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)

Human immunodeficiency virus type 1 can occasionally be detected as a cryptic or latent infection in seronegative, asymptomatic patients. To develop an animal model of host latency, cats were mucosally challenged with 10(2)-10(6) feline immunodeficiency virus (FIV)-infected T cells. Although high-dose exposure (10(4)-10(6) T cells) resulted in progressive infection, no evidence of infection was seen in 5 of 6 cats exposed to 10(2) or 10(3) T cells. However, after ex vivo CD8(+) T cell depletion and phorbol myristate acetate treatment, FIV could be reactivated in tissues from 4 cats. Thus, latent tissue viral reservoirs can be induced by low-dose cell-associated mucosal challenge, providing a model to dissect the mechanisms that control reservoir establishment.
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PMID:Mucosal administration of low-dose cell-associated feline immunodeficiency virus promotes viral latency. 1735 56

Human immunodeficiency virus type 1 (HIV) infection is characterized by progressive immunodeficiency despite of an overwhelming cellular immune activation. Patients show highly elevated serum/plasma concentrations of the proinflammatory cytokine interferon-gamma (IFN-gamma), which induces human monocytes to form neopterin, to produce reactive oxygen species (ROS) and in parallel, to degrade tryptophan. Enhanced tryptophan degradation by the enzyme indoleamine-2, 3-dioxygenase (IDO) contributes importantly to disease progression and "complications" of HIV infection: By a subsequent impairment of protein metabolism and serotonin formation, the development of neuropsychiatric disorders and weight loss in HIV infected patients can be enforced. Furthermore, increased IDO-activation efficiently suppresses the growth and proliferation of pathogens as well as host T-cells. IDO and other IFN-gamma-mediated pathways are strongly induced in patients with HIV infection and are also linked with disease progression: Neopterin formation by GTP-cyclohydrolase I sensitively reflects the stage of the disease, and determination of the pteridine in body fluids is useful to monitor the efficacy of antiretroviral therapy. Neopterin is an independent prognostic factor for the outcome of disease, and well suited to estimate the degree of immune activation in vivo and the responsiveness of immunocompetent cells to stimulation in vitro. ROS formation may contribute to the development of oxidative stress in HIV infection, resulting in depletion of antioxidants. The cause-effective role of an overwhelming Th1-type immune response together with the activation of IDO and other IFN-gamma-mediated biochemical pathways for the course of HIV infection, the development of immunodeficiency, anemia and weight loss in HIV patients is discussed.
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PMID:Indoleamine-2, 3-dioxygenase and other interferon-gamma-mediated pathways in patients with human immunodeficiency virus infection. 1743 Jan 11

Human immunodeficiency virus type 1 (HIV-1) originated from three independent cross-species transmissions of simian immunodeficiency virus (SIVcpzPtt) infecting chimpanzees (Pan troglodytes troglodytes) in west central Africa, giving rise to pandemic (group M) and non-pandemic (groups N and O) clades of HIV-1. To identify host-specific adaptations in HIV-1 we compared the inferred ancestral sequences of HIV-1 groups M, N and O to 12 full length genome sequences of SIVcpzPtt and four of the outlying but closely related SIVcpzPts (from P. t. schweinfurthii). This analysis revealed a single site that was completely conserved among SIVcpzPtt strains but different (due to the same change) in all three groups of HIV-1. This site, Gag-30, lies within p17, the gag-encoded matrix protein. It is Met in SIVcpzPtt, underwent a conservative replacement by Leu in one lineage of SIVcpzPts but changed radically to Arg on all three lineages leading to HIV-1. During subsequent diversification this site has been conserved as a basic residue (Arg or Lys) in most lineages of HIV-1. Retrospective analysis revealed that Gag-30 had reverted to Met in a previous experiment in which HIV-1 was passaged through chimpanzees. To examine whether this substitution conferred a species specific growth advantage, we used site-directed mutagenesis to generate variants of these chimpanzee-adapted HIV-1 strains with Lys at Gag-30, and tested their replication in both human and chimpanzee CD4+ T lymphocytes. Remarkably, viruses encoding Met replicated to higher titers than viruses encoding Lys in chimpanzee T cells, but the opposite was found in human T cells. Taken together, these observations provide compelling evidence for host-specific adaptation during the emergence of HIV-1 and identify the viral matrix protein as a modulator of viral fitness following transmission to the new human host.
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PMID:Adaptation of HIV-1 to its human host. 1754 88

