title: Increased replication capacity following evolution of PYxE insertion in Gag-p6 is associated with enhanced virulence in HIV-1 subtype C from East Africa.
abstract: A lower virulence of HIV-1 subtype C (HIV-1C) is suggested to be related to the global dominance of HIV-1C. In this observational study, combining in vivo (clinical monitoring) and in vitro (genotypic, biochemical, and phenotypic assays), we explored whether HIV-1C from East Africa (HIV-1CEA) is more pathogenic due to the evolution of a PYxE-insertion (CPYxEi) in the gag-p6 that also could affect the therapy response.
  
  
  
  HIV-1B (n = 112) and HIV-1CEA(n = 128)-infected individuals residing in Sweden were analyzed with regard to Gag-p6 genotype and clinically monitored. Based on the Gag-p6 characteristics, three HIV-1CEAand one HIV-1 B patient-derived p2-INT-recombinant virus (gag-p2/NCp7/p1/p6/pol-PR/RT/IN) were constructed to analyze viral growth kinetics (VGKs) and drug sensitivity assays. Reverse transcriptase (RT) from the same samples was cloned into the heterodimer expression plasmid (pRT6H-PROT) to analyze catalytic efficiency of RT.
  
  
  
  A higher viral failure rate and lower pre-therapy CD4+T-cell counts were observed in HIV-1CEA-infected patients compared to HIV-1B-infected patients. In Gag-p6, PTAP-duplication was more common in HIV-1C. HIV-1CEA-infected patients with signature CPYxEi,evidenced very low pre-therapy CD4+T-cell counts and suboptimal gain in CD4+T-cells following therapy, as compared to the non-CPYxEi-strains indicating higher virulence. VGKs showed a statistically significant higher replication capacity (RC) for the CPYxEiviruses than the other two non-CPYxEistrains. No statistically significant difference was observed in the catalytic efficiency among HIV-1C RTs.
  
  
  
  This is the first evidence of polymerase independent increased virulence and RC in HIV-1CEAfollowing PYxE-insertion that is associated with suboptimal CD4+T-cell gain following therapy initiation. J. Med. Virol. 89:106-111, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Shambhu G
authors.initials: SG
authors.lastname: Aralaguppe
authors.affiliation: University Hospital Translational Laboratory, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Dane
authors.initials: D
authors.lastname: Winner
authors.affiliation: Department of Molecular Microbiology and Immunology, Christopher Bond Life Sciences Center, University of Missouri, Columbia, Missouri.
authors.forename: Kamalendra
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Molecular Microbiology and Immunology, Christopher Bond Life Sciences Center, University of Missouri, Columbia, Missouri.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.affiliation: University Hospital Translational Laboratory, University Hospitals Case Medical Center, Cleveland, Ohio.|Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Quiñones-Mateu
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.|Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sönnerborg
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden. ujjwal.neogi@ki.se.
authors.forename: Ujjwal
authors.initials: U
authors.lastname: Neogi
mesh_terms: D000328:Adult; D000351:Africa, Eastern; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D013548:Sweden; D016896:Treatment Outcome; D014774:Virulence; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D044966:Anti-Retroviral Agents; D054301:gag Gene Products, Human Immunodeficiency Virus; C083002:p6 gag protein, Human immunodeficiency virus 1
keywords: East Africa; Gag; HIV-1 subtype C; virulence