Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple mechanisms are used by the human immunodeficiency virus type 1 (HIV-1) to interfere with host-cell immune effector functions. The 27-kD Nef protein has been shown to down-modulate specific genes of the major histocompatibility complex class I (MHC-I) on the surface of infected primary T cells, facilitating their escape from lysis by cytolytic T lymphocytes. Macrophages, as the other major immune cell type targeted by the virus, also contribute to the transmission, persistence, and pathogenesis of HIV-1. Yet, whether Nef modulates MHC-I expression on HIV-infected primary macrophages remains unclear. Currently available infectious HIV-1 molecular clones, which express a reporter gene, only infect T cells and/or do not express Nef. To overcome these limitations, we generated macrophage-tropic green fluorescent protein (GFP)-tagged HIV-1 viruses, which express the complete viral genome, and used these to assess the expression of human leukocyte antigen (HLA)-A2 on the surface of productively infected macrophages. The reporter viral genomes were replication-competent and stable, as Nef, p24 antigen, and GFP expression could be detected by immunostaining of infected, monocyte-derived macrophages (MDM) after more than 2 months postinfection. Fluorescence-activated cell sorter analyses of infected macrophages and T cells revealed that although wild-type reporter virus infection induced a statistically significant decrease in the density of surface HLA-A2, down-regulation of HLA-A2 was not seen in cells infected with reporter viruses encoding a frameshift or a single point mutation in Nef at prolines 74P and P80. The impact of Nef on HLA-A2 surface expression in MDM was also confirmed by confocal microscopy. These results suggest that the mechanisms of HLA-A2 down-modulation are similar in primary T cells and macrophages.
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PMID:HLA-A2 down-regulation on primary human macrophages infected with an M-tropic EGFP-tagged HIV-1 reporter virus. 1600 Mar 90

HIV-specific cytotoxic T lymphocyte (CTL) responses mediated by human leukocyte antigen (HLA) recognition and antiretroviral drugs exert selection pressure on HIV-1 in vivo. The selection of CTL escape mutations strongly underpins the failure of CTL control in most untreated infections whilst drug-resistance mutations predict failure of drug control. These two evolutionary forces share common target residues in HIV-1 at which their selection effects could be synergistic or antagonistic, such that the propensity to develop drug resistance and virological treatment failure may be influenced by HLA type. We examined HIV-1 reverse transcriptase (RT) and protease sequences in a large clinical observational cohort of 487 HIV-infected individuals and found evidence of site-specific interactions between specific antiretroviral drug exposures, HLA alleles and HIV sequence diversity at population level. Such interactions may have general and specific implications for explaining in vivo/in vitro discordance of drug resistance, host-specific susceptibility to drug resistance, individualization of therapy and therapeutic vaccine design.
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PMID:Interactive selective pressures of HLA-restricted immune responses and antiretroviral drugs on HIV-1. 1603 81

Southern Africa is facing an unprecedented public health crisis due to the high prevalence of human immunodeficiency virus type 1 (HIV-1). Vaccine development and testing efforts, mainly based on elicitation of HIV-specific T cells, are under way. To understand the role of human leukocyte antigen (HLA) class II alleles in HIV pathogenesis and to facilitate HLA-based HIV-1 vaccine design, we analyzed the frequencies of HLA class II alleles within the southern African country of Botswana. Common HLA class II alleles were identified within the Botswana population through the molecular genotyping of DRB and DQB1 loci. The DRB1 allele groups DRB1*01, DRB1*02/15, DRB1*03, DRB1*11, and DRB1*13 were encountered at frequencies above 20%. Within the DQB1 locus, DQB1*06 (47.7%) was the most common allele group, followed by DQB1*03 (39.2%) and DQB1*04 (25.8%). We found that DRB1*01 was more common in HIV-negative than in HIV-positive individuals and that those who expressed DRB1*08 had lower median viral loads. We demonstrate that the frequencies of certain HLA class II alleles in this Botswana population differ substantially from those in North American populations, including African-Americans. Common allele groups within Botswana cover large percentages of other African populations and could be targeted in regional vaccine designs.
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PMID:Major histocompatibility complex class II (HLA-DRB and -DQB) allele frequencies in Botswana: association with human immunodeficiency virus type 1 infection. 1614 66

Epitopes in HIV polymerase were analyzed by peptide binding to human leukocyte antigen (HLA) A0201 molecules, the most frequent HLA class in the Caucasian population. We found that HIV-1 protease peptides representing both the wild type and anticipated drug resistance variants of the sequence bound well to HLA-A0201. We also found that wild type as well as a double mutated variant of the epitope was strongly immunogenic in HLA-A0201 transgenic mice, either as individual peptides or encoded in DNA multi-CTL epitope constructs. Immunological cross-reactivity between different variants of the peptide could be seen, suggesting that it may be possible to induce a broad immune response by immunizing with drug resistance-mutated epitopes. This may be of advantage for HIV-1 infected patients since such a response may cause a better outcome of an anti-retroviral drug therapy.
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PMID:Immunological cross-reactivity against a drug mutated HIV-1 protease epitope after DNA multi-CTL epitope construct immunization. 1618 10

