The Lymphoid Cell Surface Receptor NTB-A: A Novel Monoclonal Antibody Target for Leukemia and Lymphoma Therapeutics.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4511-4511
Author(s):  
Wouter Korver ◽  
Shweta Singh ◽  
Xiaoxian Zhao ◽  
Eric D. Hsi ◽  
Arie Abo
Keyword(s):  
Cell Surface ◽  
B Lymphocytes ◽  
Cell Lines ◽  
Therapeutic Potential ◽  
Surface Protein ◽  
Lymphocytic Leukemia ◽  
Lymphoid Cells ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
Human Lymphoma

Abstract NTB-A is a CD2-related cell surface protein expressed primarily on lymphoid cells including B-lymphocytes from Chronic Lymphocytic Leukemia (CLL) and lymphoma patients. We have generated a series of murine and chimeric mAbs against NTB-A and assessed their therapeutic potential for CLL. Selective mAbs to NTB-A were further tested in functional Complement Dependent Cytotoxicity (CDC) and Antibody Dependent Cellular Cytotoxicty (ADCC) assays in cell lines and B lymphocytes freshly isolated from CLL patients. While lower levels of NTB-A were detected in T and NK cells, CDC and ADCC activity was demonstrated primarily in B cells isolated from CLL patients and B lymphoma cell lines. Knockdown of NTB-A by siRNA in target cells results in lower cytotoxicity, demonstrating the specificity of the mAbs. Furthermore, anti-NTB-A mAbs demonstrated anti-tumor activity against CA46 human lymphoma xenografts in nude mice and against systemically disseminated Raji human lymphoma cells in SCID mice. Taken together, these results demonstrate NTB-A as a potential new target for immunotherapy of leukemia and lymphomas.

Potent Anti-Cancer Activity of Anti-NTB-a Monoclonal Antibodies in Preclinical Leukemia and Lymphoma Models

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4975-4975
Author(s):  
Wouter Korver ◽  
Xiaoxian Zhao ◽  
Shweta Singh ◽  
Cecile Pardoux ◽  
Ishita Barman ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Cell Lines ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Surface Protein ◽  
Lymphocytic Leukemia ◽  
Lymphoid Cells ◽  
Complement Dependent Cytotoxicity ◽  
Promising Target

Abstract NTB-A is a CD2-related cell surface protein expressed on lymphoid cells including B-lymphocytes from Chronic Lymphocytic Leukemia (CLL) and lymphoma patients. We have generated a series of mAbs against NTB-A and assessed their therapeutic potential in preclinical models. Selected mAbs to NTB-A were further tested in functional Complement Dependent Cytotoxicity (CDC) and Antibody Dependent Cellular Cytotoxicty (ADCC) assays in cell lines and B lymphocytes freshly isolated from CLL and lymphoma patients. Potent cytotoxic activity was demonstrated against B cells isolated from CLL patients and B lymphoma cell lines. Chimeric anti-NTB-A mAbs demonstrated anti-tumor activity equal to rituximab against CA46 human lymphoma xenografts in nude mice at a low dose. In a chimpanzee safety study, a single dose of lead anti-NTB-A mAb 994.1 resulted in near-complete depletion of peripheral lymphocytes while having a minimal effect on T cell activation. Taken together, these results demonstrate NTB-A as a promising target with an acceptable safety profile for immunotherapy of leukemia and lymphomas.

IREM-1 Is a Cell Surface Receptor Expressed in AML Blasts: Potential for Targeted Immunotherapy in AML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1792-1792
Author(s):  
Xiaoxian Zhao ◽  
Wouter Korver ◽  
Shweta Singh ◽  
Eric D. Hsi ◽  
Arie Abo
Keyword(s):  
Cell Surface ◽  
Cell Lines ◽  
Bone Marrow Cells ◽  
Therapeutic Potential ◽  
Myeloid Cells ◽  
Xenograft Model ◽  
Lymphocytic Leukemia ◽  
Cell Surface Receptor ◽  
Hematopoietic Stem ◽  
Mouse Xenograft Model

