HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts

Abstract

The ability of natural killer (NK) cells to kill virus-infected cells depends on the presence of ligands for activation receptors on the target cells. We found the presence of few, if any, NKp30 and NK46 ligands on T cell blasts infected with HIV, although NKp44 ligands were found on infected cells. HIV does induce the NKG2D ligands ULBP-1, -2, and -3. These ligands are involved in triggering NK cells to kill autologous HIV-infected cells, because interfering with the interaction between NKG2D, but not NKp46, on NK cells and its ligands on HIV-infected cells drastically reduced the lysis of infected cells. Interfering with the binding of the NK-cell coreceptors NTB-A and 2B4 to their ligands also decreased destruction by NK cells. The coreceptor ligands, NTB-A and CD48, were also found to be down-regulated during the course of HIV infection. Thus, ligands for NK-cell receptors are modulated during the course of HIV infection, which may greatly alter NK cells' ability to kill the infected cells.

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

“…Reductions in NKp46 expression in HIV-unrelated in vitro experiments was demonstrated to occur upon activation and, in some cases, after direct ligation of the receptor (30,39). However, infection of CD4 + T lymphocytes with HIV does not induce the expression of NKp46 ligands (31). As such, ligation-induced downregulation is unlikely to explain the altered patterns of NKp46 expression observed on NK cells from HIV-infected individuals.…”

“…However, this raises the conundrum of how NKp46 expression is decreased on NK cells during HIV infection. Indeed, the expression of NKp46 ligands is not induced in CD4 + T lymphocytes upon HIV infection (31). As such, the direct activation of NK cells through NKp46 cannot explain the decreased expression of NKp46 observed during chronic HIV infection.…”

“…Because NKp46 expression is decreased in the absence of direct ligation during HIV infection (13,15,20,31) and given that NKp46 shares a signaling pathway with CD16 (23), we hypothesized that decreases in NKp46 expression could be induced by the activation of NK cells through CD16 ligation. Furthermore, we hypothesized that the CD16 ligation-dependent upregulation of matrix metalloproteinases (MMPs), which are responsible for decreased CD16 expression (26), contribute to decreased NKp46 expression.…”

A vaccine strategy against AIDS: An HIV gp41 peptide immunization prevents NKp44L expression and CD4 + T cell depletion in SHIV-infected macaques

“…One plausible such mechanism is the expression of a natural killer (NK) ligand on CD4 ϩ T cells during HIV infection: we (6) demonstrated that NKp44L, the ligand of NKp44 NK receptor, is expressed on CD4 ϩ T cells of HIV-infected patients and showed that cells expressing NKp44L are highly sensitive to NK lysis. Ward et al (7) have recently confirmed the specific expression of NKp44L on CD4 ϩ T cells after in vitro infection with HIV-1.…”

NCR2 (natural cytotoxicity triggering receptor 2)

“…NKp44 cellular ligand (NKp44L) is expressed on uninfected CD4 + T cells during an HIV infection, correlating with the loss of CD4 + T cells and increase of viral load (Vieillard et al, 2005). NKp44L is only expressed in high amounts on uninfected CD4 + T cells and is not responsible for inducing NK lysis of HIV-infected cells (Ward et al, 2007). To avoid NK killing of HIV infected CD4 + T cells, the Nef protein of HIV-1 retains NKp44L intracellularly, preventing cell surface expression and interaction with NKp44 (Fausther-Bovendo et al, 2009).…”