Certain human class I histocompatibility‐linked leukocyte antigen (HLA)/killer cell immunoglobulin‐like receptor (KIR) genotypic combinations confer more favourable prognoses upon exposure to human immunodeficiency virus (HIV). These combinations influence natural killer (NK) cell function, thereby implicating NK cells in protection from HIV infection or disease progression. Because CD8 + T cells restrict HIV replication, depend upon HLA class I antigen presentation and can also express KIR molecules, we investigated how these HLA/KIR combinations relate to the phenotype and function of CD8 + T cells from uninfected controls and individuals with chronic HIV infection. CD8 + T cells from KIR3DL1 and KIR3DS1 homozygous individuals, and expressing the corresponding KIR, were enumerated and phenotyped for CD127, CD57 and CD45RA expression. Ex vivo and in vitro responsiveness to antigen‐specific and polyclonal stimulation was compared between KIR‐expressing and non‐expressing CD8 + T cells by interferon‐γ production. There were higher numbers and fractions of KIR3DL1‐expressing CD8 + T cells in HIV‐infected individuals independent of HLA‐Bw4 co‐expression, whereas expansion of KIR3DS1‐expressing CD8 + T cells reflected HLA‐Bw4*80I co‐expression. KIR3DL1 + and S1 + CD8 + T cells were predominantly CD127 − CD57 + CD45RA + . KIR3DL1‐expressing CD8 + T cells were insensitive to ex vivo stimulation with peptides from HIV or common viruses, but responded to anti‐CD3 and recovered responsiveness to common viruses in vitro . Ex vivo non‐responsiveness of KIR3DL1‐expressing CD8 + T cells was also independent of HLA‐Bw4. KIR3DS1‐expressing T cells responded normally to ex vivo antigenic stimulation, illustrating functional superiority over KIR3DL1 + CD8 + T cells.

OBJECTIVE:Low CD4/CD8 T-cell ratios occur in conditions associated with reduced immune resilience, including older age and HIV infection. Effective antiretroviral therapy increases CD4/CD8 T-cell ratios, but often not to preinfection levels. The reasons for this deficit remain unclear. As cytomegalovirus (CMV) infection exacerbates falling CD4/CD8 T-cell ratios and immune senescence in the old elderly population, we investigated whether CMV infection is associated with refractory inversion of CD4/CD8 T-cell ratios and increased phenotypic evidence of immune senescence in HIV infection.DESIGN:An observational cohort study of HIV-infected individuals attending the Newfoundland and Labrador Provincial HIV Clinic in St. John's.METHODS:CMV infection status was determined by ELISA with infected cell lysate. Expression of CD28 and CD57 on CD8 T cells and cellular immune responses against CMV were measured by flow cytometry. We compared CD4/CD8 T-cell ratios, percentage of CD8 T cells expressing CD28 and percentage of CD8 T cells expressing CD57 between groups of HIV-infected persons discordant for CMV infection.RESULTS:The CMV-seronegative group had significantly higher CD4/CD8 T-cell ratios, more frequent normalization of the ratio to at least 1, and lesser phenotypic evidence of immune senescence.CONCLUSION:CMV infection is associated with reduced immune reconstitution in HIV infection, even with suppression of HIV replication below detectable levels. This suggests that CMV infection, or some related factor, influences immune resilience in the setting of HIV infection.

Hepatitis C virus (HCV) successfully evades the immune system and establishes chronic infection in ∼80% of cases. Immune evasion may involve modulating NK cell functions. Therefore, we developed a short-term assay to assess immediate effects of HCV-infected cells on ex vivo NK cytotoxicity and cytokine production. Natural cytotoxicity, Ab-dependent cell-mediated cytotoxicity, IFN-γ production, and TNF-α production were all significantly inhibited by short-term direct exposure to HCV-infected hepatoma-derived Huh-7.5 cells. Inhibition required cell-to-cell contact and increased together with multiplicity of infection and HCV protein levels. Blocking potential interaction between HCV E2 and NK CD81 did not abrogate NK cell inhibition mediated by HCV-infected cells. We observed no change in expression levels of NKG2D, NKG2A, NKp46, or CD16 on NK cells exposed to HCV-infected Huh-7.5 cells for 5 h or of human histocompatibility-linked leukocyte Ag E on HCV-infected compared with uninfected Huh-7.5 cells. Inhibition of ex vivo NK functions did correspond with reduced surface expression of the natural cytotoxicity receptor NKp30, and downregulation of NKp30 was functionally reflected in reduced anti-NKp30 redirected lysis of P815 cells. Infection of Huh-7.5 cells with HCV JFH1(T) increased surface binding of an NKp30-IgG1 Fcγ fusion protein, suggesting upregulation of an antagonistic NKp30 ligand on HCV-infected cells. Our assay demonstrates rapid inhibition of critical NK cell functions by HCV-infected cells. Similar localized effects in vivo may contribute to establishment of chronic HCV infection and associated phenotypic and functional changes in the NK population.