Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have solved the crystal structures of three HLA-B*2705-peptide complexes with the immunodominant viral peptides: EBV EBNA3C 258-266 (RRIYDLIEL), influenza (flu) nucleoprotein NP383-391 (SRYWAIRTR), and HIV gag 264-273 (KRWIILGLNK). Long-term non-progression during HIV infection has been associated with presentation by HLA-B*2705, and T cell recognition, of the highly immunodominant KRWIILGLNK peptide. The tight hydrogen-bonding network observed between the HLA-B*2705 B-pocket and the peptide P2 arginine guanadinium anchor explains why mutation of this residue during HIV infection results in loss of peptide binding, immune escape and progression to AIDS. Prominent, solvent-exposed structures within these peptides may participate in generating T cell responses to these immunodominant epitopes. In the HLA-B*2705 complex with flu NP383-391, the amino acid side chains of residues 4, 7 and 8 are solvent-exposed whilst in the HIV decamer, the main-chain bulges into the solvent around P7. Thus, HLA-B*2705 presents viral peptides in a range of conformations. Tetrameric complexes of HLA-B*2705 with the HIV and flu but not EBV peptides bound strongly to the killer-Ig-like receptor (KIR)3DL1. Substitution of EBV P8 glutamate to threonine allowed recognition by KIR3DL1. In the HLA-B*2705-EBV structure the P8 glutamate side chain is solvent-exposed and may inhibit KIR3DL1 binding through electrostatic forces.
 ...
PMID:Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA-B*2705. 1565 45

KIR and HLA loci are both highly polymorphic, and some HLA class 1 products bind and trigger cell-surface receptors specified by KIR genes. We examined whether KIR genes act in concert with HLA-B locus to control HIV-1 infection in a sample of Zambian patients. DNA samples from 88 Zambian patients with HIV-1 were examined. Patients were classified as either slow progressors (SP; n = 54) or rapid progressors (RP; n = 34) to AIDS. All were typed for HLA-B and KIR genes. Our results reveal an association between B*57 supertype (B*57s, which includes B*57 and B*58 alleles) and delayed progression to AIDS (p = 0.0007 by pc = 0.015; OR = 5.25). We also observed an increase incidence of Bw4-I80 in patients with slow progression (p = 0.001 by pc = 0.003, OR = 5). This increase was found to be secondary to B*57s. The presence of both KIR3DL1 and B*57S has a significant effect on progression to AIDS (p = 0.0008; OR = 5.61). B*57s genotypes with another HLA-B allele different from those in the trans position, which also had a specificity different to Bw4-I80 (Bw4-T80 or Bw6), was also greater in the SP than in the RP group (p = 0.00003; OR = 10.11). The presence of the inhibitory allele KIR3DL1 in combination with the HLA-B*57s alleles that contain the Bw4-I80 epitope, has a highly protective effect against progression to AIDS in Zambian patients.
 ...
PMID:Interaction between KIR3DL1 and HLA-B*57 supertype alleles influences the progression of HIV-1 infection in a Zambian population. 1578 66

Kaposi's sarcoma (KS) is an AIDS-defining condition in individuals with human immunodeficiency virus type 1 infection. We investigated the phenotype and function of the NKG2C+ NK cell population in individuals with AIDS and Kaposi's sarcoma. The staging of AIDS KS patients according to the AIDS Clinical Trial Group criteria revealed that patients with the S1 disease stage have a significantly higher proportion of NKG2C+ cells than those with the S0 disease stage. NKG2C+ cells from S1-stage patients are highly enriched for the expression of KIR3DL1, are depleted of NKp46, and respond poorly to major histocompatibility complex class I-positive target cells. These data demonstrate a link between NK cell phenotype and function and disease prognosis in AIDS.
 ...
PMID:NKG2C+ NK cells are enriched in AIDS patients with advanced-stage Kaposi's sarcoma. 1703 8

