3390/v13112331

来源: DOAJ

【 摘 要 】

We have recently reported that a recombinant HIV-1NL4.3 containing Met-to-Ile change at codon 50 of integrase (IN) (IN:M50I) exhibits suppression of the virus release below 0.5% of WT HIV, and the released viral particles are replication-incompetent due to defects in Gag/GagPol processing by inhibition of the initiation of autoprocessing of GagPol polyproteins in the virions and leads to replication-incompetent viruses. The coexisting Ser-to-Asn change at codon 17 of IN or Asn-to-Ser mutation at codon 79 of RNaseH (RH) compensated the defective IN:M50I phenotype, suggesting that both IN and RH regulate an HIV infectability. In the current study, to elucidate a distribution of the three mutations during anti-retroviral therapy among patients, we performed a population analysis using 529 plasma virus RNA sequences obtained through the MiSeq. The result demonstrated that 14 plasma HIVs contained IN:M50I without the compensatory mutations. Comparing the sequences of the 14 viruses with that of the defective virus illustrated that only Val-to-Ile change at codon 151 of IN (IN:V151I) existed in the recombinant virus. This IN:V151I is known as a polymorphic mutation and was derived from HIVNL4.3 backbone. A back-mutation at 151 from Ile-to-Val in the defective virus recovered HIV replication capability, and Western Blotting assay displayed that the back-mutation restored Gag/GagPol processing in viral particles. These results demonstrate that a combination of IN:M50I and IN:V151I mutations, but not IN:M50I alone, produces a defective virus.

【 授权许可】

Unknown