Abstract Background: Acute myeloid leukemia (AML) in adults is associated with a poor prognosis, with many patients suffering from treatment-resistant relapse. Novel targeted therapies are needed. Immune Receptor Expressed by Myeloid Cells (IREM-1), a member of the CD300L gene family, is an inhibitory receptor expressed by myeloid cells. We have generated monoclonal antibodies (mAbs) specific for IREM-1, characterized IREM-1 expression in AML blasts and explored the therapeutic potential of these antibodies in AML. Methods: mAbs were generated against the extracellular domain of IREM-1. Fresh peripheral blood or bone marrow cells from AML patients, healthy donors, or cell lines OCI-AML-2 (IREM-1+) and K562 (IREM-1−) were used for expression studies by flow cytometry (FC) with FITC-conjugated mAbs. Immunohistochemistry (IHC) was carried out on Tissue Microarrays (TMAs) of normal human tissues. mAbs were evaluated for their ability to induce lysis in Complement-dependent cytotoxicity (CDC) assays against cell lines in vitro and AML patient cells ex vivo. Results: By IHC, normal tissues lacked expression of IREM-1, with the exception of spleen and tonsil. However, using FC, expression of IREM-1 was demonstrated on monocytes, granulocytes and dendritic cells, but not on lymphocytes and platelets. FC of AML blasts showed that 18/24 (75%) cases expressed IREM-1 (range: 23.8–93.2%). The 6 negative cases of IREM-1 include 2 AML cases of inv (16) (p13q22). IREM-1 was not detectable in acute lymphocytic leukemia (ALL) blasts (n=5). CD34+ hematopoietic stem cells of control bone marrows were largely negative (n=7), only one case shown low level expression. Functionally, anti-IREM-1 antibodies mediated CDC in OCI-AML-2, while no effect was seen in IREM-1 negative K562 cells. Human embryonic kidney 293 cells only became susceptible to anti-IREM-1 antibody mediated killing after transfection with IREM-1. Furthermore, an anti-IREM-1 mAb showed dose-dependent CDC activity in all IREM-1+ AML cases tested (n=4), while no CDC activity was observed against IREM-1− AML cases (n=3) and ALL blasts (n=3). Conclusion: Our study identifies IREM-1 as a novel cell surface antigen expressed in majority of AML blasts. We have generated mAbs that are capable of mediating CDC activity against AML blasts. Currently we are testing the killing activity of anti-IREM-1 chimeric Ab and undertaking mouse xenograft model to evaluate the therapeutic impact of this target in vivo, which would offer opportunities for therapeutic intervention.

XmAb Fc engineered anti-CD19 monoclonal antibodies with enhanced in vitro efficacy against multiple lymphoma cell lines

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3021-3021
Author(s):  
E. Zhukovsky ◽  
S. Chu ◽  
M. Bernett ◽  
S. Karki ◽  
W. Dang ◽  
...  
Keyword(s):  
Cell Surface ◽  
B Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Effector Function ◽  
Antibody Engineering ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Cell Surface Receptor

3021 Background: CD19 is a pan-B cell surface receptor that is expressed from early stages of pre-B cell development through terminal differentiation into plasma cells. It is an attractive immunotherapy target for cancers of lymphoid origin since it is also expressed on the vast majority of Non-Hodgkin Lymphoma (NHL) cells as well as some leukemias. Despite major improvements in response rates and progression free survival the majority of NHL patients will relapse under the current combination chemotherapy with anti-CD20. Thus salvage regimens with new non-cross resistant antibody therapies are warranted. Methods: We employ our XmAb antibody engineering technology to increase the affinity of IgG antibodies for Fc gamma receptors (FcγR), improve the effector function of antibodies, and significantly increases their antitumor potency; we also we humanize and affinity mature such antibodies. Results: The XmAb technology was applied to a humanized anti-CD19 antibody to engineer a variant with significantly enhanced (10- to 100-fold) antibody-dependent cell-mediated cytotoxicity (ADCC). The resulting XmAb CD19 variant was assayed for ADCC against multiple cell lines representative of follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), B-cell acute lymphoblastic leukemia (B-ALL), mantle cell lymphoma (MCL), hairy cell leukemia (HCL), chronic myelogenous leukemia (CML), and Burkitt’s lymphoma (BL). The ADCC activity of the XmAb CD19 was in striking contrast to a wild type IgG1 version of the antibody that mediates little ADCC. Moreover, ADCC potency and efficacy of the anti-CD19 Fc variant antibody were superior to that of rituximab: CLL - 10- and 1.5-fold higher, ALL - 10- and 100-fold higher, and HCL - 6- and 1.2-fold higher, respectively. Further, we observed no correlation between ADCC and antigen expression based on the measured cell surface density of CD19 for these cell lines. Conclusions: The increased affinity for FcγRs exhibited by the anti-CD19 Fc variant antibody overcomes much of the dependence of cytotoxicity on surface antigen density. Our data suggest that the anti-CD19 Fc variant antibody engineered for increased effector function could be a promising next-generation NHL immunotherapeutic. No significant financial relationships to disclose.

