Inefficient Nef-Mediated Downmodulation of CD3 and MHC-I Correlates with Loss of CD4+ T Cells in Natural SIV Infection

PLoS Pathogens

Frank Kirchhoff¹  Beatrice H. Hahn²  Hui Li²  Michael Schindler³  Mohammad Khalid³  Anke Specht³  Jan Münch³  Jan Schmökel³  Donald L. Sodora⁴  Guido Silvestri⁵ 

[1] Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Institute of Virology, University of Ulm, Germany;University of Texas Southwestern Medical Center, Dallas, Texas, United States of America;Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia, United States of America

关键词: T cells;    HIV-1;    Cytotoxic T cells;    Apoptosis;    Viral diseases;    SIV;    Sequence motif analysis;    Primates;   

DOI  :  10.1371/journal.ppat.1000107

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Recent data suggest that Nef-mediated downmodulation of TCR-CD3 may protect SIVsmm-infected sooty mangabeys (SMs) against the loss of CD4+ T cells. However, the mechanisms underlying this protective effect remain unclear. To further assess the role of Nef in nonpathogenic SIV infection, we cloned nef alleles from 11 SIVsmm-infected SMs with high (>500) and 15 animals with low (<500) CD4+ T-cells/µl in bulk into proviral HIV-1 IRES/eGFP constructs and analyzed their effects on the phenotype, activation, and apoptosis of primary T cells. We found that not only efficient Nef-mediated downmodulation of TCR-CD3 but also of MHC-I correlated with preserved CD4+ T cell counts, as well as with high numbers of Ki67+CD4+ and CD8+CD28+ T cells and reduced CD95 expression by CD4+ T cells. Moreover, effective MHC-I downregulation correlated with low proportions of effector and high percentages of naïve and memory CD8+ T cells. We found that T cells infected with viruses expressing Nef alleles from the CD4low SM group expressed significantly higher levels of the CD69, interleukin (IL)-2 and programmed death (PD)-1 receptors than those expressing Nefs from the CD4high group. SIVsmm Nef alleles that were less active in downmodulating TCR-CD3 were also less potent in suppressing the activation of virally infected T cells and subsequent cell death. However, only nef alleles from a single animal with very low CD4+ T cell counts rendered T cells hyper-responsive to activation, similar to those of HIV-1. Our data suggest that Nef may protect the natural hosts of SIV against the loss of CD4+ T cells by at least two mechanisms: (i) downmodulation of TCR-CD3 to prevent activation-induced cell death and to suppress the induction of PD-1 that may impair T cell function and survival, and (ii) downmodulation of MHC-I to reduce CTL lysis of virally infected CD4+ T cells and/or bystander CD8+ T cell activation.

【 授权许可】

CC BY