ZIA BC 010791 (ZIA) | |||
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Title | Effects of genetic polymorphism in MHC, KIR, and related loci on human disease | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Carrington, Mary | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,047,897 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (10.0%) Cancer (100.0%) |
Cervical Cancer (15.0%) Head and Neck (30.0%) Kaposi Sarcoma (20.0%) Leukemia (20.0%) Lung (10.0%) Sarcoma (15.0%) |
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Research Type | |||
Cancer Progression & Metastasis Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
Infection with KSHV is required but not sufficient for development of KS, and the prevalence of KSHV seropositivity far exceeds the incidence of KS. The genes encoding HLA and related genes are centrally involved in the immunological response to infectious diseases and thus may affect the risk of developing KSHV infection or KS. We compared HLA class I and KIR HLA ligand frequencies in a 2 phase study that included 250 persons with classic KS, 280 KSHV seropositive controls, and 576 KSHV seronegative controls in Italy. This is the first comprehensive study to assess the role of HLA and KIR on the risk of KSHV seroprevalence and classic KS. The risk of KS was significantly reduced in people with A1101, and it was increased for those with C0701. A1101 is well known to be associated with decreased risk for the EBV associated nasopharyngeal carcinoma. Both KSHV and EBV are gamma herpes virus. This implies that A1101 may present herpesvirus related antigenic epitopes to cytotoxic T lymphocytes, resulting in effective control of the virus in the lytic phase. HLA C group 1 alleles, which serve as ligands for the inhibitory KIR2DL2 and 3, were significantly associated with protection against KSHV seroprevalence, but with increased risk of KS among KSHV infected subjects. This KIR HLA combination has a relatively weak NK cell inhibitory potential relative to that of KIR2DL1 in the presence of its HLA C group 2 ligand, which is strongly inhibitory. Likewise, the activating KIR3DS1 with HLA B Bw4 80I was protective against seroprevalence but associated with an increased risk of KS. We hypothesize that strong NK cell activation protects against seropositivity but is a risk factor for classic KS after KSHV infection, perhaps because of the known association of KS with inflammation. The HLA C locus is distinct relative to HLA A and HLA B in that it is less polymorphic, and it encodes molecules that have lower cell surface expression levels and more extensive interactions with the KIRs expressed by NK cells. Pathogen driven downregulation of HLA class I molecules on infected cells can result in strongly diminished CTL recognition but also enhance NK cell mediated lysis of the infected cell because of the failure of HLA ligand to bind inhibitory KIRs. The specificity of HIV1 Nef in downregulating HLA A and B molecules, but not HLA C, has been interpreted as a viral mechanism to subvert adaptive HLA A and HLA B restricted CTL responses while simultaneously protecting infected cells against innate NK cell immunity through recognition of unmodulated HLA C levels by inhibitory NK cell receptors. We measured surface expression levels of HLA class I on primary CD4+ cells infected in vitro with primary HIV1 strains. Unlike the widely studied laboratory adapted HIV1 isolate NL4 3, most primary clones of HIV1 do in fact downregulate HLA C to some extent. We determined, using several primary HIV1 strains, that the viral Vpu protein is responsible for HLA C downregulation. Notably, specific naturally occurring amino acid variants in the N terminal region of Vpu that affect the differential ability to downregulate HLA C are located within peptides known to bind HLA alleles, suggesting that the ability of HIV1 to modulate HLA C could be altered over the course of viral adaptation to certain CTL responses. Differences in HLA C expression levels have been shown to influence the outcome of HIV1 infection where higher expression levels associate inversely with viral load in the absence of antiretroviral therapy. Higher HLA C expression levels also correlate with greater frequencies of HLA C associated CTL responses and a higher degree of viral mutation, illustrating the immune pressure that higher HLA C expression exerts on the virus. That higher HLA C expression levels associate with viral control is consistent with HIV targeting HLA C for downregulation. Revision of the prevailing model in which HIV evades both CTL and NK cell immune responses through selec |