HIV Replication Under High-Level Cabotegravir Is Associated with the Appearance of 3′-PPT Mutations, Circular DNA Transcription and Recombination
The HIV integrase inhibitor, dolutegravir (DTG), in the absence of eliciting integrase (int) resistance, has been reported to select mutations in the virus 3′-polypurine tract (3′-PPT) adjacent to the 3′-LTR U3. An analog of DTG, cabotegravir (CAB), has a high genetic barrier to drug resistance and...
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| author | Xierong Wei Jonathan T. Lipscomb Ariana Santos Tino Mian-er Cong Susan Ruone Meghan L. Bentz Mili Sheth Gerardo Garcia-Lerma Jeffrey A. Johnson |
| author_facet | Xierong Wei Jonathan T. Lipscomb Ariana Santos Tino Mian-er Cong Susan Ruone Meghan L. Bentz Mili Sheth Gerardo Garcia-Lerma Jeffrey A. Johnson |
| author_sort | Xierong Wei |
| collection | DOAJ |
| description | The HIV integrase inhibitor, dolutegravir (DTG), in the absence of eliciting integrase (int) resistance, has been reported to select mutations in the virus 3′-polypurine tract (3′-PPT) adjacent to the 3′-LTR U3. An analog of DTG, cabotegravir (CAB), has a high genetic barrier to drug resistance and is used in formulations for treatment and long-acting pre-exposure prophylaxis. We examined whether mutations observed for DTG would emerge in vitro with CAB. HIV-1IIIB was cultured in paired experiments of continuous high (300 nM) CAB initiated 2 h or 24 h after infection. After eight months of CAB treatment, no int resistance was detected. Conversely, HIV RNA 3′-PPT mutants were detected within one month and were the majority virus by day 98. The appearance of 3′-PPT variants coincided with a rapid accumulation of HIV 1-LTR and 2-LTR circles. RNA amplification from the 3′-LTR TAR identified transcripts crossing 2-LTR circle junctions, which incorporated the adjacent U5 sequence identical to the 3′-PPT mutants. 3′-PPT variants were only identified in LTR circles and transcripts. Additionally, we found evidence of linear HIV and LTR circle recombination with human DNA at motifs homologous to 3′-PPT sequences. HIV persistence under CAB was associated with transcription and recombination of LTR circle sequences. |
| format | Article |
| id | doaj-art-2a66112d37c44f93874cd2b7f3561173 |
| institution | OA Journals |
| issn | 1999-4915 |
| language | English |
| publishDate | 2024-11-01 |
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| spelling | doaj-art-2a66112d37c44f93874cd2b7f35611732025-08-20T02:01:14ZengMDPI AGViruses1999-49152024-11-011612187410.3390/v16121874HIV Replication Under High-Level Cabotegravir Is Associated with the Appearance of 3′-PPT Mutations, Circular DNA Transcription and RecombinationXierong Wei0Jonathan T. Lipscomb1Ariana Santos Tino2Mian-er Cong3Susan Ruone4Meghan L. Bentz5Mili Sheth6Gerardo Garcia-Lerma7Jeffrey A. Johnson8Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USALaboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USALaboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USALaboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USALaboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USAAdvanced Diagnostics and Biotechnologies Branch, Division of Core Laboratory Services and Response, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, USAAdvanced Diagnostics and Biotechnologies Branch, Division of Core Laboratory Services and Response, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, USALaboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USALaboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USAThe HIV integrase inhibitor, dolutegravir (DTG), in the absence of eliciting integrase (int) resistance, has been reported to select mutations in the virus 3′-polypurine tract (3′-PPT) adjacent to the 3′-LTR U3. An analog of DTG, cabotegravir (CAB), has a high genetic barrier to drug resistance and is used in formulations for treatment and long-acting pre-exposure prophylaxis. We examined whether mutations observed for DTG would emerge in vitro with CAB. HIV-1IIIB was cultured in paired experiments of continuous high (300 nM) CAB initiated 2 h or 24 h after infection. After eight months of CAB treatment, no int resistance was detected. Conversely, HIV RNA 3′-PPT mutants were detected within one month and were the majority virus by day 98. The appearance of 3′-PPT variants coincided with a rapid accumulation of HIV 1-LTR and 2-LTR circles. RNA amplification from the 3′-LTR TAR identified transcripts crossing 2-LTR circle junctions, which incorporated the adjacent U5 sequence identical to the 3′-PPT mutants. 3′-PPT variants were only identified in LTR circles and transcripts. Additionally, we found evidence of linear HIV and LTR circle recombination with human DNA at motifs homologous to 3′-PPT sequences. HIV persistence under CAB was associated with transcription and recombination of LTR circle sequences.https://www.mdpi.com/1999-4915/16/12/1874cabotegravir resistanceCAB3′-PPTLTR circlesHIV recombination |
| spellingShingle | Xierong Wei Jonathan T. Lipscomb Ariana Santos Tino Mian-er Cong Susan Ruone Meghan L. Bentz Mili Sheth Gerardo Garcia-Lerma Jeffrey A. Johnson HIV Replication Under High-Level Cabotegravir Is Associated with the Appearance of 3′-PPT Mutations, Circular DNA Transcription and Recombination Viruses cabotegravir resistance CAB 3′-PPT LTR circles HIV recombination |
| title | HIV Replication Under High-Level Cabotegravir Is Associated with the Appearance of 3′-PPT Mutations, Circular DNA Transcription and Recombination |
| title_full | HIV Replication Under High-Level Cabotegravir Is Associated with the Appearance of 3′-PPT Mutations, Circular DNA Transcription and Recombination |
| title_fullStr | HIV Replication Under High-Level Cabotegravir Is Associated with the Appearance of 3′-PPT Mutations, Circular DNA Transcription and Recombination |
| title_full_unstemmed | HIV Replication Under High-Level Cabotegravir Is Associated with the Appearance of 3′-PPT Mutations, Circular DNA Transcription and Recombination |
| title_short | HIV Replication Under High-Level Cabotegravir Is Associated with the Appearance of 3′-PPT Mutations, Circular DNA Transcription and Recombination |
| title_sort | hiv replication under high level cabotegravir is associated with the appearance of 3 ppt mutations circular dna transcription and recombination |
| topic | cabotegravir resistance CAB 3′-PPT LTR circles HIV recombination |
| url | https://www.mdpi.com/1999-4915/16/12/1874 |
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