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

PLoS Pathogens

Konstantinos Chatzimichalis¹  Becca Asquith²  Nafisa-Katrin Seich al Basatena³  Frederik Graw⁴  Roland R. Regoes⁵  Simon D. W. Frost⁶ 

[1] Birkbeck University, London, United Kingdom;ETH, Zurich, Switzerland;Imperial College, London, London, United Kingdom;Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America;University of Cambridge, Cambridge, United Kingdom;University of Heidelberg, Heidelberg, Germany

关键词: T cells;    Cytotoxic T cells;    HIV-1;    Secretion;    Cell death;    Cell motility;    SIV;    Pathogen motility;   

DOI  :  10.1371/journal.ppat.1003656

学科分类：生物科学（综合）

来源: Public Library of Science

【 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.

【 授权许可】

CC BY