No abstract

The isolates of human herpesvirus-6 (HHV-6), a betaherpesvirus closely related to human cytomegalovirus (HCMV), are classified as either variants A (HHV-6A) or B (HHV-6B) but their intravariant variability has not been studied extensively so far. The full-length genes of envelope glycoproteins gB and gH from 40 distinct HHV-6-DNA-positive specimens and 11 laboratory strains were amplified using PCR, and their nucleotide sequence determined. Nucleotide divergences were observed at 156 (6.2%) and 98 (4.7%) positions in the case of gB and gH genes respectively. Phylogenetic analysis, including reference strain sequences, confirmed the unambiguous distinction between HHV-6A and HHV-6B for both genes. In the case of HHV-6B isolates, two subgroups of gB gene (designated as gB-B1 and gB-B2) and two subgroups of gH gene (gH-B1 and gH-B2) were identified but the phylogenetic trees of both genes were not fully congruent with each other. The analysis of gB and gH protein sequences showed that 26 and 39 critical amino acid changes respectively permitted the unambiguous distinction between HHV-6A and HHV-6B. Among HHV-6B isolates, gB and gH gene subgroups were characterized by specific amino acid signatures made of six, and two residues respectively. The linkage unbalance between amino acid signatures as well as the distribution of crucial nucleotide changes strongly suggested the occurrence of intravariant recombination within gB gene among HHV-6B isolates. These results indicate that, as in the case of HCMV, homologous recombination may contribute to the genetic variability of HHV-6.

No abstract

These findings suggest that a specific substitution in a 3S-based immunogen might allow the generation of specific antibodies, providing a foundation for a rational vaccine that combine a capacity to neutralize HIV-1 and to protect CD4(+) T cells.

In April 2009, we saw a 64-year-old woman with persistent indolent proliferation of CD3 Ϫ CD56 ϩ large granular lymphocytes. 1 She had no other clinical symptoms and no autoimmune events, and her clinical course has remained benign over 22 months. Neither clinical nor imaging studies have shown signs of lymphoma or acute infection. IgG serology is negative for HIV-1/2, human T cell lymphotrophic virus (HTLV)-1/2, hepatitis B virus, hepatitis C virus, and HHV8, and positive for EBV, CMV, HSV, and varicella zoster virus. Most notably, we have observed an elevated lymphocyte count, ranging from 5.2 to 8.0 ϫ 10 9 /L, extremely unbalanced with CD3 Ϫ CD56 dim natural killer (NK) cells accounting for 62.0%-83.2% of lymphocytes overall ( Figure 1A). Intriguingly, more than 95% of the NK cells simultaneously coexpress inhibitory NKG2A and triggering NKG2C receptors ( Figure 1B), although coexpression of these markers is generally observed in only 1%-2% of decidual and peripheral blood NK cells from healthy donors. Consistent with recent studies exploring the relation between NK-cell responsiveness and receptors that engage self-MHC class I molecules, 5 polyfunctional analysis showed that this patient's KIR Ϫ NKG2A ϩ NKG2C ϩ NK cells were fully functional against MHC class I-deficient target cells (K562, and 721.221) and capable of antibody-dependent cellular cytotoxicity ( Figure 1E).Inhibitory NKG2A and activating NKG2C receptors are both specific for HLA-E, a nonclassical MHC class Ib molecule expressing peptides derived from signal sequences of other HLA class I molecules. 6 Given their opposing functional effect, the coexpression of both markers raises the question of how NK cells can establish self-tolerance under this circumstance, as the lack of symptoms shows they do. A redirected killing assay against Fc␥R ϩ P815 targets in the presence of anti-NKG2C mAb showed that the NKG2C was functional, but more interestingly, costimulation of NKG2A and NKG2C with their respective mAbs demonstrated that the inhibitory function of NKG2A prevailed ( Figure 1F). The NKG2A ϩ NKG2C ϩ NK cells were clearly less polyfunctional against targets expressing HLA-E than against wild-type 721.221 cells ( Figure 1E), and HLA-E ϩ target interaction inhibited NK-cell proliferation, except in the presence of IL-2 ( Figure 1G), as described. 7 A redirect killing assay confirmed that simultaneous engagement of NKG2C and IL-2 induced a marked proliferative response, abrogated by NKG2A engagement ( Figure 1H).We therefore report that the NKG2A inhibitory receptor plays a central inhibitory role, providing a regulatory feedback mechanism for controlling the activating NKG2C receptor, reminiscent of the activation-dependent expression of CTLA-4 on T lymphocytes that counteracts CD28-mediated costimulation. 8 These findings are consistent with the higher affinity of NKG2A for HLA-E, which likely favors its competition with NKG2C for ligand engagement. 9 To our knowledge, this case provides the first in vivo evidence that, in the absence of KIR, exp...

Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post-transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem-cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery.

No abstract

Solid cancers are a major adverse outcome of orthotopic liver transplantation (OLT). Although the use of chronic immunosuppression is known to play a role in T cell impairment, recent insights into the specificities of NK cells led us to reassess the potential modulation of this innate immune cell compartment after transplantation. Our extensive phenotypic and functional study reveals that the development of specific de novo noncutaneous tumors post-OLT is linked to unusual NK cell subsets with maturation defects and to uncommon cytokine production associated with the development of specific cancers. Remarkably, in CMV+ patients, the development de novo head/neck or colorectal tumors is linked to an aberrant expansion of NK cells expressing NKG2C and a high level of intracellular TNF-α, which impact on their polyfunctional capacities. In contrast, NK cells from patients diagnosed with genitourinary tumors possessed a standard immature signature, including high expression of NKG2A and a robust production of IFN-γ. Taken together, our results suggest that under an immunosuppressive environment, the interplay between the modulation of NK repertoire and CMV status may greatly hamper the spectrum of immune surveillance and thus favor outgrowth and the development of specific de novo tumors after OLT.