scholarly journals Characterization of a cDNA encoding a cysteine-rich cell surface protein located in the flagellar pocket of the protozoan Trypanosoma brucei.

1990 ◽  
Vol 10 (9) ◽  
pp. 4506-4517 ◽  
Author(s):  
M G Lee ◽  
B E Bihain ◽  
D G Russell ◽  
R J Deckelbaum ◽  
L H Van der Ploeg
Keyword(s):  
Amino Acid ◽  
Cell Surface ◽  
Trypanosoma Brucei ◽  
Transmembrane Domain ◽  
Density Lipoprotein ◽  
Surface Protein ◽  
Integral Membrane Protein ◽  
Cell Surface Receptor ◽  
Flagellar Pocket ◽  
Cytoplasmic Extension

We have characterized a cDNA encoding a cysteine-rich, acidic integral membrane protein (CRAM) of the parasitic protozoa Trypanosoma brucei and Trypanosoma equiperdum. Unlike other membrane proteins of T. brucei, which are distributed throughout the cell surface, CRAM is concentrated in the flagellar pocket, an invagination of the cell surface of the trypanosome where endocytosis has been documented. Accordingly, CRAM also locates to vesicles located underneath the pocket, providing evidence of its internalization. CRAM has a predicted molecular mass of 130 kilodaltons and has a signal peptide, a transmembrane domain, and a 41-amino-acid cytoplasmic extension. A characteristic feature of CRAM is a large extracellular domain with a roughly 66-fold acidic, cysteine-rich 12-amino-acid repeat. CRAM is conserved among different protozoan species, including Trypanosoma cruzi, and CRAM has structural similarities with eucaryotic cell surface receptors. The most striking homology of CRAM is to the human low-density-lipoprotein receptor. We propose that CRAM functions as a cell surface receptor of different trypanosome species.

scholarly journals Specific adsorption of HTLV-I to various target human and animal cells

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1303-1311 ◽  
Author(s):  
K Krichbaum-Stenger ◽  
BJ Poiesz ◽  
P Keller ◽  
G Ehrlich ◽  
J Gavalchin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mononuclear Cells ◽  
Cultured Cells ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Lymphoid Cells ◽  
Core Antigen ◽  
Target Cells ◽  
Animal Cells ◽  
Homologous Virus

In this report, we describe a flow cytometric analysis of HTLV-I specific binding to fresh and cultured cells on a single cell basis. This assay uses rhodamine hydrocarbon tagged, purified HTLV-I virions according to the procedure originally described for avian retroviruses. Successful HTLV-I transmission was detected by analysis of integrated HTLV-I DNA, virion-associated reverse transcriptase, and/or intracellular HTLV-I core antigen p19 expression. Only a specific virus- cell interaction was detected because nonrhodamine-tagged homologous virus or related HTLV-II interfered with tagged HTLV-I binding. In contrast, an unrelated, nonlabeled animal retrovirus was unable to block tagged HTLV binding. Of the cell lines tested, 2 nonlymphoid mammalian and 3 human lymphoid bound significantly high to moderate levels of HTLV-I-tagged virions. The other three human lymphocyte cell lines were insensitive to HTLV-I adsorption. A direct correlation was observed between HTLV-I binding sites and infectivity of human lymphoid cells alone and not other nonlymphoid animal cells. Fresh normal human mononuclear cells bound low levels of HTLV-I virions. As expected, T lymphocytes demonstrated more binding than did the non-T cell population. Enhancement of HTLV-I cell binding in a subpopulation of mononuclear target cells was achieved with phytohemagglutinin (PHA) activation and interleukin 2 (IL2) stimulation, which correlates well with previously published infectivity studies.

