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Intrapatient evolution of HIV-1 in the context of coreceptor usage

Mild, Mattias LU (2007) In Faculty of Medicine Doctoral Dissertation Series
Abstract
The variable region 1 to 3 (V1-V3) of the HIV-1 envelope plays an important role in coreceptor usage. Early in infection HIV- 1 is using CCR5 as coreceptor to enter target cells (R5 viruses) whereas viruses using CXCR4 as coreceptor (X4 viruses) may appear later in infection. This broadening or switch in coreceptor usage is associated with progression to AIDS. In my thesis work, we have compared the molecular evolution of V1-V3 between virus populations that maintained CCR5 coreceptor usage (non-switch populations, nSP) with virus populations that used CXCR4 as coreceptor (switch populations, SP). We also developed a novel biological cloning system.



We found an increase in the number of potential N-linked glycosylation... (More)
The variable region 1 to 3 (V1-V3) of the HIV-1 envelope plays an important role in coreceptor usage. Early in infection HIV- 1 is using CCR5 as coreceptor to enter target cells (R5 viruses) whereas viruses using CXCR4 as coreceptor (X4 viruses) may appear later in infection. This broadening or switch in coreceptor usage is associated with progression to AIDS. In my thesis work, we have compared the molecular evolution of V1-V3 between virus populations that maintained CCR5 coreceptor usage (non-switch populations, nSP) with virus populations that used CXCR4 as coreceptor (switch populations, SP). We also developed a novel biological cloning system.



We found an increase in the number of potential N-linked glycosylation sites in V1 -V3 over time in nSP, while SP showed no change. Since glycans are an important defense against neutralizing antibodies, we hypothesize that the antibody response differed between patients with SP and nSP. We found that V2 length and evolution of V3 charge differed between R5 viruses from SP and nSP, already before coreceptor switch in SP. Therefore, these molecular properties could prove important for understanding, and maybe even for predicting, the evolution of coreceptor usage in HIV-populations. Due to the presence of the X4 subpopulations, SP evolved faster compared to nSP. In addition, R5 and X4 from SP were subjected to different selective pressures. We showed that R5 and X4 viruses recombine frequently. We hypothesize that such rearrangements may affect antibody recognition of X4 and allow for antibody escape and expansion of X4 subpopulations. (Less)
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author
supervisor
opponent
  • Associate Professor Salminen, Mika, Department of Infectious Disease Epidemiology, HIV-Laboratory, National Public Health Institute Hels
organization
publishing date
type
Thesis
publication status
published
subject
keywords
coreceptor switch, Medicine (human and vertebrates), Medicin (människa och djur), biological cloning, R5-X4, coreceptor usage, glycosylation, recombination, HIV, evolution
in
Faculty of Medicine Doctoral Dissertation Series
pages
124 pages
publisher
Lund University, Faculty of Medicine Doctoral Dissertation Series
defense location
Seminar room, BMC D15 Sölvegatan 19
defense date
2007-06-14 09:00:00
ISSN
1652-8220
ISBN
978-91-85559-86-2
language
English
LU publication?
yes
additional info
Mattias Mild, Åsa Björndal, Patrik Medstrand and Eva Maria Fenyö. 2006. Isolation of human immunodeficiency virus-type 1 (HIV-1) clones with biological and molecular properties of the primary isolate. Virology, vol 350 pp 58-66.
Mattias Mild, Joakim Esbjörnsson, Eva Maria Fenyö and Patrik Medstrand. 2007. Frequent intrapatient recombination between HIV-1 R5 and X4 envelopes: Implications for coreceptor switch. Journal of Virology, vol 81 pp 3369-76.
Mattias Mild, Anders Kvist, Joakim Esbjörnsson, Ingrid Karlsson, Eva Maria Fenyö and Patrik Medstrand. . Differences in molecular evolution between switch and non-switch HIV-1 populations. (submitted)
Mattias Mild, Anders Kvist, Eva Maria Fenyö and Patrik Medstrand. . Divergence rates and selective pressure in switch and non-switch HIV-1 populations: the influence of R5 and X4 subpopulations. (submitted)
id
e9a15a3d-eccc-4c03-89ec-90a0e542b8e8 (old id 548744)
date added to LUP
2016-04-01 16:57:23
date last changed
2019-05-21 14:21:08
@phdthesis{e9a15a3d-eccc-4c03-89ec-90a0e542b8e8,
  abstract     = {{The variable region 1 to 3 (V1-V3) of the HIV-1 envelope plays an important role in coreceptor usage. Early in infection HIV- 1 is using CCR5 as coreceptor to enter target cells (R5 viruses) whereas viruses using CXCR4 as coreceptor (X4 viruses) may appear later in infection. This broadening or switch in coreceptor usage is associated with progression to AIDS. In my thesis work, we have compared the molecular evolution of V1-V3 between virus populations that maintained CCR5 coreceptor usage (non-switch populations, nSP) with virus populations that used CXCR4 as coreceptor (switch populations, SP). We also developed a novel biological cloning system.<br/><br>
<br/><br>
We found an increase in the number of potential N-linked glycosylation sites in V1 -V3 over time in nSP, while SP showed no change. Since glycans are an important defense against neutralizing antibodies, we hypothesize that the antibody response differed between patients with SP and nSP. We found that V2 length and evolution of V3 charge differed between R5 viruses from SP and nSP, already before coreceptor switch in SP. Therefore, these molecular properties could prove important for understanding, and maybe even for predicting, the evolution of coreceptor usage in HIV-populations. Due to the presence of the X4 subpopulations, SP evolved faster compared to nSP. In addition, R5 and X4 from SP were subjected to different selective pressures. We showed that R5 and X4 viruses recombine frequently. We hypothesize that such rearrangements may affect antibody recognition of X4 and allow for antibody escape and expansion of X4 subpopulations.}},
  author       = {{Mild, Mattias}},
  isbn         = {{978-91-85559-86-2}},
  issn         = {{1652-8220}},
  keywords     = {{coreceptor switch; Medicine (human and vertebrates); Medicin (människa och djur); biological cloning; R5-X4; coreceptor usage; glycosylation; recombination; HIV; evolution}},
  language     = {{eng}},
  publisher    = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  school       = {{Lund University}},
  series       = {{Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Intrapatient evolution of HIV-1 in the context of coreceptor usage}},
  url          = {{https://lup.lub.lu.se/search/files/4828906/548746.pdf}},
  year         = {{2007}},
}