Innate and adaptive cellular immunity in chronic HCV and HIV-1 infection

Viral infections are initially countered by an innate immune response as a first line of defence followed by an adaptive immune response. However, certain viruses successfully evade cellular immune responses and establish chronic infection. Hepatitis C virus (HCV) and Human Immunodeficiency Virus 1 (HIV-1) are chronic viral infections on the rise globally. HCV/HIV-1 co-infection presents a formidable challenge to the human immune system. This thesis focuses on certain aspects of innate and adaptive immunity in chronic HCV/HIV-1 infection, and on the implications of aberrant immune responses for peg-IFNalpha and ribavirin treatment outcome.

NK cells and NKT cells most likely play important roles in protection from HCV and HIV-1 infection, and in the control of chronic infection. Here, HCV/HIV-1 coinfection was associated with a severely reduced NKT cell population that was not restored by HCV treatment. In contrast, conventional NK cells were largely unaffected with only a slight decrease in perforin content in CD56dim cells and an increased CD56bright immunoregulatory NK cell population. Interestingly, sharply elevated numbers of unconventional CD56-CD16+ NK cells, believed to be functionally impaired, accumulated in HCV/HIV-1 co-infected subjects, despite successful ART. A similar trend was seen in HCV mono-infected individuals suggesting a HCV-driven disturbance. CD56- NK cell numbers declined in parallel with HCV load in response to treatment with peg-IFNalpha and ribavirin. Furthermore, pre-treatment levels of CD56- NK cells correlated with treatment outcome. Patients with low levels of CD56- NK cells were more likely to clear HCV infection, and this was not directly linked to other viral and host factors known to influence treatment outcome.

Evaluation of adaptive immunity in HCV/HIV-1 co-infected subjects revealed a high level of activation, as measured by CD38 expression, in both CD4 and CD8 T cells. However, elevated T cell activation was not linked to altered differentiation and distribution of naïve, TCM, TEM and terminally differentiated cells. Reminiscent of CD56-NK cells, CD38+ T cells declined in response to peg-IFNalpha and ribavirin treatment. Furthermore, patients reaching a SVR had significantly lower CD8 T cell activation and higher HCV-specific T cell responses prior to treatment, as compared to patients who did not clear infection. Together, the data indicate that chronic HCV infection drives disturbances in both innate and adaptive cellular immunity in HCV/HIV-1 co-infection, which contributes to impaired control and clearance of HCV in this patient group.

Finally, we observed that chronic HCV mono-infection drives expansion of terminally differentiated CD8 T cells that express the Fc-receptor CD16. This population had NK cell-like properties and mediated ADCC towards target cells. This suggests that CD8 T cells in chronic HCV infection continue to differentiate beyond previously described stages of terminal effector cells to acquire NK-like functions. Taken together, the present thesis advances our knowledge of the immune system s relationship with HCV and HIV-1 infection, and identifies immunological biomarkers that correlate with HCV treatment outcome in HCV/HIV-1 co-infected patients.

List of scientific papers

I. Gonzalez VD, Björkström NK, Malmberg KJ, Moll M, Kuylenstierna C, Michaëlsson J, Ljunggren HG, Sandberg JK (2008). "Application of nine-color flow cytometry for detailed studies of the phenotypic complexity and functional heterogeneity of human lymphocyte subsets." J Immunol Methods 330(1-2): 64-74. Epub 2007 Dec 4
https://pubmed.ncbi.nlm.nih.gov/18083186

II. Gonzalez VD, Falconer K, Michaëlsson J, Moll M, Reichard O, Alaeus A, Sandberg JK (2008). "Expansion of CD56- NK cells in chronic HCV/HIV-1 co-infection: reversion by antiviral treatment with pegylated IFNalpha and ribavirin." Clin Immunol 128(1): 46-56. Epub 2008 May 20
https://pubmed.ncbi.nlm.nih.gov/18495540

III. Gonzalez VD, Falconer K, Björkström NK, Weiland O, Ljunggren HG, Alaeus A, Sandberg JK (2009). "CD56 negative NK cells predicts pegylated interferon-a and ribavirin treatment outcome in chronic hepatitis C virus infection." (Submitted)

IV. Gonzalez VD, Falconer K, Blom KG, Reichard O, Weis N, Alaeus, Sandberg JK (2009). "High levels of chronic immune activation in both CD8 and CD4 T cell compartments negatively influences HCV treatment outcome in HCV/HIV-1 co-infection." (Submitted)

V. Björkström NK, Gonzalez VD, Malmberg KJ, Falconer K, Alaeus A, Nowak G, Jorns C, Ericzon BG, Weiland O, Sandberg JK, Ljunggren HG (2008). "Elevated numbers of Fc gamma RIIIA+ (CD16+) effector CD8 T cells with NK cell-like function in chronic hepatitis C virus infection." J Immunol 181(6): 4219-28
https://pubmed.ncbi.nlm.nih.gov/18768879