Squamous cell carcinomas of the oropharynx (SCCO) are often infected with oncogenic human papilloma virus (HPV) subtype 16. To determine the frequency of T cells specific for human leukocyte antigen (HLA)-A2.1 restricted HPV16 E7 protein-derived epitopes, tetramer analysis was performed using peripheral blood lymphocytes of 20 HLA-A2.1+ patients and 20 HLA-A2.1+ healthy individuals. Tetramers specific for 3 HPV16 peptides (E711-20, E782-90 and E786-93), an influenza matrix peptide (a model recall antigen) or an HIV reverse transcriptase peptide (a model novel antigen) were used in multicolor flow analysis. The HPV-specific T-cell frequencies were correlated with the HPV16 E7 and p16 status in tumor sections. In vitro stimulation (IVS) with autologous dendritic cells (DC) pulsed with HPV16 E7 epitopes was performed to demonstrate proliferation and antitumor activity of the HPV-responsive T cells. Frequencies of CD8+ T cells specific for HPV16 E7 peptides were not significantly different in patients with SCCO relative to normal donors. However, patients with tumors expressing HPV16 E7 (60%) and p16 (50%) had an increased frequency (p<0.05) of T cells specific for the E711-20 epitope compared to those with tumors negative for both markers. HPV16 E711-20 and HPV16 E786-93 specific T cells were expandable upon IVS with cognate peptide-pulsed DC and were reactive against peptide-pulsed targets or, in case of the E711-20 epitope-specific T cells, against HPV16 E7 expressing CaSki cell line. Thus, in patients with HPV16+ SCCO, precursor T cells specific for E711-20 epitope are present (1/3,947) in the circulation, are responsive to stimulation with the cognate viral peptide and recognize in vitro HPV16 E7+ tumor cells. Further studies have to elucidate why those T cells are unable to eliminate the tumor in vivo and this might also allow for finding potential strategies that will increase the chances of developing a future HPV-based vaccine in patients with SCCO.
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PMID:T cells specific for HPV16 E7 epitopes in patients with squamous cell carcinoma of the oropharynx. 1628 59

The human immunodeficiency virus type 1 (HIV-1) epidemic in China is increasing rapidly at an irrepressible rate. It is caused by HIV-1 subtype B' in central China. After the full-length genome sequencing of the Henan isolate was performed, the definition of optimal cytotoxic T-lymphocyte (CTL) epitopes across the Henan isolate genome has become crucial for vaccine design. In this study, by using ELISPOT assays with synthetic peptides corresponding to the sequence of the Henan isolate, the identification and analysis of Gag-specific CTL responses among 28 treated and 26 untreated infected paid blood donors (PBDs) from the Henan and Hubei provinces of China are presented. These studies focused on CTL responses restricted by the human leukocyte antigen (HLA)-A2 and -A11 molecules, two of the most prominent HLA-A alleles in the Chinese population. The results suggested that, in the subgroup analysis, the magnitude of response in the infected treated subgroup [median, 93 spot-forming cells (SFCs) per 10(6) peripheral blood mononuclear cells (PBMCs)] was significantly lower than that in the chronically infected untreated subgroup (median, 221 SFCs per 10(6) PBMCs), and HLA-A2-restricted treated PBDs had a response of a much higher frequency and magnitude than that of HLA-A11-restricted treated PBDs. Moreover, some novel peptides restricted by the HLA-A2 and -A11 molecules were identified.
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PMID:Screening for CD8 cytotoxic T lymphocytes specific for Gag of human immunodeficiency virus type 1 subtype B' Henan isolate from China and identification of novel epitopes restricted by the HLA-A2 and HLA-A11 alleles. 1636 27

Most HIV-1-infected individuals progress to AIDS within 8 to 10 years after seroconversion. Less than 5% of them, however, remain asymptomatic, although their CD4 T-cell counts stay normal. In this study, our polymerase chain reaction sequence-specified primer (PCR-SSP) based human leukocyte antigen (HLA)-B genotyping of 28 typical progressors (TPs) and 15 long-term nonprogressors (LTNPs) revealed some evidence that an HLA-B locus polymorphism can influence the rate of disease progression in Chinese HIV-1-infected individuals: 12 of 28 TPs (43%) were HLA-Bw6 homozygotes. Only 1 of 15 LTNPs (6.7%) was homozygous for the polymorphism (P = 0.013), suggesting that HLA-Bw6 homozygosity is associated with accelerated disease progression. In contrast, 3 of 15 LTNPs (20%) were HLA-Bw4 homozygotes, whereas none of the 28 TPs were homozygotes (P = 0.037), supporting the conclusion that HLA-Bw4 homozygosity may have a protective role. Interestingly, the frequency of the HLA-B*15 allele was extremely high in the TP group (23.2%), which may be associated with faster disease progression in Chinese patients.
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PMID:Accelerating effect of human leukocyte antigen-Bw6 homozygosity on disease progression in Chinese HIV-1-infected patients. 1639 43

