Abstract
HIV evades CD8 T cell mediated pressure by viral escape mutations in targeted CD8 T cell epitopes. A viral escape mutation can lead to a decline of the respective CD8 T cell response. Our question was what happened after the decline of a CD8 T cell response and - in the case of viral escape – if a new CD8 T cell response towards the mutated antigen could be generated in a population not selected for certain HLA alleles. We studied 19 antiretroviral-naïve HIV-1 infected individuals with different disease courses longitudinally. A median number of 12 (range 2-24) CD8 T cell responses towards Gag and Nef were detected per study subject. A total of 30 declining CD8 T cell responses were studied in detail and viral sequence analyses showed amino acid changes in 25 (83%) of these. Peptide titration assays and definition of optimal CD8 T cell epitopes revealed 12 viral escape mutations with one de-novo response (8%). The de-novo response, however, showed less effector functions than the original CD8 T cell response. In addition we identified 4 shifts in immunodominance. For one further shift in immunodominance, the mutations occurred outside the optimal epitope and might represent processing changes. Interestingly, four adaptations to the virus (the de-novo response and 3 shifts in immunodominance) occurred in the group of chronically infected progressors. None of the subjects with adaptation to the changing virus carried the HLA alleles B57, B*58:01 or B27. Our results show that CD8 T cell responses adapt to the mutations of HIV. However it was limited to only 20% (5 out of 25) of the epitopes with viral sequence changes in a cohort not expressing protective HLA alleles.
Highlights
Developing a human immunodeficiency virus (HIV) vaccine is critical to end the pandemic with currently 33 million HIV infected people worldwide
Our results show that CD8 T cell responses can adapt to ongoing evolution of HIV in a cohort not expressing protective HLA alleles
We aimed to identify those CD8 T cell responses that were subject to viral escape mutations
Summary
Developing a human immunodeficiency virus (HIV) vaccine is critical to end the pandemic with currently 33 million HIV infected people worldwide. Therapeutic vaccines aim at inducing very specific immune responses e.g. towards certain CD8 T cell epitopes [1,2]. Vaccinating HIV-1 infected individuals could cause immune interferences that need to be considered beforehand. Their immune system has already been confronted with a certain viral sequence and mounted CD8 T cell responses towards the infecting virus. Re-infection with a second, new influenza strain boosted antibodies specific for the first infecting strain but not the second [3,4] This concept was extended to CD8 T cell responses in 1998 [5] and to other viral infections like HCV [6,7]. A recent publication failed to support OAS in a Listeria monocytogenes mouse model and the H-2Kbrestricted CD8 SIINFEKL epitope and its variants [8]
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