Inefficient Nef-mediated downmodulation of CD3 and MHC-I correlates with loss of CD4+T cells in natural SIV infection.
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/microl 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.
Schindler
Michael
M
Institute of Virology, University of Ulm, Germany.
Schmökel
Jan
J
Specht
Anke
A
Li
Hui
H
Münch
Jan
J
Khalid
Mohammad
M
Sodora
Donald L
DL
Hahn
Beatrice H
BH
Silvestri
Guido
G
Kirchhoff
Frank
F
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016665:Cercocebus atys; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000472:pathogenicity; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
D017252:CD3 Complex; D015395:Histocompatibility Antigens Class I; C429284:NEF protein, SIV; D054334:Viral Regulatory and Accessory Proteins