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.