In HIV-1 infection, the synergistic association of a subset of Bw4 MHC class I molecules and the activating killer inhibitory receptor (KIR), KIR3DS1, with prolonged AIDS-free survival has been reported. As KIRs represent a diverse group of MHC class I receptors, we questioned whether Bw4 MHC class I molecules expressing isoleucine at position 80 (Bw4Ile80) and in complex with HIV-1-derived T cell epitopes represented KIR3DS1 ligands. MHC class I tetramers are powerful tools for the detection of T cell receptor-MHC class I interactions, and have recently been used to evaluate KIR-MHC class I binding ex vivo. Specifically, this approach has been successfully utilized to assess binding of Bw4 MHC class I tetramers to KIR3DL1, an inhibitory KIR and allele of KIR3DS1. In this study we generated a diverse panel of HIV-1-specific Bw4Ile80 MHC class I tetramers and tested its ability to bind transiently expressed KIR3DS1 on 293-T cells. Using flow cytometry analysis, the expression of KIR3DS1 on 293-T cells was confirmed by anti-FLAG BioM2 staining, prior to incubation with PE-conjugated MHC class I tetramers. Despite choosing a broad array of peptide epitopes and diverse Bw4Ile80 MHC class I molecules, we were unable to detect tetramer binding to KIR3DS1. We speculate that our negative finding may be a consequence of the MHC class I molecules and peptide epitopes chosen, but could also relate to key amino acid differences that distinguish KIR3DS1 from KIR3DL1.
AIDS Res Hum Retroviruses 2007 Mar
PMID:Lack of KIR3DS1 binding to MHC class I Bw4 tetramers in complex with CD8+ T cell epitopes. 1741 78

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.
 ...
PMID:Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. 1753 64

KIR3DL1 is a highly polymorphic killer cell Ig-like receptor gene with at least 23 alleles described, including its activating counterpart, KIR3DS1. Recently, the KIR3DS1 allele has been shown to slow progression to AIDS in individuals expressing HLA-Bw4 with isoleucine at position 80. However, due to the lack of a specific Ab, KIR3DS1 expression and function is not well characterized. In this study, we demonstrate KIR3DS1 expression on a substantial subset of peripheral natural killer cells through its recognition by the mAb Z27. The fidelity of this detection method was confirmed by analysis of KIR3DS1 transfectants and the identification of a novel KIR3DS1 null allele. Interestingly, KIR3DS1 is also expressed by a small proportion of CD56(+) T cells. We show that ligation of KIR3DS1 by Z27 leads to NK cell IFN-gamma production and degranulation as assessed by expression of CD107a. Furthermore, we document the persistence of KIR3DS1(+) NK cells in HIV-1 viremic patients. The high frequency of KIR3DS1 expression, along with its ability to activate NK cells, and its maintenance during HIV-1 viremia are consistent with the epidemiological data suggesting a critical role for this receptor in controlling HIV-1 pathogenesis.
 ...
PMID:Detection of KIR3DS1 on the cell surface of peripheral blood NK cells facilitates identification of a novel null allele and assessment of KIR3DS1 expression during HIV-1 infection. 1764 Oct 29

Natural killer (NK) cells play an important role in the detection and elimination of tumors and virus-infected cells by the innate immune system. Human NK cells use cell surface receptors (KIR) for class I MHC to sense alterations of class I on potential target cells. Individual NK cells only express a subset of the available KIR genes, generating specialized NK cells that can specifically detect alteration of a particular class I molecule or group of molecules. The probabilistic behavior of human KIR bi-directional promoters is proposed to control the frequency of expression of these variegated genes. Analysis of a panel of donors has revealed the presence of several functionally relevant promoter polymorphisms clustered mainly in the inhibitory KIR family members, especially the KIR3DL1 alleles. We demonstrate for the first time that promoter polymorphisms affecting the strength of competing sense and antisense promoters largely explain the differential frequency of expression of KIR3DL1 allotypes on NK cells. KIR3DL1/S1 subtypes have distinct biological activity and coding region variants of the KIR3DL1/S1 gene strongly influence pathogenesis of HIV/AIDS and other human diseases. We propose that the polymorphisms shown in this study to regulate the frequency of KIR3DL1/S1 subtype expression on NK cells contribute substantially to the phenotypic variation across allotypes with respect to disease resistance.
 ...
PMID:Genetic control of variegated KIR gene expression: polymorphisms of the bi-directional KIR3DL1 promoter are associated with distinct frequencies of gene expression. 1900 43

