Can non-lytic CD8+ T cells drive HIV-1 escape?
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.
Imperial College, London, London, United Kingdom.
Nafisa-Katrin
NK
Seich Al Basatena
Konstantinos
K
Chatzimichalis
Frederik
F
Graw
Simon D W
SD
Frost
Roland R
RR
Regoes
Becca
B
Asquith
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D018448:Models, Immunological