Nef-mediated primate lentiviral immune evasion mechanisms
LicenseStandard (Fassung vom 01.10.2008)
One of the best established and conserved Nef activities between primate lentiviruses is the downmodulation of human major histocompatibility complex class I (MHC-I) molecules. HIV-1 Nef is capable of selectively downmodulating human leucocyte antigen (HLA)-A and -B, but not -C and -E molecules to evade both cytotoxic T lymphocyte (CTL) and natural killer (NK) cell surveillance. This selectivity is based on amino acid differences in cytoplasmic domains of MHC-I molecules. It remained elusive, however, whether the ability of specific MHC-I modulation is conserved between HIV and its simian precursors as well as in different lentiviral lineages and in recently, naturally or experimentally infected hosts. Previously it has been shown that genetic host factors, like a single-nucleotide polymorphism (SNP), rs9264942, which is located upstream of the HLA-C gene (HLA-C SNP) are associated with a better immune control, leading to low viral loads (VLs) in HIV-1-infected patients. HIV-1 is unable to remove HLA-C from the surface of infected cells to prevent HLA-C-mediated antigen presentation to CTLs. However, adaptive evolution of HIV-1 to its host allows the virus to "learn" how to efficiently persist in some HLA-C SNP individuals, causing high VLs. Thus, one goal of this study was to determine which adaptive changes in Nef occur in these patients. The present thesis shows that primate lentiviral Nefs efficiently manipulate the immune system in different hosts by the important and highly conserved mechanism of specific MHC-I downregulation to avoid CTL and NK cell lysis. Genetic host factors, like a HLA-C SNP, can disrupt the balance between both immune evasion mechanisms, leading to an improved immune control of the virus. However, high VLs are also observed in HLA-C SNP individuals and are associated with the emergence of Nef variants, which manipulate the antigen presenting process by indirect mechanisms rather than by downregulating HLA-C. Thus, the selective pressure in vivo to avoid the removal of HLA-C from the surface of infected cells, even in hosts where this might be beneficial, supports the potency of antiviral therapies aiming to induce HLA-C-mediated immune responses to achieve a better control of viral replication.
Subject HeadingsAffenimmundefizienzvirus [GND]
Gen nef [GND]
Simian immunodeficiency virus [MeSH]
Viral regulatory and accessory proteins [MeSH]