Abstract
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.
Highlights
There is good evidence that CD8+ T cells control replication of human (HIV-1) and simian (SIV) immunodeficiency virus [1]
We wanted to understand whether viral escape is proof that HIV-1- and SIV-specific CD8+ T cells kill infected cells, determine the factors that facilitate viral escape, and investigate the comparative efficiency of lytic and non-lytic responses in controlling viral infections
A similar approach has been successfully used to investigate T and B cell dynamics [51,52,53,54]. Using this approach we investigate whether non-lytic CD8+ T cell responses can select for HIV-1 escape variants; we identify factors involved in variant outgrowth and quantify the relationship between viral control and the outgrowth rate
Summary
There is good evidence that CD8+ T cells control replication of human (HIV-1) and simian (SIV) immunodeficiency virus [1]. Some studies [10,11,12,13,14,15], but not all [16,17], have reported that the CD8+ T cell-secreted cytokine IFN-c has a suppressive effect on HIV-1 (by upregulating MHC class I expression and inducing the expression of intrinsic defence factors including TRIM1a, APOBEC and tetherin) Chemokines such as RANTES, MIP-1a and MIP-1b which bind CCR5 and act as competitive inhibitors of CCR5mediated HIV/SIV entry [18] are thought to play a role, polymorphisms in the RANTES promoter which increase mRNA transcription are associated with slower disease progression [19,20]. CD8+ cell antiviral factor (CAF) is reported to inhibit HIV-1 replication by blocking transcription [23,24,25]
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