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

Mattias Mild

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

Mattias Mild

Avdelningen för medicinsk mikrobiologi

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Sammanfattning

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.

Originalspråk	engelska
Kvalifikation	Doktor
Tilldelande institution	Institutionen för laboratoriemedicin
Handledare	Medstrand, Patrik, handledare
Tilldelningsdatum	2007 juni 14
Förlag	Lund University, Faculty of Medicine Doctoral Dissertation Series
ISBN (tryckt)	978-91-85559-86-2
Status	Published - 2007

Bibliografisk information

Defence details

Date: 2007-06-14
Time: 09:00
Place: Seminar room, BMC D15 Sölvegatan 19

External reviewer(s)

Name: Salminen, Mika
Title: Associate Professor
Affiliation: Department of Infectious Disease Epidemiology, HIV-Laboratory, National Public Health Institute Hels

---

<div class="article_info">Mattias Mild, Åsa Björndal, Patrik Medstrand and Eva Maria Fenyö. <span class="article_issue_date">2006</span>. <span class="article_title">Isolation of human immunodeficiency virus-type 1 (HIV-1) clones with biological and molecular properties of the primary isolate.</span> <span class="journal_series_title">Virology</span>, <span class="journal_volume">vol 350</span> <span class="journal_pages">pp 58-66</span>.</div>
<div class="article_info">Mattias Mild, Joakim Esbjörnsson, Eva Maria Fenyö and Patrik Medstrand. <span class="article_issue_date">2007</span>. <span class="article_title">Frequent intrapatient recombination between HIV-1 R5 and X4 envelopes: Implications for coreceptor switch.</span> <span class="journal_series_title">Journal of Virology</span>, <span class="journal_volume">vol 81</span> <span class="journal_pages">pp 3369-76</span>.</div>
<div class="article_info">Mattias Mild, Anders Kvist, Joakim Esbjörnsson, Ingrid Karlsson, Eva Maria Fenyö and Patrik Medstrand. <span class="article_issue_date"></span>. <span class="article_title">Differences in molecular evolution between switch and non-switch HIV-1 populations.</span> (submitted)</div>
<div class="article_info">Mattias Mild, Anders Kvist, Eva Maria Fenyö and Patrik Medstrand. <span class="article_issue_date"></span>. <span class="article_title">Divergence rates and selective pressure in switch and non-switch HIV-1 populations: the influence of R5 and X4 subpopulations.</span> (submitted)</div>

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@phdthesis{e9a15a3deccc4c0389ec90a0e542b8e8,

title = "Intrapatient evolution of HIV-1 in the context of coreceptor usage",

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 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.",

keywords = "coreceptor switch, Medicine (human and vertebrates), Medicin (m{\"a}nniska och djur), biological cloning, R5-X4, coreceptor usage, glycosylation, recombination, HIV, evolution",

author = "Mattias Mild",

note = "Defence details Date: 2007-06-14 Time: 09:00 Place: Seminar room, BMC D15 S{\"o}lvegatan 19 External reviewer(s) Name: Salminen, Mika Title: Associate Professor Affiliation: Department of Infectious Disease Epidemiology, HIV-Laboratory, National Public Health Institute Hels --- <div class={"}article_info{"}>Mattias Mild, {\AA}sa Bj{\"o}rndal, Patrik Medstrand and Eva Maria Feny{\"o}. <span class={"}article_issue_date{"}>2006</span>. <span class={"}article_title{"}>Isolation of human immunodeficiency virus-type 1 (HIV-1) clones with biological and molecular properties of the primary isolate.</span> <span class={"}journal_series_title{"}>Virology</span>, <span class={"}journal_volume{"}>vol 350</span> <span class={"}journal_pages{"}>pp 58-66</span>.</div> <div class={"}article_info{"}>Mattias Mild, Joakim Esbj{\"o}rnsson, Eva Maria Feny{\"o} and Patrik Medstrand. <span class={"}article_issue_date{"}>2007</span>. <span class={"}article_title{"}>Frequent intrapatient recombination between HIV-1 R5 and X4 envelopes: Implications for coreceptor switch.</span> <span class={"}journal_series_title{"}>Journal of Virology</span>, <span class={"}journal_volume{"}>vol 81</span> <span class={"}journal_pages{"}>pp 3369-76</span>.</div> <div class={"}article_info{"}>Mattias Mild, Anders Kvist, Joakim Esbj{\"o}rnsson, Ingrid Karlsson, Eva Maria Feny{\"o} and Patrik Medstrand. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>Differences in molecular evolution between switch and non-switch HIV-1 populations.</span> (submitted)</div> <div class={"}article_info{"}>Mattias Mild, Anders Kvist, Eva Maria Feny{\"o} and Patrik Medstrand. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>Divergence rates and selective pressure in switch and non-switch HIV-1 populations: the influence of R5 and X4 subpopulations.</span> (submitted)</div>",

