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Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection.

ABSTRACT: Hepatitis C virus (HCV) infection develops into chronic hepatitis in over two-thirds of acute infections. While current treatments with direct-acting antivirals (DAAs) achieve HCV eradication in >95% of cases, no vaccine is available and re-infection can readily occur. Natural killer (NK) cells represent a key cellular component of the innate immune system, participating in early defence against infectious diseases, viruses, and cancers. When acute infection becomes chronic, however, NK cell function is altered. This has been well studied in the context of HCV, where changes in frequency and distribution of NK cell populations have been reported. While activating receptors are downregulated on NK cells in both acute and chronic infection, NK cell inhibiting receptors are upregulated in chronic HCV infection, leading to altered NK cell responsiveness. Furthermore, chronic activation of NK cells following HCV infection contributes to liver inflammation and disease progression through enhanced cytotoxicity. Consequently, the NK immune response is a double-edged sword that is a significant component of the innate immune antiviral response, but persistent activation can drive tissue damage during chronic infection. This review will summarise the role of NK cells in HCV infection, and the changes that occur during HCV therapy.

SUBMITTER: Njiomegnie GF

PROVIDER: S-EPMC7230811 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection.

Njiomegnie Gaitan Fabrice GF Read Scott A SA Fewings Nicole N George Jacob J McKay Fiona F Ahlenstiel Golo G

Journal of clinical medicine 20200406 4

Hepatitis C virus (HCV) infection develops into chronic hepatitis in over two-thirds of acute infections. While current treatments with direct-acting antivirals (DAAs) achieve HCV eradication in >95% of cases, no vaccine is available and re-infection can readily occur. Natural killer (NK) cells represent a key cellular component of the innate immune system, participating in early defence against infectious diseases, viruses, and cancers. When acute infection becomes chronic, however, NK cell fun ...[more]

PMID: 32268490

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Project description:Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection.Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, ?(4)?(7)). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p?=?0.03 and p<0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r?=?0.68;p<0.0001; post-infection, during primary infection r?=?0.074;p?=?0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r?=?0.32'p?=?0.04 and r?=?0.35;p?=?0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIR(pos)) NK cells increased following HIV acquisition (p?=?0.006), and KIR(pos) NK cells were less activated than KIR(neg) NK cells amongst individuals sampled while seronegative or serodiscordant (p?=?0.001;p<0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p?=?0.006 and p?=?0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p<0.0001).Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.

Dataset Information

Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection.

Publications

Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection.

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