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Quantifying the Impact of Human Immunodeficiency Virus-1 Escape From Cytotoxic T-Lymphocytes
被引:17
作者:

Kadolsky, Ulrich D.
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Univ London Imperial Coll Sci Technol & Med, Div Med, Dept Immunol, London, England Univ London Imperial Coll Sci Technol & Med, Div Med, Dept Immunol, London, England

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机构:
[1] Univ London Imperial Coll Sci Technol & Med, Div Med, Dept Immunol, London, England
基金:
英国惠康基金;
关键词:
CELL RESPONSES;
HIV-1;
INFECTION;
CTL ESCAPE;
VIRAL LOAD;
IMMUNE ESCAPE;
HLA-B;
TYPE-1;
GAG;
PROGRESSION;
ASSOCIATION;
D O I:
10.1371/journal.pcbi.1000981
中图分类号:
Q5 [生物化学];
学科分类号:
071010 ;
081704 ;
摘要:
HIV-1 escape from the cytotoxic T-lymphocyte (CTL) response leads to a weakening of viral control and is likely to be detrimental to the patient. To date, the impact of escape on viral load and CD4(+) T cell count has not been quantified, primarily because of sparse longitudinal data and the difficulty of separating cause and effect in cross-sectional studies. We use two independent methods to quantify the impact of HIV-1 escape from CTLs in chronic infection: mathematical modelling of escape and statistical analysis of a cross-sectional cohort. Mathematical modelling revealed a modest increase in log viral load of 0.051 copies ml(-1) per escape event. Analysis of the cross-sectional cohort revealed a significant positive association between viral load and the number of "escape events", after correcting for length of infection and rate of replication. We estimate that a single CTL escape event leads to a viral load increase of 0.11 log copies ml(-1) (95% confidence interval: 0.040-0.18), consistent with the predictions from the mathematical modelling. Overall, the number of escape events could only account for approximately 6% of the viral load variation in the cohort. Our findings indicate that although the loss of the CTL response for a single epitope results in a highly statistically significant increase in viral load, the biological impact is modest. We suggest that this small increase in viral load is explained by the small growth advantage of the variant relative to the wildtype virus. Escape from CTLs had a measurable, but unexpectedly low, impact on viral load in chronic infection.
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共 76 条
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h-index: 0
机构:
Massachusetts Gen Hosp East, Partners AIDS Res Ctr, Charlestown, MA 02129 USA Massachusetts Gen Hosp East, Partners AIDS Res Ctr, Charlestown, MA 02129 USA
[10]
Human leukocyte antigen-specific polymorphisms in HIV-1 Gag and their association with viral load in chronic untreated infection
[J].
Brumme, Zabrina L.
;
Tao, Iris
;
Szeto, Sharon
;
Brumme, Chanson J.
;
Carlson, Jonathan A.
;
Chan, Dennison
;
Kadie, Carl
;
Frahm, Nicole
;
Brander, Christian
;
Walker, Bruce
;
Heckerman, David
;
Harrigan, P. Richard
.
AIDS,
2008, 22 (11)
:1277-1286

Brumme, Zabrina L.
论文数: 0 引用数: 0
h-index: 0
机构:
Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

Tao, Iris
论文数: 0 引用数: 0
h-index: 0
机构:
BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

Szeto, Sharon
论文数: 0 引用数: 0
h-index: 0
机构:
BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

Brumme, Chanson J.
论文数: 0 引用数: 0
h-index: 0
机构:
Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

Carlson, Jonathan A.
论文数: 0 引用数: 0
h-index: 0
机构:
Microsoft Res, Redmond, WA USA
Univ Washington, Dept Comp Sci, Seattle, WA 98195 USA Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

Chan, Dennison
论文数: 0 引用数: 0
h-index: 0
机构:
BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

Kadie, Carl
论文数: 0 引用数: 0
h-index: 0
机构:
Microsoft Res, Redmond, WA USA Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

Frahm, Nicole
论文数: 0 引用数: 0
h-index: 0
机构:
Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

论文数: 引用数:
h-index:
机构:

Walker, Bruce
论文数: 0 引用数: 0
h-index: 0
机构:
Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA
Howard Hughes Med Inst, Chevy Chase, MD USA Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

Heckerman, David
论文数: 0 引用数: 0
h-index: 0
机构:
Microsoft Res, Redmond, WA USA Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA

Harrigan, P. Richard
论文数: 0 引用数: 0
h-index: 0
机构:
BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada
Univ British Columbia, Div AIDS, Vancouver, BC V5Z 1M9, Canada Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA