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Co-evolution of the HIV-1 R5 phenotype and the viral envelope glycoproteins

Repits, Johanna LU (2008) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2008:108.
Abstract
To gain entry into target cells, HIV-1 binds to CD4 via the viral glycoprotein gp120. This interac-tion initiates a series of events including binding of a coreceptor, CCR5 and/or CXCR4, and ulti-mately leads to gp41-mediated fusion of the viral and cell membranes. CCR5-restricted (R5) vi-ruses predominate in early, asymptomatic stages of the infection. Emergence of viruses able to use CXCR4 instead of, or in addition to, CCR5 for cell entry has been correlated with rapid progres-sion to AIDS. Importantly, approximately 50% of HIV-1 infected individuals progress to AIDS while maintaining viruses that are restricted to CCR5.

The major reason for today’s inadequate treatment of HIV-1 infection and failure to develop a potent... (More)
To gain entry into target cells, HIV-1 binds to CD4 via the viral glycoprotein gp120. This interac-tion initiates a series of events including binding of a coreceptor, CCR5 and/or CXCR4, and ulti-mately leads to gp41-mediated fusion of the viral and cell membranes. CCR5-restricted (R5) vi-ruses predominate in early, asymptomatic stages of the infection. Emergence of viruses able to use CXCR4 instead of, or in addition to, CCR5 for cell entry has been correlated with rapid progres-sion to AIDS. Importantly, approximately 50% of HIV-1 infected individuals progress to AIDS while maintaining viruses that are restricted to CCR5.

The major reason for today’s inadequate treatment of HIV-1 infection and failure to develop a potent vaccine is the fast evolution of the virus. Due to an error-prone reverse transcriptase en-zyme (RT), mutations are continuously introduced into the viral genome, which result in pheno-typic variation of the virus. Thus, the intra-host virus evolution can be traced by analyzing the changes in the viral genome over time. We have studied the intra-patient evolution of the R5 phe-notype and the viral envelope glycoproteins in patients that maintain an exclusive CCR5-restricted virus population. We used a panel of sequentially isolated viruses from patients who all progressed to AIDS. Isolations were done at the chronic, asymptomatic phase and after AIDS onset, at which time the patients were all severely immunodeficient. Our results revealed emergence of virus vari-ants with enhanced viral fitness during end-stage disease. After AIDS onset viruses with higher infectivity and replicative capacity dominated. These viruses were also more resistant to inhibition by several entry inhibiting compounds, which suggests a central role of the viral Env (gp120/gp41 complex) in the evolution of viral properties towards increased fitness.

To dissect the evolution of the viral Env at the molecular level, we cloned, sequenced and analyzed full length gp160 env clones. We discovered that the Env of end-stage R5 viruses were less glycosylated and had higher net charge. These changes were all mapped to gp120 and specifi-cally to the variable regions, i.e., the outer surface of the Env. Furthermore, the reduced glycan shield correlated with a decreased ability to infect target cells in DC-SIGN-mediated trans-infection and increased sensitivity to MAb neutralization. Viruses with increased Env charge are selected for during severe immunodeficiency and correlated with enhanced cell attachment and properties of viral fitness. Both reduced glycosylation and increased net charge of Env correlated with reduced CD4+ T cell count at time of R5 virus isolation.

In summary, during end-stage disease, R5 virus variants emerge with increased viral fitness. The elevated fitness is a result of altered phenotypic properties. The underlying mechanisms can be mapped to the molecular properties of the viral Env. Thus, after AIDS onset, viruses with al-tered phenotypic properties may evolve, in an opportunistic manner, and result in the emergence of HIV-1 R5 variants with enhanced pathogenicity. (Less)
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author
supervisor
opponent
  • Professor Olofsson, Sigvard, Dep of Virology, University of Göteborg
organization
publishing date
type
Thesis
publication status
published
subject
keywords
envelope, R5, HIV-1, evolution
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2008:108
pages
120 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Segerfalksalen, Lund University
defense date
2008-11-28 09:00
ISSN
1652-8220
ISBN
978-91-86059-61-3
language
English
LU publication?
yes
id
d6c5a246-1a7f-46eb-a093-9cf30720d563 (old id 1272102)
date added to LUP
2008-12-01 14:42:55
date last changed
2016-09-19 08:44:48
@phdthesis{d6c5a246-1a7f-46eb-a093-9cf30720d563,
  abstract     = {To gain entry into target cells, HIV-1 binds to CD4 via the viral glycoprotein gp120. This interac-tion initiates a series of events including binding of a coreceptor, CCR5 and/or CXCR4, and ulti-mately leads to gp41-mediated fusion of the viral and cell membranes. CCR5-restricted (R5) vi-ruses predominate in early, asymptomatic stages of the infection. Emergence of viruses able to use CXCR4 instead of, or in addition to, CCR5 for cell entry has been correlated with rapid progres-sion to AIDS. Importantly, approximately 50% of HIV-1 infected individuals progress to AIDS while maintaining viruses that are restricted to CCR5.<br/><br>
 The major reason for today’s inadequate treatment of HIV-1 infection and failure to develop a potent vaccine is the fast evolution of the virus. Due to an error-prone reverse transcriptase en-zyme (RT), mutations are continuously introduced into the viral genome, which result in pheno-typic variation of the virus. Thus, the intra-host virus evolution can be traced by analyzing the changes in the viral genome over time. We have studied the intra-patient evolution of the R5 phe-notype and the viral envelope glycoproteins in patients that maintain an exclusive CCR5-restricted virus population. We used a panel of sequentially isolated viruses from patients who all progressed to AIDS. Isolations were done at the chronic, asymptomatic phase and after AIDS onset, at which time the patients were all severely immunodeficient. Our results revealed emergence of virus vari-ants with enhanced viral fitness during end-stage disease. After AIDS onset viruses with higher infectivity and replicative capacity dominated. These viruses were also more resistant to inhibition by several entry inhibiting compounds, which suggests a central role of the viral Env (gp120/gp41 complex) in the evolution of viral properties towards increased fitness.<br/><br>
 To dissect the evolution of the viral Env at the molecular level, we cloned, sequenced and analyzed full length gp160 env clones. We discovered that the Env of end-stage R5 viruses were less glycosylated and had higher net charge. These changes were all mapped to gp120 and specifi-cally to the variable regions, i.e., the outer surface of the Env. Furthermore, the reduced glycan shield correlated with a decreased ability to infect target cells in DC-SIGN-mediated trans-infection and increased sensitivity to MAb neutralization. Viruses with increased Env charge are selected for during severe immunodeficiency and correlated with enhanced cell attachment and properties of viral fitness. Both reduced glycosylation and increased net charge of Env correlated with reduced CD4+ T cell count at time of R5 virus isolation.<br/><br>
 In summary, during end-stage disease, R5 virus variants emerge with increased viral fitness. The elevated fitness is a result of altered phenotypic properties. The underlying mechanisms can be mapped to the molecular properties of the viral Env. Thus, after AIDS onset, viruses with al-tered phenotypic properties may evolve, in an opportunistic manner, and result in the emergence of HIV-1 R5 variants with enhanced pathogenicity.},
  author       = {Repits, Johanna},
  isbn         = {978-91-86059-61-3},
  issn         = {1652-8220},
  keyword      = {envelope,R5,HIV-1,evolution},
  language     = {eng},
  pages        = {120},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Co-evolution of the HIV-1 R5 phenotype and the viral envelope glycoproteins},
  volume       = {2008:108},
  year         = {2008},
}