(O2) Frequency of co-expression of inhibitory receptors early in HIV infection determines progression rate in untreated patients.
Scharf L, Olsen LR, Tauriainen J, Buggert M[3,4], Deeks SG, Lund O, Hecht FM, Karlsson AC
1: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. 2: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. 3: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. 4: Department of Microbiology, University of Pennsylvania, Philadelphia, United States of America. 5: Department of Medicine, University of California, San Francisco, United States of America.
The rate of disease progression in HIV infection is highly variable when left untreated. One host factor associated with slower progression is the HLA class I allele HLA-B*57. Despite their inability to completely clear the virus in acute infection, CD8 T cells significantly reduce viral replication at this state, but gradually lose their efficiency during the subsequent chronic stage. This deterioration, called CD8 T cell exhaustion characterized by upregulation of inhibitory receptors, is seen to various degrees in chronic viral infections as well as cancer. In this study we aimed to investigate if differences in HIV-specific CD8 T cell functionality and exhaustion are influenced by HLA-B*57 following untreated primary HIV-infection.
Our patient cohort comprised six HLA-B*57-positive and six HLA-B*57-–negative patients followed longitudinally from primary infection while not receiving treatment for up to seven years. We performed multicolor flow-cytometry of peptide-stimulated peripheral blood mononucleated cells (PBMCs). The responding cells were identified by cytokine production prior to analysis of inhibitory receptor expression and differentiation profiles using the software tools FlowJo, SPICE and R.
HLA-B*57-restricted responses increasingly distributed towards central/transitional memory phenotype during the chronic infection. This shift was not apparent in the non-HLA-B*57-restricted responses. HLA-B*57-restricted and the non-HLA-B*57-restricted responses differed in inhibitory receptor expression during the early stages of chronic infection, but those differences were blunted in the later stages when progression towards acquired immunodeficiency syndrome (AIDS) became apparent in all patients. The early differences were dominated by cell populations expressing the inhibitory receptors programmed death-1 (PD-1), T cell immunoglobulin and ITIM domain (TIGIT) along with any additional receptor analyzed in this study (CD160, CD244 or killer cell lectin like receptor family member G1 – KLRG-1).
Our analysis revealed the importance of PD-1/TIGIT co-expression during early chronic infection in the discrimination of HLA-B*57-positive and -negative patients. The higher frequency of HIV-specific CD8 T cells expressing PD-1 and TIGIT along with any third inhibitory receptor links the severity of CD8 T cell exhaustion to the faster progression seen in patients lacking HLA-B*57.
Targeting the viral replication has led to substantial success in HIV therapy, but fails to cure patients. Thus, the search for additional treatment options has turned to alternative strategies that, driven by the success in cancer immunotherapy, have led to a new focus on T cell-based approaches. Blocking inhibitory receptors was approved for a number of cancers and first clinical studies are testing this approach to combat HIV. Our results suggest favorable outcomes for strategies that simultaneously target TIGIT and PD-1, due to the devastating effect of their co-expression on CD8 T cell exhaustion in HIV infection.