Primary HIV-1 R5 isolates from end-stage disease display enhanced viral fitness in parallel with increased gp120 net charge.
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.
Repits
Johanna
J
Department of Laboratory Medicine, Lund University, Sweden. johanna.repits@med.lu.se
Sterjovski
Jasminka
J
Badia-Martinez
Daniel
D
Mild
Mattias
M
Gray
Lachlan
L
Churchill
Melissa J
MJ
Purcell
Damian F J
DF
Karlsson
Anders
A
Albert
Jan
J
Fenyö
Eva Maria
EM
Achour
Adnane
A
Gorry
Paul R
PR
Jansson
Marianne
M
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
D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D012367:RNA, Viral; C514793:gp120 protein, Human immunodeficiency virus 1