Differential natural killer cell–mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes

Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, MA 02129, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 12/2007; 204(12):3027-36. DOI: 10.1084/jem.20070695
Source: PubMed

ABSTRACT Decline of peak viremia during acute HIV-1 infection occurs before the development of vigorous adaptive immunity, and the level of decline correlates inversely with the rate of AIDS progression, implicating a potential role for the innate immune response in determining disease outcome. The combined expression of an activating natural killer (NK) cell receptor, the killer immunoglobulin-like receptor (KIR) 3DS1, and its presumed ligand, human leukocyte antigen (HLA)-B Bw4-80I, has been associated in epidemiological studies with a slow progression to AIDS. We examined the functional ability of NK cells to differentially control HIV-1 replication in vitro based on their KIR and HLA types. NK cells expressing KIR3DS1 showed strong, significant dose- and cell contact-dependent inhibition of HIV-1 replication in target cells expressing HLA-B Bw4-80I compared with NK cells that did not express KIR3DS1. Furthermore, KIR3DS1+ NK cells and NKLs were preferentially activated, and lysed HIV-1 infected target cells in an HLA-B Bw4-80I-dependent manner. These data provide the first functional evidence that variation at the KIR locus influences the effectiveness of NK cell activity in the containment of viral replication.

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    ABSTRACT: HIV/SIV infections break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation and associated disease progression. Innate lymphoid cells (ILCs), distinguishable by high expression of NKp44 and RORγt, play key roles in mucosal defense and homeostasis, but are depleted from gastrointestinal (GI) tract large bowel during chronic SIV infection. However, less is known about the kinetics of ILC loss, or if it occurs systemically. In acute SIV infection, we found a massive, up to 8-fold, loss of NKp44+ILCs in all mucosae as early as day 6 post-infection, which was sustained through chronic disease. Interestingly, no loss of ILCs was observed in mucosa-draining lymph nodes. In contrast, classical NK cells were not depleted either from gut or draining lymph nodes. Both ILCs and NK cells exhibited significantly increased levels of apoptosis as measured by increased Annexin-V expression, but while classical NK cells also showed increased proliferation, ILCs did not. Interestingly, ILCs, which are normally noncytolytic, dramatically upregulated cytotoxic functions in acute and chronic infection and acquired a polyfunctional phenotype secreting IFN-γ, MIP1-β, and TNF-α, but decreased production of the prototypical cytokine, IL-17. Classical NK cells had less dramatic functional change, but upregulated perforin expression and increased cytotoxic potential. Finally, we show that numerical and functional loss of ILCs was due to increased apoptosis and ROR γt suppression induced by inflammatory cytokines in the gut milieu. Herein we demonstrate the first evidence for acute, systemic, and permanent loss of mucosal ILCs during SIV infection associated with reduction of IL-17. The massive reduction of ILCs involves apoptosis without compensatory de novo development/proliferation, but the full mechanism of depletion and the impact of functional change so early in infection remain unclear.
    PLoS Pathogens 12/2014; 10(12):e1004551. DOI:10.1371/journal.ppat.1004551 · 8.14 Impact Factor
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    ABSTRACT: Herpesviruses are ubiquitous pathogens which after an often asymptomatic infection establish lifelong latency in the host. Control of the viral infection depends on both innate and adaptive immune system. Clinical evidence and murine models have firmly established a decisive role of Natural Killer (NK) cells in the early control of herpesvirus infections. In order to escape adaptive T cell responses, herpesviruses target antigen presentation in the infected host cell. This usually leads to downregulation of MHC class I molecules which in turn should increase susceptibility to NK cells. However, a broad arsenal of viral gene products counteracts this danger and interferes with NK cell recognition on various levels. The studies in this thesis address three of these immunoevasins in human cytomegalovirus (HCMV) are discussed: UL16, UL18 and UL40. In paper I we showed that productive HCMV infection induces ULBP1, ULBP2, ULBP3 and MICA, ligands for the NK cell activating receptor NKG2D. The upregulation of ULBP1 and ULBP2 was delayed on the cell surface in the presence of the viral protein UL16, known to bind to these two molecules. Using a HCMV mutant deficient for UL16, we observed higher levels of NKG2D ligands on infected target cells and this increase resulted in a higher susceptibility to NKG2D-mediated polyclonal NK cell responses. This is one of the first studies demonstrating the direct viral targeting of an NK cell activating pathway during productive infection. In paper II we tried to investigate the molecular reasons for the previously known extraordinary high affinity of the viral UL18 protein, an MHC class I homolog, to the inhibitory cellular receptor LIR-1, that had been reported earlier. Based on a model of the UL18 structure, we introduced mutations in different sites of UL18 and assessed their influence on binding and on the functional consequences for the LIR-1/UL18 interaction. Substitutions of residues K42/A43 and Q202, located in the alpha1- and alpha3-domain respectively, reduced the binding affinity between UL18 and LIR-1 by about half. Disruption of an additional disulfide bridge, predicted by our model, completely abolished binding of UL18 to beta2m and the interaction with LIR-1. We propose that the high binding affinity of UL18 for LIR-1 is in part due to a more stable alpha3-domain and a larger binding interface when compared to HLA-A2/LIR-1 In paper III we extended the concept of herpesvirus interference with the NKG2D pathway to Herpes simplex virus (HSV) type I. We detected higher NKG2D levels on NK cells recovered from patients with acute blister formation. In vitro we could demonstrate that HSV downregulates the NKG2D ligand MICA by an as of yet undefined late viral gene. Surprisingly, the lysis of HSV infected target cells by polyclonal NK cells became more dependent on NKG2D, possibly indicating that other viral evasion mechanisms targeting NK cell recognition operate in parallel. In paper IV we revisited the HCMV protein UL40, that has been described to upregulate HLA-E on infected cells and thereby transduce inhibitory signals via the NK cell receptor CD94/NKG2A.We hypothesized that UL40 may have additional functions and using an HCMV mutant deficient for UL40, observed decreased levels of cellular heat shock protein (Hsp) 60 and 70, when compared to cells infected with a wild type virus. Functional knockdown of these molecules resulted in higher susceptibility to NK cell lysis and apoptotic stimuli, suggesting that HCMV induces Hsps in order to prevent target cell death. Based on previous reports regarding the role of Hsp derived sequences in the context of CD94/NKG2A-HLA-E dependent recognition, we propose a model for UL40 action that can reconcile our findings with the existing literature. The multiple recognition strategies of NK cells and the multiple immune evasion molecules of herpesviruses offer a fascinating system to learn more not only about viruses but also about the immune system and the co-evolution driven by host-virus interactions.
    06/2008, Degree: PhD, Supervisor: Klas Kärre
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    ABSTRACT: A cure for HIV is still greatly needed and has become a global research priority. A unique subset of HIV-infected individuals who spontaneously control HIV exists, and these are known as 'elite controllers'. They may represent a natural model for a 'functional cure' in which there is long term control of viral replication and remission from symptoms of HIV infection in the absence of antiretroviral therapy. However, controllers have evidence of ongoing inflammation, CD4(+) T cell depletion, and perhaps even inflammation-associated cardiovascular disease, suggesting that this natural long term virologic control may be coming at an immunologic and clinical cost. These individuals may continue to provide continued insights into mechanisms of host control; however, they may not represent the best model of a functional cure, if we believe that a cure should require a disease-free (and not just a treatment-free) state. Copyright © 2014. Published by Elsevier Ltd.
    Trends in Microbiology 12/2014; 23(2). DOI:10.1016/j.tim.2014.11.003 · 9.81 Impact Factor

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