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

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 inhibit...

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Autores principales:	Jun Yang, Ming Hao, Muhammad A. Khan, Muhammad T. Rehman, Helene C. Highbarger, Qian Chen, Suranjana Goswami, Brad T. Sherman, Catherine A. Rehm, Robin L. Dewar, Weizhong Chang, Tomozumi Imamichi
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	polymorphisms integrase M50I V151I autoprocessing maturation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d3ccaabb87b0429cb3c47bc2cede4361
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spelling	oai:doaj.org-article:d3ccaabb87b0429cb3c47bc2cede43612021-11-25T19:14:39ZA Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing10.3390/v131123311999-4915https://doaj.org/article/d3ccaabb87b0429cb3c47bc2cede43612021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4915/13/11/2331https://doaj.org/toc/1999-4915We 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.Jun YangMing HaoMuhammad A. KhanMuhammad T. RehmanHelene C. HighbargerQian ChenSuranjana GoswamiBrad T. ShermanCatherine A. RehmRobin L. DewarWeizhong ChangTomozumi ImamichiMDPI AGarticlepolymorphismsintegraseM50IV151IautoprocessingmaturationMicrobiologyQR1-502ENViruses, Vol 13, Iss 2331, p 2331 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	polymorphisms integrase M50I V151I autoprocessing maturation Microbiology QR1-502
spellingShingle	polymorphisms integrase M50I V151I autoprocessing maturation Microbiology QR1-502 Jun Yang Ming Hao Muhammad A. Khan Muhammad T. Rehman Helene C. Highbarger Qian Chen Suranjana Goswami Brad T. Sherman Catherine A. Rehm Robin L. Dewar Weizhong Chang Tomozumi Imamichi A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing
description	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.
format	article
author	Jun Yang Ming Hao Muhammad A. Khan Muhammad T. Rehman Helene C. Highbarger Qian Chen Suranjana Goswami Brad T. Sherman Catherine A. Rehm Robin L. Dewar Weizhong Chang Tomozumi Imamichi
author_facet	Jun Yang Ming Hao Muhammad A. Khan Muhammad T. Rehman Helene C. Highbarger Qian Chen Suranjana Goswami Brad T. Sherman Catherine A. Rehm Robin L. Dewar Weizhong Chang Tomozumi Imamichi
author_sort	Jun Yang
title	A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing
title_short	A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing
title_full	A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing
title_fullStr	A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing
title_full_unstemmed	A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing
title_sort	combination of m50i and v151i polymorphic mutations in hiv-1 subtype b integrase results in defects in autoprocessing
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d3ccaabb87b0429cb3c47bc2cede4361
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A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing

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