Human immunodeficiency virus type 1 (HIV-1) and HIV-2 are genetically distinct viruses that each can cause AIDS. Approximately 1 million people are infected with both HIV-1 and HIV-2. Additionally, these two viruses use the same receptor and coreceptors and can therefore infect the same target cell populations. To explore potential genetic interactions, we first examined whether RNAs from HIV-1 and HIV-2 can be copackaged into the same virion. We used modified near-full-length viruses that each contained a green fluorescent protein gene (gfp) with a different inactivating mutation. Thus, a functional gfp could be reconstituted via recombination, which was used to detect the copackaging of HIV-1 and HIV-2 RNAs. The GFP-positive (GFP(+)) phenotype was detected in approximately 0.2% of the infection events, which was 35-fold lower than the intrasubtype HIV-1 rates. We isolated and characterized 54 GFP(+) single-cell clones and determined that all of them contained proviruses with reconstituted gfp. We then mapped the general structures of the recombinant viruses and characterized the recombination junctions by DNA sequencing. We observed several different recombination patterns, including those that had crossovers only in gfp. The most common hybrid genomes had heterologous long terminal repeats. Although infrequent, crossovers in the viral sequences were also identified. Taken together, our study demonstrates that HIV-1 and HIV-2 can recombine, albeit at low frequencies. These observations indicate that multiple factors are likely to restrict the generation of viable hybrid HIV-1 and HIV-2 viruses. However, considering the large coinfected human population and the high viral load in patients, these rare events could provide the basis for the generation of novel human immunodeficiency viruses.
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PMID:Genetic recombination between human immunodeficiency virus type 1 (HIV-1) and HIV-2, two distinct human lentiviruses. 1805 56

Human immunodeficiency virus type 1 (HIV-1) Nef downregulates HLA-A and -B molecules, but not HLA-C or -E molecules, based on amino acid differences in their cytoplasmic domains to simultaneously evade cytotoxic T lymphocyte (CTL) and natural killer cell surveillance. Rhesus macaques and sooty mangabeys express orthologues of HLA-A, -B, and -E, but not HLA-C, and many of these molecules have unique amino acid differences in their cytoplasmic tails. We found that these differences also resulted in differential downregulation by primary simian immunodeficiency virus (SIV) SIV(smm/mac) and HIV-2 Nef alleles. Thus, selective major histocompatibility complex class I downregulation is a conserved mechanism of immune evasion for pathogenic SIV infection of rhesus macaques and nonpathogenic SIV infection of sooty mangabeys.
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PMID:Selective downregulation of rhesus macaque and sooty mangabey major histocompatibility complex class I molecules by Nef alleles of simian immunodeficiency virus and human immunodeficiency virus type 2. 1819 57

Deletions in the beta 3-beta 4 hairpin loop of human immunodeficiency virus type 1 reverse transcriptase (RT) are associated with the emergence of multidrug resistance. Common mutational patterns involve the deletion of Asp67 (Delta 67) and mutations such as K70R and T215F or T215Y, or the deletion of Thr69 (Delta 69) and mutations of the Q151M complex. Human immunodeficiency virus type 1 clones containing Delta 69 in a multidrug-resistant sequence background, including the Q151M complex and substitutions K103N, Y181C, M184V, and G190A, showed high-level resistance to all tested nucleoside RT inhibitors. In a multidrug-resistant sequence context, the deletion increases viral replication capacity. By itself, Delta 69 conferred increased susceptibility to beta-d-(+)-3'-azido-3'-deoxythymidine (AZT) and beta-l-(-)-2',3'-dideoxy-3'-thiacytidine resistance. Here, we use transient kinetics to show that, in a wild-type sequence background, Delta 69 does not affect the discrimination between AZT triphosphate and 2'-deoxythymidine 5'-triphosphate, but decreases the catalytic efficiency of the incorporation of beta-l-(-)-2',3'-dideoxy-3'-thiacytidine triphosphate relative to 2'-deoxycytidine 5'-triphosphate. In comparison with the wild-type RT, the Delta 69 mutant showed decreased ability to excise primers terminated with AZT monophosphate in the presence of ATP or pyrophosphate (PPi). These data support the role of the excision mechanism in mediating AZT hypersusceptibility. In addition, we demonstrate that the deletion has no effect on resistance to foscarnet (a PPi analogue) on phenotypic and nucleotide incorporation assays carried out with viral clones and recombinant enzymes, respectively. The results of molecular modeling studies suggest that the side chains of Lys65, Asp67, and Lys219 could play an important role in AZT hypersusceptibility mediated by Delta 69, whereas in the absence of Thr69, local structural rearrangements affecting the beta 3-beta 4 and beta 11a-beta 12 loops of the 66-kDa subunit of the RT could reduce the accessibility of the PPi donor to the terminating nucleotide at the 3' end of the primer.
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PMID:Mechanistic basis of zidovudine hypersusceptibility and lamivudine resistance conferred by the deletion of codon 69 in the HIV-1 reverse transcriptase coding region. 1866 1

