Primary HIV-1 R5 isolates from end-stage disease display enhanced viral fitness in parallel with increased gp120 net charge

• Published in: Virology (New York, N.Y.) N.Y.), 2008-09, Vol.379 (1), p.125-134
• Main Authors: Repits, Johanna, Sterjovski, Jasminka, Badia-Martinez, Daniel, Mild, Mattias, Gray, Lachlan, Churchill, Melissa J, Purcell, Damian F.J, Karlsson, Anders, Albert, Jan, Fenyö, Eva Maria, Achour, Adnane, Gorry, Paul R, Jansson, Marianne
• Format: Article
• Language: English
• Subjects: Acquired Immunodeficiency Syndrome - immunology; Acquired Immunodeficiency Syndrome - virology; AIDS; Amino Acid Substitution - genetics; Basic Medicine; CD4 Lymphocyte Count; Cloning, Molecular; Env; Evolution; Evolution, Molecular; gp120; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - genetics; HIV Fusion Inhibitors - pharmacology; HIV-1; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - isolation & purification; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; Infectious Disease; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Microbiology in the medical area; Mikrobiologi inom det medicinska området; Models, Molecular; Molecular Sequence Data; Net charge; RNA, Viral - genetics; Sequence Analysis, DNA; Sequence Homology; Viral fitness; Virus Attachment
• ISSN: 0042-6822; 1096-0341; 1096-0341
• DOI: 10.1016/j.virol.2008.06.014

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.