CD127 Expression, Exhaustion Status and Antigen Specific Proliferation Predict Sustained Virologic Response to IFN in HCV/HIV Co-Infected Individuals

Abstract

Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in the HIV co-infected population. Interferon-alpha (IFN-α) remains a major component of anti-HCV therapy despite its deleterious effects on the immune system. Furthermore, IFN-α was recently shown to diminish the size of the latent HIV reservoir. The objectives of this study were to monitor the impact of IFN-α on T cell phenotype and proliferation of HIV and HCV-specific T cells during IFN therapy, and to identify immune markers that can predict the response to IFN in HICV/HIV co-infected patients. We performed longitudinal analyses of T cell numbers, phenotype and function in co-infected patients undergoing IFN-α therapy with different outcomes including IFN-α non-responders (NR) (n = 9) and patients who achieved sustained virologic response (SVR) (n = 19). We examined the expression of activation (CD38, HLA-DR), functional (CD127) and exhaustion markers (PD1, Tim-3, CD160 and CD244) on total CD4 and CD8 T cells before, during and after therapy. In addition, we examined the HIV- and HCV-specific proliferative responses against HIV-p24 and HCV-NS3 proteins. Frequencies of CD127+ CD4 T cells were higher in SVR than in NR patients at baseline. An increase in CD127 expression on CD8 T cells was observed after IFN-α therapy in all patients. In addition, CD8 T cells from NR patients expressed a higher exhaustion status at baseline. Finally, SVR patients exhibited higher proliferative response against both HIV and HCV antigens at baseline. Altogether, SVR correlated with higher expression of CD127, lower T cell exhaustion status and better HIV and HCV proliferative responses at baseline. Such factors might be used as non-invasive methods to predict the success of IFN–based therapies in co-infected individuals.

T‐cell homeostasis in chronic HCV‐infected patients treated with interferon and ribavirin or an interferon‐free regimen

“…In contrast, interferon-a does not seem to affect the proportion of T cells expressing IL-7Ra. Thus, we found no effect of PEG/ R AE 1.PI treatment on the proportion of IL-7Ra+ T cells and a decrease in the proportion of IL-7Ra+ T cells post SVR which is in agreement with previous studies (23,25). Furthermore, the reduced proportion of IL-7Ra+ T cells post SVR is consistent with our previous study demonstrating higher proportions of IL-7Ra+ CD4+ T cells in chronic HCV patients with fibrosis compared to healthy controls (16).…”

“…Stimulation of IL-7R causes elevated levels of Bcl-2 that decreases the susceptibility of cell apoptosis which is illustrated in the present data with the decreased proportion of IL-7Ra+ T cells and higher proportion of apoptotic T cells after SVR. These changes may also be affected by an alteration in immune activation (25,26). However, we investigated LPS in plasma as a measurement of microbial translocation and the expression of CD38 on CD8+ T cells as a measurement of chronic immune activation.…”

Coinhibitory Receptor Expression and Immune Checkpoint Blockade: Maintaining a Balance in CD8+ T Cell Responses to Chronic Viral Infections and Cancer

“…CD8 + T cells elicited in response to coinfections exhibit a more exhausted phenotype compared to cells from monoinfections ( 104 , 105 ). A study by Vali et al compared PD-1 and TIM-3 coexpression on HCV-specific CD8 + T cells during HIV/HCV coinfection ( 106 ).…”

On the impact of hepatitis C virus and heterologous immunity on alloimmune responses following liver transplantation

“…[23][24][25] We previously reported that in HCV-infected LT recipients undergoing protocolized T cell proliferative responses. [28][29][30] What was unexpected in our study was the finding that HCV infection had a stronger impact on antidonor CD8 + T cell responses than on those directed against Although the prevalence of clinically apparent immune-mediated events was low, it should be taken into account that many clinicians routinely increase the doses of immunosuppressive drugs in patients receiving anti-HCV medications. Furthermore, in the absence of protocolized liver biopsies it is not possible to exclude the development of subclinical rejection-type liver allograft damage, which is much more frequent than originally thought.…”