Human immunodeficiency virus type 1 and simian immunodeficiency virus possess three closely spaced, highly conserved sites for N-linked carbohydrate attachment in the extracellular domain of the transmembrane protein gp41. We infected rhesus monkeys with a variant of cloned SIVmac239 lacking the second and third sites or with a variant strain lacking all three of SIVmac239's glycosylation sites in gp41. For each mutation, asparagine (N) in the canonical N-X-S/T recognition sequence for carbohydrate attachment was changed to the structurally similar glutamine such that two nucleotide changes would be required for a reversion of the mutated codon. By 16 weeks, experimentally infected monkeys made antibodies that neutralized the mutant viruses to high titers. Such antibodies were not observed in monkeys infected with the parental virus. Thus, new specificities were revealed as a result of the carbohydrate attachment mutations, and antibodies of these specificities had neutralizing activity. Unlike monkeys infected with the parental virus, monkeys infected with the mutant viruses made antibodies that reacted with peptides corresponding to the sequences in this region. Furthermore, there was strong selective pressure for the emergence of variant sequences in this region during the course of infection. By analyzing the neutralization profiles of sequence variants, we were able to define three mutations (Q625R, K631N, and Q634H) in the region of the glycosylation site mutations that conferred resistance to neutralization by plasma from the monkeys infected with mutant virus. Based on the reactivity of antibodies to peptides in this region and the colocalization of neutralization escape mutations, we conclude that N-linked carbohydrates in the ectodomain of the transmembrane protein shield underlying epitopes that would otherwise be the direct targets of neutralizing antibodies.
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PMID:Glycosylation of gp41 of simian immunodeficiency virus shields epitopes that can be targets for neutralizing antibodies. 1882 51

Human immunodeficiency virus type 2 (HIV-2)/simian immunodeficiency virus SIV(SM) Vpx is incorporated into virion particles and is thus present during the early steps of infection, when it has been reported to influence the nuclear import of viral DNA. We recently reported that Vpx promoted the accumulation of full-length viral DNA following the infection of human monocyte-derived dendritic cells (DCs). This positive effect was exerted following the infection of DCs with cognate viruses and with retroviruses as divergent as HIV-1, feline immunodeficiency virus, and even murine leukemia virus, leading us to suggest that Vpx counteracted an antiviral restriction present in DCs. Here, we show that Vpx is required, albeit to a different extent, for the infection of all myeloid but not of lymphoid cells, including monocytes, macrophages, and monocytoid THP-1 cells that had been induced to differentiate with phorbol esters. The intracellular localization of Vpx was highly heterogeneous and cell type dependent, since Vpx localized differently in HeLa cells and DCs. Despite these differences, no clear correlation between the functionality of Vpx and its intracellular localization could be drawn. As a first insight into its function, we determined that SIV(SM)/HIV-2 and SIV(RCM) Vpx proteins interact with the DCAF1 adaptor of the Cul4-based E3 ubiquitin ligase complex recently described to associate with HIV-1 Vpr and HIV-2 Vpx. However, the functionality of Vpx proteins in the infection of DCs did not strictly correlate with DCAF1 binding, and knockdown experiments failed to reveal a functional role for this association in differentiated THP-1 cells. Lastly, when transferred in the context of a replication-competent viral clone, Vpx was required for replication in DCs.
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PMID:Characterization of simian immunodeficiency virus SIVSM/human immunodeficiency virus type 2 Vpx function in human myeloid cells. 1882 61

Human immunodeficiency virus type 2 (HIV-2) emerged following cross-species transmission of simian immunodeficiency virus (SIV) from sooty mangabeys to humans several decades ago. The epidemic groups of HIV-2 have been established in the human population for at least 50 years. However, it is likely that new divergent SIVs can infect humans and lead to new outbreaks. We report the isolation of a new strain of HIV-2, HIV2-NWK08F, from an immunodeficient Sierra Leone immigrant. Health care providers in Sierra Leone and elsewhere need to be alerted that a subtype of HIV-2, which is not detected by PCR for epidemic HIV-2 strains, exists and can lead to immunosuppression.
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PMID:Isolation of a new HIV-2 group in the US. 1901 99

Human immunodeficiency virus type 1 (HIV-1) arose in humans via zoonotic transmissions of simian immunodeficiency viruses (SIV(cpz)) from common chimpanzees, Pan troglodytes. Despite the close relatedness of the two viruses and their hosts, we do not yet understand what causes SIV(cpz) to be nonpathogenic in chimpanzees, and HIV/AIDS to be one of the most devastating infectious diseases to have emerged in humans. There have been a number of genes identified in humans that confer disease resistance/susceptibility toward HIV-1, but little is known about the evolution and diversity of most of these chemokine receptor genes in chimpanzees. Here we show that genetic variation in chimpanzees differs across the various loci related to HIV-1, and that the pattern of variation differs among the chimpanzee subspecies. For all three subspecies, low diversity at CCR5 is confined to a small area of chromosome 3, suggesting that a selective sweep at this locus may have predated subspeciation. In contrast, diversity and neutrality tests suggest differing evolutionary forces among subspecies at CXCR4 and CX(3)CR1, with directional selection (in Pan troglodytes vellerosus) and demographic expansion (Pan troglodytes troglodytes) offering the most likely scenarios. These are some of the first data demonstrating differentiation in functional loci among chimpanzee subspecies.
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PMID:Patterns of diversity in HIV-related loci among subspecies of chimpanzee: concordance at CCR5 and differences at CXCR4 and CX3CR1. 1918 24


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