Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HLA-B57 has been shown to be strongly associated with slow disease progression in human immunodeficiency virus type 1 (HIV-1)-infected patients from the Amsterdam Cohort. Since HIV-1-specific CTL can control and eliminate virus-infected cells, we sought to characterize the dominant HLA-B57-restricted CTL responses at the epitope level. It was found that HLA-B57-restricted CTL responses were targeted at multiple proteins of HIV-1, with CTL specific for Gag and RT being the most pronounced. Gag-specific CTL recognized peptides ISPRTLNAW (aa 147-155) and STLQEQIGW (aa 241-249), which had previously been reported as HLA-B57-restricted. The RT-specific CTL response in one long-term survivor studied in great detail persisted for > 10 years and was dominated by HLA-B57-restricted CTL that recognized the newly defined epitope IVLPEKDSW (RT(LAI), aa 244-252). This epitope could be recognized in the context of both HLA-B*5701 and HLA-B*5801. Interestingly, three epitope variants of IVLPEKDSW were observed, which coincided with the strongest detectable CTL response to RT. One variant (T2E7) was not recognized by IVLPEKDSW-specific CTL despite the fact that this variant bound to HLA-B*5701 with a similar affinity as the index peptide. Finally, only viruses which contained the epitope index sequence were obtained suggesting efficient virus control by CTL. In conclusion, we report the characterization of dominant HIV-1 Gag- and RT-derived, HLA-B57-restricted CTL epitopes which are associated with longer time to AIDS. Further characterization of CTL responses restricted by HLA-B57 and other protective HLA alleles may contribute to the development of effective AIDS vaccines.
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PMID:Characterization of HLA-B57-restricted human immunodeficiency virus type 1 Gag- and RT-specific cytotoxic T lymphocyte responses. 974 28

A patient with cervical non-Hodgkin lymphoma was treated with chemotherapy. Fourteen months after the diagnosis of the lymphoma, an endometrial adenocarcinoma was detected as a secondary malignant tumor. The patient was treated with surgery followed by radiotherapy. Approximately 7 years after the diagnosis of endometrial cancer, vaginal invasive squamous cell carcinoma was diagnosed as the third primary malignancy, and a second-line palliative radiotherapy was applied. Seven months after the last radiotherapy, postradiational sarcoma in the vagina was diagnosed. Congenital and acquired immune system disorders, viral oncogenes, and various human leukocyte antigen (HLA) types were investigated. Total blood count and lymphocyte subset analysis were performed, and CD4+ lymphopenia was detected. Serologic tests were carried out for human immunodeficiency virus, hepatitis B virus, human papillomavirus, Epstein-Barr virus, and herpes simplex virus infection. Epstein-Barr virus viral capsid antigen IgG was found positive. Low-risk human papillomavirus panel was detected by Hybrid Capture method in the cervical smear. The HLA investigation revealed HLA-A2, HLA-A3, HLA-B57, HLA-B35, HLA-B4, HLA-B6, HLA-DR3, HLA-DR1, HLA-DR51, HLA-DR52, HLA-DQ6(1), and HLA-DQ7(3). The patient died because of the disease.
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PMID:A case with multiple gynecological malignancies. 1582 28

Several HLA class I alleles have been associated with slow human immunodeficiency virus (HIV) disease progression, supporting the important role HLA class I-restricted cytotoxic T lymphocytes (CTL) play in controlling HIV infection. HLA-B63, the serological marker for the closely related HLA-B*1516 and HLA-B*1517 alleles, shares the epitope binding motif of HLA-B57 and HLA-B58, two alleles that have been associated with slow HIV disease progression. We investigated whether HIV-infected individuals who express HLA-B63 generate CTL responses that are comparable in breadth and specificity to those of HLA-B57/58-positive subjects and whether HLA-B63-positive individuals would also present with lower viral set points than the general population. The data show that HLA-B63-positive individuals indeed mounted responses to previously identified HLA-B57-restricted epitopes as well as towards novel, HLA-B63-restricted CTL targets that, in turn, can be presented by HLA-B57 and HLA-B58. HLA-B63-positive subjects generated these responses early in acute HIV infection and were able to control HIV replication in the absence of antiretroviral treatment with a median viral load of 3,280 RNA copies/ml. The data support an important role of the presented epitope in mediating relative control of HIV replication and help to better define immune correlates of controlled HIV infection.
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PMID:HLA-B63 presents HLA-B57/B58-restricted cytotoxic T-lymphocyte epitopes and is associated with low human immunodeficiency virus load. 1605 15

Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcomes for individuals infected with human immunodeficiency virus type 1 (HIV-1), but the mechanisms for their effects remain undefined. An early CD8(+) T-cell escape mutation in the dominant HLA-B57-restricted Gag epitope TW10 (TSTLQEQIGW) has been shown to impair HIV-1 replication capacity in vitro. We demonstrate here that this T(242)N substitution in the capsid protein is associated with upstream mutations at residues H(219), I(223), and M(228) in the cyclophilin A (CypA)-binding loop in B57(+) individuals with progressive disease. In an independent cohort of epidemiologically linked transmission pairs, the presence of these substitutions in viruses encoding T(242)N was associated with significantly higher plasma viremia in donors, further suggesting that these secondary mutations compensated for the replication defect of T(242)N. Using NL4-3 constructs, we illustrate the ability of these CypA loop changes to partially restore replication of the T(242)N variant in vitro. Notably, these mutations also enhanced viral resistance to the drug cyclosporine A, indicating a reduced dependence of the compensated virus on CypA that is normally essential for optimal infectivity. Therefore, mutations in TW10 allow HIV-1 to evade a dominant early CD8(+) T-cell response, but the benefits of escape are offset by a defect in capsid function. These data suggest that TW10 escape variants undergo a postentry block that is partially overcome by changes in the CypA-binding loop and identify a mechanism for an HIV-1 fitness defect that may contribute to the slower disease progression associated with HLA-B57.
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PMID:Escape and compensation from early HLA-B57-mediated cytotoxic T-lymphocyte pressure on human immunodeficiency virus type 1 Gag alter capsid interactions with cyclophilin A. 1772 32

The human leukocyte antigen (HLA) B57 allele and the closely related HLA-B5801 allele are overrepresented among human immunodeficiency virus type 1 (HIV-1)-infected individuals with a long-term nonprogressive clinical course of disease (known as "long-term nonprogressors" [LTNPs]). These alleles are, however, also present among individuals with normal disease progression (known as "progressors"). In a comparison of HLA-B57/5801-expressing progressors and LTNPs, we observed a similar prevalence of escape mutations in 4 Nef epitopes and a similar reactivity of CD8+ T cells against 3 of 4 of these epitopes and their autologous escape variants. However, LTNPs tended to have frequent and preserved CD8+ T cell interferon-gamma responses against the wild-type HW9 Nef epitope, whereas progressors did not maintain a specific CD8+ T cell response. This finding is in line with the findings of a more exhausted phenotype of CD8+ T cells in progressors, as is demonstrated by their enhanced level of expression of inhibitory receptor "programmed death 1" (PD-1). The results of the present study suggest that preservation of HW9-specific T cell responses is associated with a more benign clinical course of infection.
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PMID:A nonprogressive clinical course in HIV-infected individuals expressing human leukocyte antigen B57/5801 is associated with preserved CD8+ T lymphocyte responsiveness to the HW9 epitope in Nef. 1827 72