Natural killer (NK) cells are believed to play a role in human immunodeficiency virus 1 (HIV-1) disease progression, and NK cell levels are reduced in individuals with chronic HIV-1 infection. In the present study, we compared the frequency and phenotype of peripheral blood CD3-CD56+ NK cells in HIV-1 infected patients in China who were infected through different routes of transmission, including heterosexual and homosexual sexual contact, and blood transmission through injection drug use or importation of blood or blood products. The results showed significantly reduced numbers of CD3-CD56+ NK cells with no association with route of transmission. The expression of CD16 on CD3-CD56+ NK cells in HIV-1 infected patients was similar to that in healthy controls. Among the examined receptor (KIR3DL1, NKp80, NKp44, CD244, NKG2D, and NTBA) expressions, only KIR3DL1 and NKp80 expressions on CD3-CD56+ NK cells were suppressed in HIV-1-infected patients compared to healthy controls, and no significant difference was observed between patients upon comparison of different routes of transmission. A subset of CD3(dim)/CD56+ cells was dramatically increased in HIV-1-infected patients. This study suggests that changes in NK cell count and receptors are not related to the route of HIV-1 transmission. A new subset of CD3(dim)/CD56+ cells emerged only in HIV-1-infected patients, and may play a role in limiting viral spread, eliminating infected cells, and slowing the progression from HIV-1 infection to AIDS.
 ...
PMID:Changes in NK cell counts and receptor expressions and emergence of CD3(dim)/CD56+ cells in HIV-1 infected patients in China. 1932 97

Epidemiological studies in humans have implicated carriage of combinations of genes encoding certain KIR3DL1 (killer Ig-like receptor 3DL1) alleles and their HLA-Bw4 ligands in slower progression to AIDS, lower viral load and protection from infection. Given that the KIR3DL1*h/*y/HLA-B*57 genetic combination is strongly associated with favorable HIV outcomes, we measured responses from NK cells isolated from these individuals by multiparametric flow cytometry for cytokine secretion and degranulation in response to stimulation with HLA-devoid cells to assess whether the KIR/HLA compound genotypes linked to better HIV outcome favor increased NK cell functional potential. Our results indicate that NK cells from these individuals had increased functional potential, particularly in the KIR3DL1(+) NK cell subset. These results support a link between KIR/HLA genotypes and NK cell function and could provide an explanation for the observation that some KIR/HLA combinations are associated protective phenotypes in the context of host-HIV interactions.
 ...
PMID:HIV protective KIR3DL1 and HLA-B genotypes influence NK cell function following stimulation with HLA-devoid cells. 2006 7

Natural killer (NK) cells are believed to play a role in the progression of human immunodeficiency virus 1 (HIV-1) disease, and NK cell levels are reduced in individuals with chronic HIV-1 infection. To assess the effects on quantity of NK cells and the changes of NK cell receptors in HIV-1 infected children via mother-to-child transmission, the percentage of NK cells is quantified and the changes in the NK cell receptor profiles in 20 HIV-1 infected children who are not progressing into AIDS were examined. The results showed that NK cell percentage was decreased in the HIV-1 infected children. The expression of NKp30 on NK cells was increased, while the expressions of CD16, NKp44, NKp46, NKp80, NTB-A, CD244, KIR2D, KIR3DL1 and NKG2D on NK cells were decreased in the HIV-1 infected children. NK cell cytolytic activity was elevated in HIV-1 infected children. These results indicate that the acute changes in NK cell percentage and NK cell receptors in HIV-1 infected children are different from the HIV-1 infected adult individuals. Moreover, serum concentrations of IL-18 were elevated in HIV-infected children compared to HIV-uninfected controls. These differences probably play a role in protecting against transmission of maternal HIV-1 virus and guiding the therapeutic strategies for HIV-1 infected children.
 ...
PMID:Differences in natural killer cell quantification and receptor profile expression in HIV-1 infected Chinese children. 2067 58


1 2 3 Next >>