Background:  CD81 is a trans-membrane protein and was shown to bind hepatitis C virus envelope 2 protein. CD81 cross-linking enhances anti-CD3 activation of T cells in regard to IFN-g production and is required for maintainance of a T–helper response necessary to preserve strong CTL function. Cross-linking of CD81 blocks NK cell activation, cytokine production, cytotoxic granule release, and proliferation.

Methods:  Aim of the study was to analyze CD81 cell surface and mRNA expression on CD4⁺ and CD8⁺ lymphocytes in healthy controls, HIV-1, HCV, and dually infected subjects. CD81 expression on NK cells was also evaluated in 51 HIV-1⁺ patients and 15 HC. CD81 cell surface expression was measured by means of flow cytometry; we measured the mean fluorescence (MFI) channel of CD81 positive peak on gated CD4⁺, CD8⁺, and CD16⁺ cells. mRNA quantitation was performed with relative quantitative PCR using TaqMan on CD4 and CD8 T cells sorted with magnetic beads. Statistical analysis was performed with Student’s t-Test.

Results:  MFI for CD81 on CD4 lymphocytes was significantly lower in HIV⁺HCV^- patients (median value 29,152) and in HIV⁺HCV⁺ patients (median value 27,151) compared both with HIV^-HCV⁺ patients (median value 37,683) and with HIV^-HCV^- healthy controls (median value 39,568, 5) (p <0.05), therefore stratifying  the studied population according to HIV infection MFI for CD81 was significantly lower on CD4 cells from HIV⁺ patients than in HIV^- patients (p = 0.007). No difference in MFI for CD81 was observed on CD8 T cells among the four groups. NK cells from HIV-1 infected individuals displayed an increased expression of surface CD81 compared to HC even though the difference did not reach statistical significance. CD81 mRNA in CD4⁺ cells was significantly higher in HIV⁺ patients compared to HIV^- subjects (p = 0.002).

Conclusions:  Our results show that HIV-1 infection down-regulates CD81 on CD4⁺ T cells and  upregulates CD81 on NK cells. As CD81 cross-linking mediates completely different signals in NK cells vs T cells, modulation of CD81 by HIV-1 can alter both innate immunity through inhibition of IFN-g production by NK cells.and acquired immunity because of a reduction of IFN-g production and weakness of CTL specific response and therefore favor HIV-1 disease progression and cause susceptibility to different infectious agents and to Epstein-Barr virus-induced oncogenesis. Up-regulation of CD81 mRNA on CD4⁺ cells indicates that down-regulation of CD81 protein occurs at the posttranscriptional/translational level.

Keywords: CD81; NK; T lymphocytes