Lymphocyte Subpopulations in Human Malnutrition: Cytotoxic and Suppressor Cells

PEDIATRICS ◽  
1977 ◽  
Vol 59 (3) ◽  
pp. 423-427
Author(s):  
R. K. Chandra
Keyword(s):  
B Lymphocytes ◽  
Peripheral Blood ◽  
Relative Proportion ◽  
Suppressor Cells ◽  
Lymphocyte Subpopulations ◽  
Lymphoid Cells ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Surface Markers ◽  
And Function

Lymphocytes in the peripheral blood of young children with protein-calorie undernutrition were evalutated for surface markers and function. Thymus-dependent lymphocytes were reduced and the immunoglobulin-bearing B lymphocytes were unchanged. The relative proportion of the remaining "null" lymphoid cells was increased. Null cells and, to a lesser extent, B lymphocytes showed cytotoxic activity against xenogeneic target cells and suppressed phytohemagglutinin-induced DNA synthesis by normal T lymphocytes. It is suggested that these alterations in lymphoid subpopulations contribute to depressed cell-mediated immunity in malnutrition.

scholarly journals CD81 is a novel immunotherapeutic target for B cell lymphoma

2019 ◽  
Vol 216 (7) ◽  
pp. 1497-1508 ◽  
Author(s):  
Felipe Vences-Catalán ◽  
Chiung-Chi Kuo ◽  
Ranjani Rajapaksa ◽  
Caroline Duault ◽  
Noemi Andor ◽  
...  
Keyword(s):  
B Cell ◽  
Therapeutic Potential ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Lymphoid Cells ◽  
Antiproliferative Effects ◽  
Biopsy Specimens ◽  
Human Lymphoma ◽  
Human B Cell

The tetraspanin CD81 was initially discovered by screening mAbs elicited against a human B cell lymphoma for their direct antiproliferative effects. We now show that 5A6, one of the mAbs that target CD81, has therapeutic potential. This antibody inhibits the growth of B cell lymphoma in a xenograft model as effectively as rituximab, which is a standard treatment for B cell lymphoma. Importantly, unlike rituximab, which depletes normal as well as malignant B cells, 5A6 selectively kills human lymphoma cells from fresh biopsy specimens while sparing the normal lymphoid cells in the tumor microenvironment. The 5A6 antibody showed a good safety profile when administered to a mouse transgenic for human CD81. Taken together, these data provide the rationale for the development of the 5A6 mAb and its humanized derivatives as a novel treatment against B cell lymphoma.

scholarly journals DC-SIGN and L-SIGN Are Attachment Factors That Promote Infection of Target Cells by Human Metapneumovirus in the Presence or Absence of Cellular Glycosaminoglycans

2016 ◽  
Vol 90 (17) ◽  
pp. 7848-7863 ◽  
Author(s):  
Leah Gillespie ◽  
Kathleen Gerstenberg ◽  
Fernanda Ana-Sosa-Batiz ◽  
Matthew S. Parsons ◽  
Rubaiyea Farrukee ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cho Cells ◽  
Experimental System ◽  
Human Metapneumovirus ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
Transmembrane Receptors ◽  
Hmpv Infection ◽  
Attachment Factor

