Significant NK cell activation associated with decreased cytolytic function in peripheral blood of HIV‐1‐infected patients

Abstract

One of the hallmarks of HIV-1 infection is represented by the finding of massive T cell activation in peripheral blood lymphocytes of infected patients. An impairment of NK cell function during HIV-1 infection is also detected, and is associated with decreased expression of natural cytotoxicity receptors (NCR). In this study we tried to determine whether also NK cells are affected by relevant activation and whether this could be associated with decreased NK cell function. In 18 viremic HIV-1-infected patients, freshly drawn purified peripheral NK cells displayed significant levels of activation with an incomplete pattern (HLA-DR + CD69 + CD25 -NKp44 -). Activated (HLA-DR + CD69 + ) peripheral NK cells expressed an NCR dull phenotype as determined by cytofluorometric analysis in all the patients, and did not derive from a homogeneous/oligoclonal expansion in vivo as analyzed by expression of HLA-specific inhibitory NK cell receptors. As determined by cytotoxicity assays, activated NK cells showed a decreased cytolytic function in HIV-1-infected patients. Thus, the decrease in NK cell function observed during HIV-1 infection is associated not only with decreased NCR expression, but also with significant and incomplete NK cell activation in vivo. These results suggest a consistent continuous involvement of the innate immune response in the failure to control viral replication.

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…In addition, the To determine whether peripheral NK cell activation could be associated with chronic HCV replication and with increased NCR expression, the expression of molecules associated with cell activation was also investigated. Flow cytometric analysis of HLA-DR expression on purified NK cells from viremic HCV patients was not different from healthy controls, while, in line with previous reports [26,27], increased HLA-DR expression was observed in a group of HIV-1 viremic patients (Fig. 1D).…”

“…The NKp30-mediated killing of immature DC (iDC) and the ability of mDC to activate NK cells provide evidence for mechanisms that could help focusing T cell responses through the selection of optimally stimulating mDC [18][19][20]. Recent findings of altered function and target cell killing by NK cells in HIV-1 infection [25][26][27][28] highlight the potential contribution of reduced NCR expression to the inefficiency of adaptive immune responses in clearing chronic persistent viruses. Similar findings from patients with acute myelogenous leukemia (AML) [43] suggest that this could be a mechanism applying to different diseases and could imply caution in the use of DCmediated immunotherapy in certain settings [44], which may be extended to HIV-1 infection.…”

“…Given the findings of relevant perturbations of NCR and of their involvement in the immune responses against chronic persistent infections including HIV and Mycobacterium tuberculosis [21][22][23][24][25][26][27][28] as well as the possible posttranscriptional regulation of NCR in the presence of increasing concentrations of TGF-b [38], we tried to determine whether HCV-infected patients show relevant modifications of triggering receptor expression and of NK cell functional derangement during the chronic phase of HCV infection. We report here on the analysis of freshly separated peripheral blood NK cells from HCV-infected patients, showing modified patterns of NCR expression and cytokine production.…”

“…During Mycobacterium tuberculosis infection in vitro, NK cells control pathogen replication in monocytes via natural cytotoxicity receptor (NCR) killing [21], and removal of NK cells from the peripheral blood of patients with latent tuberculosis significantly reduces mycobacterium-specific CD8 + CTL function [22]. Similarly, the dysfunction of NK cells observed during HIV-1 infection [23,24] has been recently associated with decreased expression of the major NCR (NKp30, NKp46 and NKp44), with a significant level of peripheral NK cell activation and inefficient lysis of HIVinfected CD4 + T cells [25][26][27][28].With respect to an involvement of innate immune responses in HCV-infected patients, so far there is contrasting evidence of either normal or reduced numbers or function of circulating myeloid or plasmacytoid DC [29][30][31][32]. Additional suggestion of the involvement of innate immune mechanism(s) in the establishment of chronic HCV infection derive from the description of NK cell dysfunction (inhibition) following CD16-mediated triggering when CD81 molecules on NK cells are bound to HCV E2 protein [33].…”

“…Additional suggestion of the involvement of innate immune mechanism(s) in the establishment of chronic HCV infection derive from the description of NK cell dysfunction (inhibition) following CD16-mediated triggering when CD81 molecules on NK cells are bound to HCV E2 protein [33]. In addition, reduced NK cell triggering mediated by reduced expression of NKG2D ligands (MIC-A and MIC-B) on mature DC (mDC) [34] as well as increased NK cell inhibition through increased CD94/NKG2A expression and TGF-b and IL-10 production [35,36,37] have been suggested to occur during HCV infection.Given the findings of relevant perturbations of NCR and of their involvement in the immune responses against chronic persistent infections including HIV and Mycobacterium tuberculosis [21][22][23][24][25][26][27][28] as well as the possible posttranscriptional regulation of NCR in the presence of increasing concentrations of TGF-b [38], we tried to determine whether HCV-infected patients show relevant modifications of triggering receptor expression and of NK cell functional derangement during the chronic phase of HCV infection. We report here on the analysis of freshly separated peripheral blood NK cells from HCV-infected patients, showing modified patterns of NCR expression and cytokine production.…”