Frequency and Env determinants of HIV-1 subtype C strains from antiretroviral therapy-naive subjects that display incomplete inhibition by maraviroc.
BACKGROUND
Entry of human immunodeficiency virus type 1 (HIV-1) into cells involves the interaction of the viral gp120 envelope glycoproteins (Env) with cellular CD4 and a secondary coreceptor, which is typically one of the chemokine receptors CCR5 or CXCR4. CCR5-using (R5) HIV-1 strains that display reduced sensitivity to CCR5 antagonists can use antagonist-bound CCR5 for entry. In this study, we investigated whether naturally occurring gp120 alterations in HIV-1 subtype C (C-HIV) variants exist in antiretroviral therapy (ART)-naïve subjects that may influence their sensitivity to the CCR5 antagonist maraviroc (MVC).


RESULTS
Using a longitudinal panel of 244 R5 Envs cloned from 20 ART-naïve subjects with progressive C-HIV infection, we show that 40% of subjects (n = 8) harbored viruses that displayed incomplete inhibition by MVC, as shown by plateau's of reduced maximal percent inhibitions (MPIs). Specifically, when pseudotyped onto luciferase reporter viruses, 16 Envs exhibited MPIs below 98% in NP2-CCR5 cells (range 79.7-97.3%), which were lower still in 293-Affinofile cells that were engineered to express high levels of CCR5 (range 15.8-72.5%). We further show that Envs exhibiting reduced MPIs to MVC utilized MVC-bound CCR5 less efficiently than MVC-free CCR5, which is consistent with the mechanism of resistance to CCR5 antagonists that can occur in patients failing therapy. Mutagenesis studies identified strain-specific mutations in the gp120 V3 loop that contributed to reduced MPIs to MVC.


CONCLUSIONS
The results of our study suggest that some ART-naïve subjects with C-HIV infection harbor HIV-1 with reduced MPIs to MVC, and demonstrate that the gp120 V3 loop region contributes to this phenotype.
Center for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.|Department of Microbiology, La Trobe University, Melbourne, VIC, Australia.
Katharina
K
Borm
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Martin R
MR
Jakobsen
School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University, Melbourne, VIC, 3001, Australia.
Kieran
K
Cashin
Center for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.|School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University, Melbourne, VIC, 3001, Australia.|Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia.
Jacqueline K
JK
Flynn
Center for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.|School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University, Melbourne, VIC, 3001, Australia.
Paula
P
Ellenberg
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Lars
L
Ostergaard
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Benhur
B
Lee
Center for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.|Department of Medicine, Monash University, Melbourne, VIC, Australia.|Department of Microbiology, Monash University, Melbourne, VIC, Australia.
Melissa J
MJ
Churchill
Center for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia. michael.roche@unimelb.edu.au.|The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, VIC, 3000, Australia. michael.roche@unimelb.edu.au.
Michael
M
Roche
Center for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia. paul.gorry@rmit.edu.au.|School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University, Melbourne, VIC, 3001, Australia. paul.gorry@rmit.edu.au.
Paul R
PR
Gorry
D023241:Antiretroviral Therapy, Highly Active; D065100:CCR5 Receptor Antagonists / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D003510:Cyclohexanes / Q000494:pharmacology*; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D000077592:Maraviroc; D016296:Mutagenesis; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics*; D019713:Receptors, CCR5 / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*; D053586:Virus Internalization
D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc
CCR5; Env; HIV-1; Maraviroc; Subtype C; gp120