Soluble ligands for the NKG2D receptor are released during HIV‐1 infection and impair NKG2D expression and cytotoxicity of NK cells

Abstract

In humans, the interaction of the natural killer group 2 member D (NKG2D)-activating receptor on natural killer (NK) and CD8(+) T cells with its major histocompatibility complex class I-related chain (MIC) and UL16 binding protein (ULBP) ligands (NKG2DLs) promotes recognition and elimination of stressed cells, such as tumor or infected cells. Here, we investigated the capacity of HIV-1 to modulate NKG2DL expression and escape NGK2D-mediated immunosurveillance. In CD4(+) T lymphocytes, both cell surface expression and release of MICA, MICB, and ULBP2 were up-regulated >2-fold by HIV-1 infection. In HIV-infected CD4(+) T lymphocytes or Jurkat T-cell lines, increased shedding of soluble NKG2DLs (sNKG2DLs) was impaired by a matrix metalloproteinase inhibitor (MMPI). Moreover, naive HIV(+) patients displayed increased plasma sMICA and sULBP2 levels and reduced NKG2D expression on NK and CD8(+) T cells compared to patients receiving highly active antiretroviral therapy (HAART) or healthy donors. In individual patients, HAART uptake resulted in the drop of sNKG2DL and recovery of NKG2D expression. Finally, sNKG2DLs in patients' plasma down-regulated NKG2D on NK and CD8(+) T cells and impaired NKG2D-mediated cytotoxicity of NK cells. Thus, NKG2D detuning by sNKG2DLs may promote HIV-1 immune evasion and compromise host resistance to opportunistic infections, but HAART and MMPI have the potential to avoid such immune dysfunction.

The Exonuclease Domain of Lassa Virus Nucleoprotein Is Involved in Antigen-Presenting-Cell-Mediated NK Cell Responses

“…Intracellular BAT3 can be released in exosomes by DC and bind to NKp30, thereby triggering NK cell functions (26). Similarly, NKG2D ligands including ULBP molecules are shed in response to HIV-1 and inhibit NKG2D-mediated NK cell activation (27). Further investigation of the expression of such soluble ligands of NK cell-activating receptors during LASV infection would be informative.…”

HIV-1 Nef and Vpu Interfere with L-Selectin (CD62L) Cell Surface Expression To Inhibit Adhesion and Signaling in Infected CD4+T Lymphocytes

“…CD62L downmodulation on HIV-1-infected T cells could be due to increased protein shedding by MMPs, a family of enzymes activated during HIV-1 infection through poorly understood mechanisms (29). To address this point, we measured by ELISA the amounts of sCD62L accumulating in the medium of primary CD4 ϩ T lymphocytes infected or not with HIV-1 and cultivated with a broad-spectrum MMPI (25 M) or equivalent amounts of DMSO solvent, a procedure that we previously set up (30). In control cultures (DMSO), noninfected and HIV-infected cells released amounts of sCD62L that were comparable and ϳ2-fold higher than that of nonactivated cells, indicating that CD62L shedding induced by T cell activation occurs independently of HIV-1 (Fig.…”

“…For each target, forward (F) and reverse (R) primers were designed across exons to avoid amplification of genomic DNA, as validated in pilot assays: CD62L(F), 5=-CAGCCCTCTGTTACACAGCTT-3=; CD62L(R), 5=-GCCCATAGTACCCCACATCA-3=; G6PDH(F), 5=-ATC GACCACTACCTGGGCAA-3=; and G6PDH(R), 5=-TTCTGCATCACG TCCCGGA-3=. The number of cycles (30) was set to the exponential phase of the PCR in order to allow semiquantitative comparisons among samples.…”

A cross-sectional study of C-type lectin receptors (CD94 and CD314) in patients with HIV/AIDS and cancer

“…Therefore, it is possible that this behavior is due to the partial immune recovery of HAART during the early years of treatment, even in cancer conditions. Previous studies have shown that HAART modulates the NKG2D receptor expression among individuals infected with HIV-1 [24][25]. However, there are few studies that have set out to examine the NKG2D expression in NK cells in chronically infected patients [23].…”