title: Functional bottlenecks for generation of HIV-1 intersubtype Env recombinants.
abstract: BACKGROUND
  Intersubtype recombination is a powerful driving force for HIV evolution, impacting both HIV-1 diversity within an infected individual and within the global epidemic. This study examines if viral protein function/fitness is the major constraint shaping selection of recombination hotspots in replication-competent HIV-1 progeny. A better understanding of the interplay between viral protein structure-function and recombination may provide insights into both vaccine design and drug development.
  
  
  RESULTS
  In vitro HIV-1 dual infections were used to recombine subtypes A and D isolates and examine breakpoints in the Env glycoproteins. The entire env genes of 21 A/D recombinants with breakpoints in gp120 were non-functional when cloned into the laboratory strain, NL4-3. Likewise, cloning of A/D gp120 coding regions also produced dead viruses with non-functional Envs. 4/9 replication-competent viruses with functional Env's were obtained when just the V1-V5 regions of these same A/D recombinants (i.e. same A/D breakpoints as above) were cloned into NL4-3.
  
  
  CONCLUSIONS
  These findings on functional A/D Env recombinants combined with structural models of Env suggest a conserved interplay between the C1 domain with C5 domain of gp120 and extracellular domain of gp41. Models also reveal a co-evolution within C1, C5, and ecto-gp41 domains which might explain the paucity of intersubtype recombination in the gp120 V1-V5 regions, despite their hypervariability. At least HIV-1 A/D intersubtype recombination in gp120 may result in a C1 from one subtype incompatible with a C5/gp41 from another subtype.
authors.affiliation: Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. bsb44@case.edu.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Bagaya
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. jose.vega@case.edu.
authors.forename: José F
authors.initials: JF
authors.lastname: Vega
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5C1, Canada. mtian27@uwo.ca.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Tian
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. gcn4@case.edu.
authors.forename: Gabrielle C
authors.initials: GC
authors.lastname: Nickel
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. yxl111@case.edu.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. kendallkrebs78@gmail.com.
authors.forename: Kendall C
authors.initials: KC
authors.lastname: Krebs
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5C1, Canada. earts@uwo.ca.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Arts
authors.affiliation: Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. yxg18@case.edu.|Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA. yxg18@case.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
mesh_terms: D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011995:Recombination, Genetic
chemical_list: D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1