Abstract
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.
Highlights
All primate lentiviruses are referred to as human and simian ‘‘immunodeficiency’’ viruses (HIV and SIV, respectively), SIVs do generally not cause disease in their natural monkey hosts [1,2]
To better understand the role of Nef in natural nonpathogenic SIV infection, we compared the function of Nef alleles from two groups of SIVsmm-infected sooty mangabeys: (i) those that maintained normal CD4+ T cell counts and (ii) a small subset (10%–15%) of animals that exhibited a considerable loss of CD4+ helper T cells
We found that the efficiency of two specific Nef functions, i.e., downmodulation of T cell receptor (TCR)-CD3 and MHC-I, correlated with preserved CD4+ T cell homeostasis, as well as with other immunological features, such as high numbers of proliferating CD4+ Ki67+ T cells
Summary
All primate lentiviruses are referred to as human and simian ‘‘immunodeficiency’’ viruses (HIV and SIV, respectively), SIVs do generally not cause disease in their natural monkey hosts [1,2]. This is in contrast to HIV-1-infected humans and SIVmacinfected macaques, who develop immunodeficiency and AIDS in the absence of antiretroviral therapy [3]. A consistent difference between pathogenic and nonpathogenic primate lentiviral infections is that high levels of chronic immune activation associated with accelerated T cell turnover and apoptosis are observed in HIV-1-infected humans and SIVmac-infected macaques but not in naturally SIV-infected primates [1,2]. It is believed that infection-associated chronic immune activation and T cell apoptosis drive the progressive destruction of the human immune system
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