Hepatitis: Romero V

Romero V, Azocar J, Zúñiga J, Clavijo OP, Terreros D, Gu X, Husain Z, Chung RT, Amos C, Yunis EJ. · Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. · Mol Immunol. · Pubmed #18289678 links to  free full text

Abstract: Natural killer cells are important in innate defense against viral infections. The interplay between stimulatory and inhibitory natural killer cell receptors and their corresponding human leukocyte antigen ligands are known to influence the outcome of acute Hepatitis C virus infection. Frequencies of NK receptor genes (8 inhibitory, 6 activating and 2 pseudogenes) and HLA class II alleles (DRB1, DQB1) were analyzed in 160 Puerto-Rican American drug users with Hepatitis C virus infection; 121 had chronic viremia (CV) and 39 were spontaneous clearance (SC). We further ruled out genetic stratification using short tandem repeats. Interaction between KIR gene receptor 2DL3/2DL3 and its ligand, C1/C1 of HLA-Cw alleles and spontaneous clearance was confirmed (p=0.03, OR=3.05). We also found a new interaction between the KIR receptor gene 2DL3 with HLA-DRB1*1201 (p=0.0001, OR=22) associated with SC, and an association of HLA DQB1*0501 (p=0.05, OR=0.30) with CV. Our findings suggested a role for MHC class II alleles in Hepatitis C virus peptide presentation to T cells together with NK ligand interaction involving pathways that will be useful for the development of immunotherapeutic interventions.

Zúñiga J, Romero V, Azocar J, Terreros D, Vargas-Rojas MI, Torres-García D, Jiménez-Alvarez L, Vargas-Alarcón G, Granados-Montiel J, Husain Z, Chung RT, Alper CA, Yunis EJ. · Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City, Mexico. · Mol Immunol. · Pubmed #19552960 No free full text.

Abstract: Intravenous drug use has become the principal route of hepatitis C virus (HCV) transmission due to the sharing of infected needles. In this study, we analyzed the distribution of HLA-KIR genotypes among 160 Puerto Rican intravenous drug users (IDUs) with HCV infection and 92 HCV-negative Puerto Rican IDUs. We found a significant association between the presence of different combinations of KIR inhibitory receptor genes (KIR2DL2 and/or KIR2DL3, pC=0.01, OR=0.07; KIR2DL2 and/or KIR2DL3+KIR2DS4, pC=0.01, OR=0.39) and HLA-C1 homozygous genotypes (HLA-C1+KIR2DS4, pC=0.02, OR=0.43; HLA-C1+KIR2DL2+KIR2DS4, pC=0.02, OR=0.40) together with the activating receptor KIR2DS4 (HLA-C1+KIR2DS4+KIR2DL3 and/or KIR2DL2, pC=0.004, OR=0.38) with protection from HCV infection. Our findings in HCV-infected and non-infected IDUs suggest an important role for KIRs (KIR2DL2 and KIR2DL3) with group HLA-C1 molecules, in the presence of activating KIR2DS4, in protection from HCV infection. These results support the hypothesis that activator signaling, mediated by KIR2DS4, plays a determinant role in the regulation of NK cell antiviral-activity.

Romero V, Fellows E, Jenne DE, Andrade F. · Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México. · Cell Death Differ. · Pubmed #19039329 No free full text.

Abstract: Granzymes are key components of the cytotoxic arm of the immune response, which play critical roles in eliminating host cells infected by intracellular pathogens and transformed cells. Although the induction of cell death is likely a central process underlying the function of these enzymes, little is known about whether granzymes use additional mechanisms to exert their antipathogen activity. This study identifies La, a phosphoprotein involved in multiple roles in cellular and viral RNA metabolism, as the first nonapoptotic substrate of granzyme H (gzmH), a cytotoxic granule protease that is constitutively expressed by NK cells. Cleavage of La by gzmH occurs at Phe-364 (P(1) site) and generates a COOH-terminal truncated form of La that loses nuclear localization and decreases HCV (hepatitis C virus)-internal ribosome entry site (IRES)-mediated translational activity. The ability of gzmH to cleave host proteins involved in essential viral functions provides a novel mechanism by which granzymes can mediate direct antiviral activities.