title: Short Communication: A Recombinant Variant with Increased Envelope Entry Efficiency Emerged During Early Infection of an HIV-1 Subtype C Dual Infected Rapid Progressor.
abstract: Mutations in functionally constrained sites of the HIV envelope (Env) can affect entry efficiency and are potential targets for vaccine and drug design. We investigated Du151, a dual-infected individual with rapid disease progression. At her death 19 months postinfection (mpi), she was infected with a recombinant variant, which outgrew both parental viruses. We aimed to determine whether the recombinant virus had enhanced Env entry efficiency compared to the parental viruses and to identify the functional determinant. We generated 15 env clones at 1, 2, 8, and 19 mpi. Pseudovirus carrying a recombinant Env clone (PSV clone), C18 (19 mpi), had significantly higher entry efficiency compared to the parents, suggesting that the recombinant virus had enhanced fitness. To identify the functional determinant, we compared two recombinant PSV clones (C18 and C63)-differing in entry efficiency (2-fold) and by four and three amino acids in gp120 and gp41, respectively. The increased entry efficiency of a C18-gp41 PSV chimera indicated that the three amino acids in the C18 gp41 region were involved (K658, G671, and F717). Site-directed mutagenesis of the three amino acids of C63 showed that a single amino acid mutation, R658K, increased pseudovirion entry efficiency. The introduction of R658 into two PSV clones (C1 and C18) decreased their entry efficiency, suggesting that R658 carries a fitness cost. Thus, our data suggest that a recombinant virus emerged at 19 mpi with enhanced Env entry efficiency. Therefore, K658 in gp41 could in part be a contributing factor to the increased viral load and rapid disease progression of Du151.
authors.affiliation: 1 Department of Molecular and Cell Biology, University of Cape Town , Cape Town, South Africa .
authors.forename: Kerry
authors.initials: K
authors.lastname: Gordon
authors.affiliation: 1 Department of Molecular and Cell Biology, University of Cape Town , Cape Town, South Africa .
authors.forename: Shatha
authors.initials: S
authors.lastname: Omar
authors.affiliation: 2 Division of Medical Virology and the Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town, South Africa .
authors.forename: Andile
authors.initials: A
authors.lastname: Nofemela
authors.affiliation: 2 Division of Medical Virology and the Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town, South Africa .
authors.forename: Gama
authors.initials: G
authors.lastname: Bandawe
authors.affiliation: 2 Division of Medical Virology and the Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town, South Africa .|3 National Health Laboratory Services, Groote Schuur Hospital , Cape Town, South Africa .
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
authors.affiliation: 1 Department of Molecular and Cell Biology, University of Cape Town , Cape Town, South Africa .
authors.forename: Zenda
authors.initials: Z
authors.lastname: Woodman
mesh_terms: D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000473:pathology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000235:genetics; D011995:Recombination, Genetic; D019562:Viral Load; D053586:Virus Internalization; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D054299:env Gene Products, Human Immunodeficiency Virus