Despite reports of viral genetic defects in persons who control human immunodeficiency virus type 1 (HIV-1) in the absence of antiviral therapy, the extent to which such defects contribute to the long-term containment of viremia is not known. Most previous studies examining for such defects have involved small numbers of subjects, primarily focused on subjects expressing HLA-B57, or have examined single viral genes, and they have focused on cellular proviral DNA rather than plasma viral RNA sequences. Here, we attempted viral sequencing from 95 HIV-1 elite controllers (EC) who maintained plasma viral loads of <50 RNA copies/ml in the absence of therapy, the majority of whom did not express HLA-B57. HIV-1 gene fragments were obtained from 94% (89/95) of the EC, and plasma viral sequences were obtained from 78% (61/78), the latter indicating the presence of replicating virus in the majority of EC. Of 63 persons for whom nef was sequenced, only three cases of nef deletions were identified, and gross genetic defects were rarely observed in other HIV-1 coding genes. In a codon-by-codon comparison between EC and persons with progressive infection, correcting for HLA bias and coevolving secondary mutations, a significant difference was observed at only three codons in Gag, all three of which represented the historic population consensus amino acid at the time of infection. These results indicate that the spontaneous control of HIV replication is not attributable to shared viral genetic defects or shared viral polymorphisms.
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PMID:Genetic characterization of human immunodeficiency virus type 1 in elite controllers: lack of gross genetic defects or common amino acid changes. 1856 30

Expression of HLA-B57 is associated with restricted replication of human immunodeficiency virus (HIV), but the mechanism for its protective effect remains unknown. If this advantage depends upon CD8 T-cell recognition of B57-restricted epitopes, mother-to-child transmission of escape mutations within these epitopes could nullify its protective effect. However, if the B57 advantage is largely mediated by selection for fitness-attenuating viral mutations within B57-restricted epitopes, such as T242N in TW10-Gag, then the transmission of such mutations could facilitate viral control in the haploidentical infant. We assessed the consequences of B57-associated mutations on replication capacity, viral control, and clinical outcome after vertical transmission in 13 mother-child pairs. We found that expression of HLA-B57 was associated with exceptional control of HIV during infancy, even when mutations within TW10 and most other B57-restricted epitopes were transmitted, subverting the natural immunodominance of HLA-B57. In contrast, most B57-negative infants born to B57-positive mothers progressed rapidly to AIDS. The presence of T242N led to a reproducible reduction in viral fitness, as demonstrated by in vitro assays using NL4-3 constructs encoding p24 sequences from individual mothers and infants. Associated compensatory mutations within p24-Gag were observed to reverse this impairment and to influence the propensity of T242N to revert after transmission to B57-negative hosts. Moreover, primary failure to control viremia was observed in one infant to whom multiple compensatory mutations were transmitted along with T242N. These parallel in vivo and in vitro data suggest that HLA-B57 confers its advantage primarily by driving and maintaining a fitness-attenuating mutation in p24-Gag.
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PMID:Maternal transmission of human immunodeficiency virus escape mutations subverts HLA-B57 immunodominance but facilitates viral control in the haploidentical infant. 1951 64

Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals ('elite controllers') maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8(+) T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.
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PMID:Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection. 2051 67

Epidemiological studies have shown the protective effect of KIR3DL1/HLA-Bw4 genotypes in human immunodeficiency virus type 1 (HIV-1) infection; however, the functional correlates for the protective effect remain unknown. We investigated whether human leukocyte antigen (HLA)-Bw4-presented HIV-1 peptides could affect the interaction between the inhibitory natural killer (NK) cell receptor KIR3DL1 and its ligand HLA-Bw4. Distinct HIV-1 epitopes differentially modulated the binding of KIR3DL1 to HLA-Bw4. Furthermore, cytotoxic T lymphocyte (CTL) escape mutations within the immunodominant HLA-B57 (Bw4)-restricted Gag epitope TSTLQEQIGW abrogated KIR3DL1 binding to HLA-B57, suggesting that sensing of CTL escape variants by NK cells can contribute to the protective effect of the KIR3DL1/HLA-Bw4 compound genotype.
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PMID:Common HIV-1 peptide variants mediate differential binding of KIR3DL1 to HLA-Bw4 molecules. 2147 Dec 46

The human leukocyte antigens HLA-B27 and HLA-B57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B27 and HLA-B57 are unable to control HIV-1. Here we found that HLA-B27-restricted CD8(+) T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B57-restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.
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PMID:TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection. 2271 21


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