Characterization Of Nk Cell Adcc Function Changes In Hiv-1 Infected Populations

Acquired immunodeficiency syndrome (AIDS), resulting from HIV-1 infection, is one of the serious infectious diseases against the human health and the social stability in the world.Natural killer cells (NK cells) are critical effector cells with natural cytotoxity of the innate immune response to malignancy and infection. And they have a wide array of direct antiviral activities and have been critically implicated in the regulation and induction of an effective adaptive immune response. NK cell cytolysis can be induced directly through diverse receptor families or can be induced indirectly through Fc receptors by antibodies mediating antibody-dependent cellular cytotoxicity (ADCC). Although the pivotal role of this cell subset in the context of a number of viral infections is well established, the role of NK cells in HIV-1 infection is less well understood.To intensive understand the potential NK function especially the ADCC function in different HIV-1 infection stages, 75 HIV-1 infected individuals were recruited from China and the United States of American in this study including 33 Chinese and 42 American people. With flow cytometry and quantitative reverse transcription-PCR, we also investigated the potential underlying mechanism for the impaired NK cell functions in the HIV-1 infection.The main results are as follows:1. Chronically HIV-1 infected individuals expressed an elevated frequency of anergic CD56negative NK cells and a lower frequency of the cytolytic CD56dim NK cells.2. NK cell activation (CD69 expression) was significantly associated with CD4 count in chronically HIV-1 infected individuals.3. Both HLA-B (NKB1) and HLA-C (CD158a/b) binding KIR+ NK cells responded more potently to ADCC inducing target cells.4. NK functions, especially the ADCC function, dramatically decresed in progressive HIV-1 infection.5. The CD16 expression was significantly verified at different stages of HIV-1 infection.6. MMPs expression was elevated in chronic HIV-1 infection.7. Inhibition of elevated MMPs activity with MMPs inhibitor resulted in a specific reconstitution of NK functions, especially of NK cell-mediated ADCC function. In conclusion, we demonstrate a similar loss of NK cell function especially a loss of ADCC function with progressive HIV-1 infected individuals from China and the United States of American. We also find that defects in the capacity of NK cells to respond to Ab-coated target cells in HIV-1 infection are attributable to elevated MMPs expression and activity. The therapeutic use of MMP inhibitor may specifically target and improve the quality of NK cell-mediated ADCC and may offer a new approach to improve control over viral replication. Increasing this effector function may provide subjects with an opportunity to harness the cytolytic power of NK cells through naturally occurring nonneutralizing HIV-specific Abs generated during infection.