Can Non-lytic CD8+T Cells Drive HIV-1 Escape?

被引:21
作者
al Basatena, Nafisa-Katrin Seich [1 ]
Chatzimichalis, Konstantinos [2 ]
Graw, Frederik [3 ,4 ]
Frost, Simon D. W. [5 ]
Regoes, Roland R. [6 ]
Asquith, Becca [1 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, London, England
[2] Birkbeck Univ, London, England
[3] Los Alamos Natl Lab, Los Alamos, NM USA
[4] Heidelberg Univ, Heidelberg, Germany
[5] Univ Cambridge, Cambridge, England
[6] ETH, Zurich, Switzerland
基金
英国惠康基金; 奥地利科学基金会;
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; LONG TERMINAL REPEAT; DYNAMICS IN-VIVO; ANTIGEN PRESENTATION; VIRAL ESCAPE; TYPE-1; REPLICATION; GENETIC-VARIATION; MULTIPLE TARGETS; INTERFERON-GAMMA;
D O I
10.1371/journal.ppat.1003656
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The CD8+ T cell effector mechanisms that mediate control of HIV-1 and SIV infections remain poorly understood. Recent work suggests that the mechanism may be primarily non-lytic. This is in apparent conflict with the observation that SIV and HIV-1 variants that escape CD8+ T cell surveillance are frequently selected. Whilst it is clear that a variant that has escaped a lytic response can have a fitness advantage compared to the wild-type, it is less obvious that this holds in the face of non-lytic control where both wild-type and variant infected cells would be affected by soluble factors. In particular, the high motility of T cells in lymphoid tissue would be expected to rapidly destroy local effects making selection of escape variants by non-lytic responses unlikely. The observation of frequent HIV-1 and SIV escape poses a number of questions. Most importantly, is the consistent observation of viral escape proof that HIV-1- and SIV-specific CD8+ T cells lyse infected cells or can this also be the result of non-lytic control? Additionally, the rate at which a variant strain escapes a lytic CD8+ T cell response is related to the strength of the response. Is the same relationship true for a non-lytic response? Finally, the potential anti-viral control mediated by non-lytic mechanisms compared to lytic mechanisms is unknown. These questions cannot be addressed with current experimental techniques nor with the standard mathematical models. Instead we have developed a 3D cellular automaton model of HIV-1 which captures spatial and temporal dynamics. The model reproduces in vivo HIV-1 dynamics at the cellular and population level. Using this model we demonstrate that non-lytic effector mechanisms can select for escape variants but that outgrowth of the variant is slower and less frequent than from a lytic response so that non-lytic responses can potentially offer more durable control.
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页数:12
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