ABSTRACTIt is well established that glycosaminoglycans (GAGs) function as attachment factors for human metapneumovirus (HMPV), concentrating virions at the cell surface to promote interaction with other receptors for virus entry and infection. There is increasing evidence to suggest that multiple receptors may exhibit the capacity to promote infectious entry of HMPV into host cells; however, definitive identification of specific transmembrane receptors for HMPV attachment and entry is complicated by the widespread expression of cell surface GAGs. pgsA745 Chinese hamster ovary (CHO) cells are deficient in the expression of cell surface GAGs and resistant to HMPV infection. Here, we demonstrate that the expression of the Ca2+-dependent C-type lectin receptor (CLR) DC-SIGN (CD209L) or L-SIGN (CD209L) rendered pgsA745 cells permissive to HMPV infection. Unlike infection of parental CHO cells, HMPV infection of pgsA745 cells expressing DC-SIGN or L-SIGN was dynamin dependent and inhibited by mannan but not by pretreatment with bacterial heparinase. Parental CHO cells expressing DC-SIGN/L-SIGN also showed enhanced susceptibility to dynamin-dependent HMPV infection, confirming that CLRs can promote HMPV infection in the presence or absence of GAGs. Comparison of pgsA745 cells expressing wild-type and endocytosis-defective mutants of DC-SIGN/L-SIGN indicated that the endocytic function of CLRs was not essential but could contribute to HMPV infection of GAG-deficient cells. Together, these studies confirm a role for CLRs as attachment factors and entry receptors for HMPV infection. Moreover, they define an experimental system that can be exploited to identify transmembrane receptors and entry pathways where permissivity to HMPV infection can be rescued following the expression of a single cell surface receptor.IMPORTANCEOn the surface of CHO cells, glycosaminoglycans (GAGs) function as the major attachment factor for human metapneumoviruses (HMPV), promoting dynamin-independent infection. Consistent with this, GAG-deficient pgaA745 CHO cells are resistant to HMPV. However, expression of DC-SIGN or L-SIGN rendered pgsA745 cells permissive to dynamin-dependent infection by HMPV, although the endocytic function of DC-SIGN/L-SIGN was not essential for, but could contribute to, enhanced infection. These studies provide direct evidence implicating DC-SIGN/L-SIGN as an alternate attachment factor for HMPV attachment, promoting dynamin-dependent infection via other unknown receptors in the absence of GAGs. Moreover, we describe a unique experimental system for the assessment of putative attachment and entry receptors for HMPV.

288 CHARACTERIZATION OF PORCINE ADIPOSE TISSUE-DERIVED ADULT STEM CELL SURFACE PROTEINS

2009 ◽  
Vol 21 (1) ◽  
pp. 241
Author(s):  
K. J. Williams ◽  
R. A. Godke ◽  
K. R. Bondioli
Keyword(s):  
Tissue Engineering ◽  
Adipose Tissue ◽  
Stem Cell ◽  
Cell Surface ◽  
Cell Lines ◽  
Adult Stem Cell ◽  
Surface Protein ◽  
Surface Proteins ◽  
Early Passage ◽  
Cell Surface Proteins

