Primary HIV-1 R5 isolates from end-stage disease display enhanced viral fitness in parallel with increased gp120 net charge
Johanna Repits, Jasminka Sterjovski, Daniel Badia-Martinez, Mattias Mild, Lachlan Gray, Melissa J Churchill, Damian FJ Purcell, Anders Karlsson, Jan Albert, Eva Maria Fenyoe, Adnane Achour, Paul R Gorry, Marianne Jansson
VIROLOGY | ACADEMIC PRESS INC ELSEVIER SCIENCE | Published : 2008
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,..View full abstract
Awarded by Australian National Health and Medical Research Council (NHMRC)
We thank Dr Joseph Sodroski for providing the pSVIIIenv expression plasmid and Cf2th-CD4/CCR5 cells, Dr Hiroo Hoshino for the NP-2 cell lines, Dr Daniel Littman for U87.CD4.CCR5 cell line, Dr Peter D Kwong and Dr Marie Pancera for molecular models and Hannes Uchtenhagen for suggestions on the manuscript. T20 fusion inhibitor from Roche and TAK-779 were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAD, NIH. DNA sequencing was performed at the SWEGENE Centre of Genomic Ecology at Lund University supported by the Knut and Alice Wallenberg Foundation through the SWEGENE consortium. The work was supported by grants provided to MJ from the Swedish Research Council and to MJ and EMF from the Swedish international Development Agency/Department for Research Cooperation (Sida/SAREC). Grants were also provided by the Magn. Bergvall's Foundation, the Physicians Against AIDS Research Foundation, Clas Groschinskys Foundation, the Royal Physiographic Society ill Lund, Sweden. JR was given a travel grant from the Solander Foundation for a six month visit to the laboratory of PRG. PRG was supported in part by a grant from the Australian National Health and Medical Research Council (NHMRC) (433915). JS and LG were supported by Australian NHMRC Dora Lush Biomedical Postgraduate Research Scholarships. PRG is the recipient of an Australian NHMCR R. Douglas Wright Biomedical Career Development Award.