Clinical and subclinical human papillomavirus (HPV) infections are the most common sexually transmitted infections in the world, and most sexually-active individuals are likely to be exposed to HPV infection during their lifetimes. More than 40 genotypes of HPV infect the epithelial lining of the anogenital tract and other mucosal areas of the body; of these, 13-18 types are considered to be high-oncogenic risk HPV types (HR-HPV). Persistent infection with HR-HPVs is now unequivocally established as a necessary cause of cervical cancer and is likely to be responsible for a substantial proportion of other anogenital neoplasms and upper aero-digestive tract cancers. Low oncogenic risk HPV types (LR-HPV) are also responsible for considerable morbidity as the cause of genital warts. Youth and certain sexual characteristics are key risk factors for HPV acquisition and persistence of HPV infection, but other mediating factors include smoking, oral contraceptive (OC) use, other STIs (e.g. chlamydia, herpes simplex virus), chronic inflammation, immunosuppressive conditions including HIV infection, parity, dietary factors, and polymorphisms in the human leukocyte antigen system. Not surprisingly, these factors are also established or candidate cofactors identified in epidemiologic studies of cervical cancer. HPV transmissibility and molecular events in HPV-induced carcinogenesis have been the focus of recent multidisciplinary epidemiologic studies. This shift in research focus coincides with a shift in cancer prevention techniques towards immunization with HPV vaccines and HPV testing of precancerous lesions.
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PMID:The epidemiology of genital human papillomavirus infection. 1640 26

Understanding the role of cytotoxic T lymphocytes (CTLs) in controlling HIV-1 infection is vital for vaccine design. However, it is difficult to assess the importance of CTLs in natural infection. Different human leukocyte antigen (HLA) class I alleles are associated with different rates of progression to AIDS, indicating that CTLs play a protective role. Yet virus clearance rates following antiretroviral therapy are not impaired in individuals with advanced HIV disease, suggesting that weakening of the CTL response is not the major underlying cause of disease progression and that CTLs do not have an important protective role. Here we reconcile these apparently conflicting studies. We estimate the selection pressure exerted by CTL responses that drive the emergence of immune escape variants, thereby directly quantifying the efficiency of HIV-1-specific CTLs in vivo. We estimate that only 2% of productively infected CD4+ cell death is attributable to CTLs recognising a single epitope. We suggest that CTLs kill a large number of infected cells (about 10(7)) per day but are not responsible for the majority of infected cell death.
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PMID:Inefficient cytotoxic T lymphocyte-mediated killing of HIV-1-infected cells in vivo. 2007 53

Human immunodeficiency virus type 1 (HIV-1) genetic diversity is a major obstacle for the design of a successful vaccine. Certain viral polymorphisms encode human leukocyte antigen (HLA)-associated immune escape, potentially overcoming limited vaccine protection. Although transmission of immune escape variants has been reported, the overall extent to which this phenomenon occurs in populations and the degree to which it contributes to HIV-1 viral evolution are unknown. Selection on the HIV-1 env gene at transmission favors neutralization-sensitive variants, but it is not known to what degree selection acts on the internal HIV-1 proteins to restrict or enhance the transmission of immune escape variants. Studies have suggested that HLA class I may determine susceptibility to HIV-1 infection, but a definitive role for HLA at transmission remains unproven. Comparing populations of acute seroconverters and chronically infected patients, we found no evidence of selection acting to restrict transmission of HIV-1 variants. We found that statistical associations previously reported in chronic infection between viral polymorphisms and HLA class I alleles are not present in acute infection, suggesting that the majority of viral polymorphisms in these patients are the result of transmission rather than de novo adaptation. Using four episodes of HIV-1 transmission in which the donors and recipients were both sampled very close to the time of infection we found that, despite a transmission bottleneck, genetic variants of HIV-1 infection are transmitted in a frequency-dependent manner. As HIV-1 infections are seeded by unique donor-adapted viral variants, each episode is a highly individual antigenic challenge. Host-specific, idiosyncratic HIV-1 antigenic diversity will seriously tax the efficacy of immunization based on consensus sequences.
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PMID:Passive sexual transmission of human immunodeficiency virus type 1 variants and adaptation in new hosts. 1680 28


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