Human adipose tissue-derived adult stem (ADAS) cells are a self-renewing population of cells with a multilineage plasticity similar to bone marrow-derived mesenchymal stem cells. Human ADAS have promise for use in combination with various biomaterials for reconstructive tissue engineering. The phenotypic profile of human ADAS cell surface proteins has been partially characterized for stem cell-associated cluster differentiation molecules including CD29, CD44, and CD90. Porcine ADAS cells, an animal model for tissue engineering, also have the ability to self-renew and differentiate into multiple tissue lineages. However, the surface protein phenotype has not been described. Because porcine ADAS are isolated from fat depots likely different from human ADAS liposuction aspirates, it is important to characterize these cells. In this study, we have partially characterized the surface protein phenotype of undifferentiated porcine ADAS cells in comparison with the immunophenotype of undifferentiated human ADAS cells as reported in the literature. Flow cytometry and enhanced chemiluminescence Western blot analysis of early passage (passages 0–4) porcine ADAS cell populations demonstrated that the profiles are not similar to the human ADAS cell surface. Immunoblot detection paired with an enhanced chemiluminescence kit revealed a positive expression for CD44 and CD90 in human ADAS cells as indicated by bands present at the expected sizes and a negative expression for CD44 and CD90 in porcine ADAS cells. Flow cytometric analysis also indicated differences between human and early passage porcine ADAS cell surfaces with a relatively low expression of CD29 (5 cell lines with a mean percent positive of 4.5 ± 1.7 and a range of 2.5–7.2%) and CD44 (5 cell lines with a mean percent positive of 0.66 ± 0.67 and a range of 0.0–1.8%) compared with human ADAS values of 98 ± 1 and 60 ± 15, respectively (Gronthos et al. 2001). Other cell surface proteins analyzed at early passages include CD3 (3 cell lines; 0.07 ± 0.06% positive and 0.0–0.1 range), CD8 (3 cell lines; 0.10 ± 0.10% positive and 0–0.2 range), and CD90 [5 cell lines; 12.7 ± 11.9% positive and 2.4–33 range; human ADAS geometric mean 25.96% (Zuk et al. 2002)]. Analysis of late passage (passages 5–11) porcine ADAS cell populations revealed an increased expression of CD29 (3 cell lines; 26.4 ± 7.2% positive and 21.2–34.6 range). The expression level of CD90 at late passages were 21.3 and 26.9% positive for 2 cell lines and CD44 remained low (3 cell lines; 4.1 ± 3.5% positive and 0.2–7.0 range). Later passages were also analyzed for c-Kit (CD117), which was expressed at low levels (2 cell lines; 0.3 and 0.4% positive). The characterization of adipose tissue-derived adult stem cell surface proteins present at different stages of in vitro culture from a model animal, such as the pig, could have valuable impacts on tissue engineering research. These results suggest that care should be taken when interpreting results from animal models of somatic stem cells.

scholarly journals Divergent Traits and Ligand-Binding Features of the Cytomegalovirus CD48 Gene Family

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 23
Author(s):  
Pablo Martinez-Vicente ◽  
Domènec Farré ◽  
Elena Gracia-Latorre ◽  
Pablo Engel ◽  
Ana Angulo
Keyword(s):  
Cell Surface ◽  
Nk Cell ◽  
Viral Evolution ◽  
Costimulatory Molecule ◽  
Surface Protein ◽  
Gene Families ◽  
Biochemical Properties ◽  
Cell Surface Receptor ◽  
Type I ◽  
Independent Functions

The genesis of gene families through the capture of host genes and their subsequent duplication is a crucial process in the evolution of large DNA viruses. CD48 is a cell surface protein with an ectodomain composed of two immunoglobulin (Ig) domains. Via its N-terminal Ig domain, CD48 interacts with the cell surface receptor 2B4, triggering signal transduction events that regulate leukocyte cytotoxicity. We previously reported the presence of five CD48 homologs (vCD48s) in two related cytomegaloviruses, derived from a common host CD48 ancestor gene acquired by retrotranscription. Recently, we examined one member of this family, A43, showing that it acts as a functional viral decoy receptor, binding with high affinity and stability to 2B4 and impairing NK-cell cytotoxicity. Here, we have characterized the rest of the vCD48s. We show that they are highly glycosylated type I transmembrane proteins that display remarkably distinct features: dissimilar structures (e.g., different size stalks and cytoplasmic tails), biochemical properties, locations (cell surface/soluble), and temporal kinetic classes. We found that, in contrast to A43, none of them interacts with 2B4. Consistent with this, the molecular modeling of the N-terminal Ig domains of these vCD48s evidences significant changes in the numbers and lengths of their β-strands and inter-sheet loops that participate in the interaction of CD48 with 2B4. This suggests that these vCD48s have diverged to perform new 2B4-independent functions. Interestingly, we determined that one of them, S30, tightly binds CD2, a T- and NK-cell adhesion and costimulatory molecule whose primary ligand is CD58. Thus, altogether, our results show how a key host immune receptor captured by a virus can be subsequently remodeled during viral evolution to yield new molecules with improved affinities to their cognate receptors or with shifted binding specificities to additional immune targets, expanding the repertoire of viral immunoevasins.

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