title: Primary HIV-1 R5 isolates from end-stage disease display enhanced viral fitness in parallel with increased gp120 net charge.
abstract: To better understand the evolution of the viral envelope glycoproteins (Env) in HIV-1 infected individuals who progress to AIDS maintaining an exclusive CCR5-using (R5) virus population, we cloned and sequenced the env gene of longitudinally obtained primary isolates. A shift in the electrostatic potential towards an increased net positive charge was revealed in gp120 of end-stage viruses. Residues with increased positive charge were primarily localized in the gp120 variable regions, with the exception of the V3 loop. Molecular modeling indicated that the modifications clustered on the gp120 surface. Furthermore, correlations between increased Env net charge and lowered CD4(+) T cell counts, enhanced viral fitness, reduced sensitivity to entry inhibitors and augmented cell attachment were disclosed. In summary, this study suggests that R5 HIV-1 variants with increased gp120 net charge emerge in an opportunistic manner during severe immunodeficiency. Thus, we here propose a new mechanism by which HIV-1 may gain fitness.
authors.affiliation: Department of Laboratory Medicine, Lund University, Sweden. johanna.repits@med.lu.se
authors.forename: Johanna
authors.initials: J
authors.lastname: Repits
authors.forename: Jasminka
authors.initials: J
authors.lastname: Sterjovski
authors.forename: Daniel
authors.initials: D
authors.lastname: Badia-Martinez
authors.forename: Mattias
authors.initials: M
authors.lastname: Mild
authors.forename: Lachlan
authors.initials: L
authors.lastname: Gray
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Churchill
authors.forename: Damian F J
authors.initials: DF
authors.lastname: Purcell
authors.forename: Anders
authors.initials: A
authors.lastname: Karlsson
authors.forename: Jan
authors.initials: J
authors.lastname: Albert
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Fenyö
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: Marianne
authors.initials: M
authors.lastname: Jansson
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology*; D019943:Amino Acid Substitution / Q000235:genetics; D018791:CD4 Lymphocyte Count; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification* / Q000502:physiology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D053585:Virus Attachment
chemical_list: D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D012367:RNA, Viral; C514793:gp120 protein, Human immunodeficiency virus 1