HLA and Killer Cell Immunoglobulin-like Receptors Influence the Natural Course of CMV Infection

Bona, Danilo Di; Scafidi, V.; Plaia, Antonella; Colomba, Claudia; Nuzzo, Domenico; Occhino, Cecilia; Tuttolomondo, Antonino; Giammanco, Anna; Grazia, Simona De; Montalto, Giuseppe; Duro, Giovanni; Cippitelli, Marco; Caruso, Calogero

doi:10.1093/infdis/jiu226

Cited by 30 publications

(41 citation statements)

References 25 publications

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“…These findings confirm previous literature data on the crucial role of KIR repertoire on the surface of NK cells in host defense against herpetic infection [9,10].…”

Section: Discussion/conclusionsupporting

confidence: 92%

“…The expression of activating and inhibitory receptors by NK cells at their surface regulates the extent of NK cell activation [15,20]. KIR are highly polymorphic members of the immunoglobulin superfamily, which influence the response of NK cells as different KIR can transmit inhibitory or activating signals to the cell [10,13]. These findings were the presupposition for assessing KIR allotype in patients affected with cutaneous angioproliferative lesions.…”

Section: Discussion/conclusionmentioning

confidence: 99%

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High prevalence of specific KIR types in patients with HHV-8 positive cutaneous vascular lesions: a possible predisposing factor?

et al. 2016

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Human herpesvirus 8 (HHV8) has been hypothesized to be a potential cofactor for the development of diverse cutaneous vascular proliferative lesions, including eruptive cherry angiomas. Recent reports evidenced the influence of killer cell immunoglobulin-like receptor (KIR) gene diversity in defining the susceptibility to symptomatic herpesvirus infections. In this study, skin samples from vascular lesions and healthy controls were characterized simultaneously for the presence of HHV8 and for the KIR genotype, focusing upon the presence of the KIR2DL2/DS2 and KIR2DL3 genes, which have been associated to herpesvirus susceptibility. The results showed that about 64 % of the vascular lesions resulted positive for the presence of HHV8, whereas no control healthy skin samples harbored HHV8 DNA. HHV8-positive patients had a significantly increased frequency of KIR2DL2/DS2 homozigosity and a concomitant decrease of the homozygous KIR2DL3 genotype, compared to healthy controls or HHV8-negative patients. Notably, the simultaneous presence of KIR2DL2/DS2 homozygosity and HHV8 infection resulted in a significantly increased risk to develop cutaneous lesions (OR 5.7) compared to the individual factors alone, suggesting that specific KIR genotypes might predispose to HHV8 symptomatic infection, allowing the virus to exert its angioproliferative activity at skin level.

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“…These findings confirm previous literature data on the crucial role of KIR repertoire on the surface of NK cells in host defense against herpetic infection [9,10].…”

Section: Discussion/conclusionsupporting

confidence: 92%

Section: Discussion/conclusionmentioning

confidence: 99%

High prevalence of specific KIR types in patients with HHV-8 positive cutaneous vascular lesions: a possible predisposing factor?

et al. 2016

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“…Recent studies have suggested that NK cells play a role in protection against CMV because they are rapidly reconstituted post-transplantation (Cook et al, 2006;Foley et al, 2012;Munoz-Cobo et al, 2012;Della Chiesa et al, 2014), and donoractivating killer cell immunoglobulin-like receptor (KIR) genes have been associated with protection from CMV reactivation in recipients (Zaia et al, 2009;Gallez-Hawkins et al, 2011;Behrendt et al, 2013;Di Bona et al, 2014). Additionally, studies using several mouse models and assessing patients' NK cell reactions to CMV infection have demonstrated that (i) CMV reactivation post-transplantation promotes a lasting increase in educated NKG2C+ NK cells (Foley et al, 2012;Beziat et al, 2013), (ii) the expanded educated NKG2C+ NK cells are mainly self-MHC class I-licensed cells, as shown by immunophenotyping (Beziat et al, 2013), and (iii) impaired NK cell education diminishes resistance to murine cytomegalovirus (MCMV) infection (Wei et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Recipient‐donor KIR ligand matching prevents CMV reactivation post‐haploidentical T cell‐replete transplantation

Zhao

Luo

et al. 2017

Br J Haematol

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Licensed natural killer (NK) cells have been demonstrated to have anti-cytomegalovirus (CMV) activity. We prospectively analysed the human leucocyte antigen typing of donor-recipient pairs and the killer cell immunoglobulin-like receptor (KIR) typing of donors for 180 leukaemia patients to assess the predictive roles of licensed NK cells on CMV reactivation post-T-cell-replete haploidentical stem cell transplantation. Multivariate analysis showed that donor-recipient KIR ligand graft-versus-host or host-versus-graft direction mismatch was associated with increased refractory CMV infection (Hazard ratio = 2·556, 95% confidence interval, 1·377-4·744, P = 0·003) post-transplantation. Donor-recipient KIR ligand matching decreased CMV reactivation [51·65% (46·67, 56·62%) vs. 75·28% (70·87, 79·69%), P = 0·012], refractory CMV infection [17·58% (13·77, 21·40%) vs. 35·96% (31·09, 40·82%), P = 0·004] and CMV disease [3·30% (1·51, 5·08%) vs. 11·24% (8·04, 14·43%), P = 0·024] by day 100 post-transplantation. In addition, the percentage of γ-interferon expression on donor-derived NK cells was significantly higher in the recipients among the recipient-donor pairs with a KIR ligand match compared with that in the recipients among the pairs with a KIR ligand graft-versus-host or host-versus-graft direction mismatch on days 30 and 100 post-transplantation (P = 0·036 and 0·047, respectively). These findings have suggested that donor-recipient KIR ligand matching might promote the NK cell licensing process, thereby increasing NK cell-mediated protection against CMV reactivation.

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“…Several studies have reported an association between the KIR and HLA genotype and the development of CMV infection following hematopoietic stem cell (37) and solid-organ (38,39) transplantation. Moreover, a recent study (22) showed increased susceptibility to developing symptomatic primary CMV infection in immunocompetent adults carrying an AA haplotype or the HLA-Bw4 T allele. However, by comparing KIR and HLA genotypes of the HCMV Ϫ and HCMV ϩ control groups, we could not identify a specific combination.…”

Section: Discussionmentioning

confidence: 99%

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

Riou

Bressollette-Bodin

Boutoille³

et al. 2017

J Virol

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Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMVseronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C ϩ NK cells, CD16 ϩ V␦2(Ϫ) ␥␦ T cells, and conventional HCMV-specific CD8 ϩ T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals.IMPORTANCE HCMV-specific immune responses have been extensively documented in immunocompromised patients and during in utero acquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains.

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HLA and Killer Cell Immunoglobulin-like Receptors Influence the Natural Course of CMV Infection

Abstract: Immunocompetent subjects carrying the homozygous A haplotype or the HLABw4(T) allele are at higher risk of developing symptomatic disease after primary CMV infection.

Cited by 30 publications

References 25 publications

High prevalence of specific KIR types in patients with HHV-8 positive cutaneous vascular lesions: a possible predisposing factor?

High prevalence of specific KIR types in patients with HHV-8 positive cutaneous vascular lesions: a possible predisposing factor?

Recipient‐donor KIR ligand matching prevents CMV reactivation post‐haploidentical T cell‐replete transplantation

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

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