year = "2007",

language = "English",

isbn = "978-91-85559-86-2",

series = "Faculty of Medicine Doctoral Dissertation Series",

publisher = "Lund University, Faculty of Medicine Doctoral Dissertation Series",

type = "Doctoral Thesis (compilation)",

school = "Department of Laboratory Medicine",

}

TY - THES

T1 - Intrapatient evolution of HIV-1 in the context of coreceptor usage

AU - Mild, Mattias

N1 - Defence details Date: 2007-06-14 Time: 09:00 Place: Seminar room, BMC D15 Sölvegatan 19 External reviewer(s) Name: Salminen, Mika Title: Associate Professor Affiliation: Department of Infectious Disease Epidemiology, HIV-Laboratory, National Public Health Institute Hels --- <div class="article_info">Mattias Mild, Åsa Björndal, Patrik Medstrand and Eva Maria Fenyö. <span class="article_issue_date">2006</span>. <span class="article_title">Isolation of human immunodeficiency virus-type 1 (HIV-1) clones with biological and molecular properties of the primary isolate.</span> <span class="journal_series_title">Virology</span>, <span class="journal_volume">vol 350</span> <span class="journal_pages">pp 58-66</span>.</div> <div class="article_info">Mattias Mild, Joakim Esbjörnsson, Eva Maria Fenyö and Patrik Medstrand. <span class="article_issue_date">2007</span>. <span class="article_title">Frequent intrapatient recombination between HIV-1 R5 and X4 envelopes: Implications for coreceptor switch.</span> <span class="journal_series_title">Journal of Virology</span>, <span class="journal_volume">vol 81</span> <span class="journal_pages">pp 3369-76</span>.</div> <div class="article_info">Mattias Mild, Anders Kvist, Joakim Esbjörnsson, Ingrid Karlsson, Eva Maria Fenyö and Patrik Medstrand. <span class="article_issue_date"></span>. <span class="article_title">Differences in molecular evolution between switch and non-switch HIV-1 populations.</span> (submitted)</div> <div class="article_info">Mattias Mild, Anders Kvist, Eva Maria Fenyö and Patrik Medstrand. <span class="article_issue_date"></span>. <span class="article_title">Divergence rates and selective pressure in switch and non-switch HIV-1 populations: the influence of R5 and X4 subpopulations.</span> (submitted)</div>

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

KW - coreceptor switch

KW - Medicine (human and vertebrates)

KW - Medicin (människa och djur)

KW - biological cloning

KW - R5-X4

KW - coreceptor usage

KW - glycosylation

KW - recombination

KW - HIV

KW - evolution

M3 - Doctoral Thesis (compilation)

SN - 978-91-85559-86-2

T3 - Faculty of Medicine Doctoral Dissertation Series

PB - Lund University, Faculty of Medicine Doctoral Dissertation Series

ER -

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

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Ämnesklassifikation (UKÄ)

FN:s Globala mål

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