BackgroundNatural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood.ResultsWe analyzed Tim-3 and Gal-9 expression in a cohort of 85 individuals with early and chronic HIV-1 infection, and in 13 HIV-1 seronegative control subjects. HIV-1 infection was associated with reduced expression of Tim-3 on NK cells, which was normalized by HAART. Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals. Interestingly, Gal-9 expression in immune cells was significantly elevated in early infection, with monocytes and dendritic cells displaying the highest expression levels, which correlated with HIV-1 viral loads. In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.ConclusionsOur data suggest that high expression levels of Gal-9 during early HIV-1 infection can lead to enhanced NK cell activity, possibly allowing for improved early control of HIV-1. In contrast, persistent Gal-9 production might impair Tim-3 activity and contribute to NK cell dysfunction in chronic HIV-1 infection.

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Evidence suggests natural killer (NK) cells can mediate antiviral activity in HIV-infected humans. Here, we sought to investigate whether the level of NK cell activation in primary HIV infection not only influences the NK cell mediated elimination of HIV infected cells, but also affects the longevity and effectiveness of HIV-specific T cell responses. To address this hypothesis, we monitored HIV viral loads and HIV-specific adaptive immune responses in a humanized BLT mouse model of HIV infection, comparing NK cell-depleted and control mice. Depletion was achieved through the use of an anti-NKp46 antibody prior to HIV infection. Proportions of immune cell subsets and viremia were assessed at baseline and then once a week for at least 5 weeks post-infection using flow cytometry and qRT-PCR. We observed that the impact of NK cells on plasma viral loads varied between batches of mice reconstituted with different tissues. One set of NK cell depleted mice displayed a 4-fold increase in viremia as well as decreased levels of T cell immune activation at 3 weeks post-infection. In a second group of mice reconstituted with independent human tissue, NK cell depletion had no significant effect on viral loads. These results suggest that further investigation is warranted to identify factors accounting for an increased control of HIV replication associated with NK cells in some individuals and not others, such as expression of a protective combination of KIR and HLA alleles.

α/β integrin heterodimers are cell surface proteins involved in cellular communication. The integrin CD11b/CD18 is the predominant integrin found in neutrophils, macrophages and monocoytes and has been implicated as a signaling protein for the inflammation response. Recently, a class of small molecule drugs that activate the integrin CD11b/CD18 was reported. Using molecular docking experiments and site‐directed mutagenesis, we have identified a putative drug binding site in the ligand‐binding aA domain of CD11b, which suggest an allosteric activation of the integrin.