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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV infection and its outcome is complex because there is great heterogeneity not only in clinical presentation, incomplete clinical information of markers of immunodeficiency and in measurements of viral loads. Also, there many gene variants that control not only viral replication but immune responses to the virus; it has been difficult to study the role of the many AIDS restricting genes (ARGs) because their influence vary depending on the ethnicity of the populations studies and because the cost to follow infected individuals for many years. Nevertheless, at least genes of the major histocompatibility locus (MHC) such as HLA alleles have been informative to classify infected individuals following HIV infection; progression to AIDS and long-term-non-progressors (LTNP). For example, progressors could be defined as up to 5 years, up to 11 years or as we describe in this report up to 15 years from infection, and LTNP could be individuals with normal CD4+ T cell counts for more than 15 years with or without high viral loads. In this review, we emphasized that in the studies of ARGs the HLA alleles are important in LTNP; HLA-B alleles influencing the advantage to pathogens to produce immune defense mediated by CD8+ T cells (cognate immunuity). Our main point we make in this report is that contrary to recent reports claiming that this dominant effect was unlikely due to differences in NK activation through ligands such as HLA-Bw4 motif, we believe that cognate immunity as well as innate immunity conferred by NK cells are involved. The main problem is that HLA-Bw4 alleles can be classified according the aminoacid in position 80. Isoleucine determines LTNP, which is a ligand for 3DS1. Such alleles did not include HLA-B*44. B*13 and B*27 which have threonine at that position. The authors have not considered the fact that in addition to the NK immunoglobulin receptors, NK receptors can be of the lectin like such as NKG2A/HLA-E to influence the HIV infection outcome. HLA-Bw4 as well as HLA-Bw6 alleles can be classified into those with threonine or methionine in the second position of their leader peptides. These leader peptides are ligands for NKG2A in which methionine influences the inhibitory role of NKG2A for killing infected targets. Functional studies have not been done as well as studies of these receptors in infected individuals. However, analyses of the leader peptides of HLA-B alleles in published reports, suggested that threonine in the second position can explain the importance of HLA-B*57, B*13, B*44 as well as certain Bw6 alleles in LNTP. In addition, we analyzed the San Francisco database that was reported and found that the association of HLA-B alleles with LNTP or with progressors can be due to the presence of threonine or methionine in their second position. Therefore, studies of outcome of HIV infection should include not only mechanisms of cognate immunity mediated by peptides and CD8+ T cells but also, NK receptors of two types, NKG2A as well as 3DSI. We propose that the SCID mouse should be used to understand mechanisms mediated by many of the ARGs especially the importance of thymus derived cells as well as NK receptor interactions with their ligands in this experimental animal transplanted with human stem cells, thymus or NK cells obtained from individuals of known HLA genotypes.
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PMID:Natural Killer Cell Receptor NKG2A/HLA-E Interaction Dependent Differential Thymopoiesis of Hematopoietic Progenitor Cells Influences the Outcome of HIV Infection. 1900 83

The conserved membrane-proximal external region (MPER) of the HIV-1 gp41 envelope protein is the established target for very rare but broadly neutralizing monoclonal antibodies (NAbs) elicited during natural human infection. Nevertheless, attempts to generate an HIV-1 neutralizing antibody response with immunogens bearing MPER epitopes have met with limited success. Here we show that the MPER peptide (residues 662-683) forms a labile alpha-helical trimer in aqueous solution and report the crystal structure of this autonomous folding subdomain stabilized by addition of a C-terminal isoleucine zipper motif. The structure reveals a parallel triple-stranded coiled coil in which the neutralization epitope residues are buried within the interface between the associating MPER helices. Accordingly, both the 2F5 and 4E10 NAbs recognize the isolated MPER peptide but fail to bind the trimeric MPER subdomain. We propose that the trimeric MPER structure represents the prefusion conformation of gp41, preceding the putative prehairpin intermediate and the postfusion trimer-of-hairpins structure. As such, the MPER trimer should inform the design of new HIV-1 immunogens to elicit broadly neutralizing antibodies.
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PMID:Structure of the HIV-1 gp41 membrane-proximal ectodomain region in a putative prefusion conformation. 1922 63

Trimerization of the human immunodeficiency virus (HIV-1) envelope glycoproteins is mediated by the ectodomain of the gp41 transmembrane glycoprotein. Here we investigate oligomer-specific conformations of gp41 by using monoclonal antibodies (MAbs) from HIV-1-infected humans. Human MAbs directed against the cluster I region of gp41 recognized trimeric, dimeric, and monomeric forms of soluble envelope glycoproteins; thus, the integrity of the cluster I epitopes is minimally affected by the oligomeric state. In contrast, human MAbs to the cluster II region were all oligomers specific. One cluster II MAb, 126-6, recognized exclusively the trimeric form of envelope glycoproteins, whereas the others recognized both trimeric and dimeric forms. Thus, a distinct trimer-specific conformation exists in the cluster II region of gp41. Analysis of soluble envelope glycoprotein mutants revealed that gp41 sequences immediately N-terminal to isoleucine 646 contribute to the formation of both the trimer and the trimer-specific conformational epitope.
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PMID:Oligomer-specific conformations of the human immunodeficiency virus (HIV-1) gp41 envelope glycoprotein ectodomain recognized by human monoclonal antibodies. 1929 93

The CBD1 peptide (SLEQIWNNMTWMQWDK), corresponding to the consensus caveolin-1 binding domain in HIV-1 envelope glycoprotein gp41 (CBD1), elicits the production of antibodies that inhibit infection of primary CD4(+) T lymphocytes by various primary HIV-1 isolates. Here we show that HIV-neutralizing antibodies against CBD1 react with multiple conformational epitopes that overlap the highly conserved caveolin-1 binding motif (CBM) with the N-terminal conserved isoleucine residue. The CBM-based peptides IWNNMTWMQW and IWNNMTW when fused to a T helper epitope are immunogenic by inducing high titer CBM-specific antibodies capable of neutralizing HIV-1 infection in primary T lymphocyte cultures. Interestingly, neutralizing immune sera raised against a given peptide do not cross-react with related CBM-derived peptides, thus suggesting the existence of distinct neutralizing epitopes that probably reflect the dynamic conformational features of CBD1. In accord with this, the mixture of neutralizing immune sera raised against several CBM-derived peptides exerts a synergistic neutralizing activity against HIV-1 infection. Finally, the existence of several distinct overlapping epitopes in CBD1 is confirmed by murine monoclonal antibodies that we generated against the CBM-derived chimeric peptides. Our results indicate that CBD1- and CBM-based peptides mimic distinct dynamic conformations of CBD1, and thus such peptides could provide specific immunogens for an efficient vaccine preparation against HIV/AIDS infection.
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PMID:The caveolin-1 binding domain of HIV-1 glycoprotein gp41 (CBD1) contains several overlapping neutralizing epitopes. 1946 43

The ability of surface plasmon resonance to precisely measure kinetic binding constants was exploited here to indirectly evaluate the thermodynamic dissociation trimerization constant (K(d)) of a designed chimeric protein, IZN-23, derived from an isoleucine zipper and a portion of the N-terminal helix residues of HIV-1 gp41. The method uses two monoclonal antibodies (mAbs) that display different off-rates when binding the monomeric or trimeric IZN-23. A detailed description of the data analysis strategy employed to unravel the K(d) trimerization constant from the observed off-rate kinetic values is presented, and the potential exploitation of this technique in different fields is highlighted.
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PMID:An indirect method to measure trimerization constants using surface plasmon resonance. 1952 36

Helix-helix interactions in the putative three-helix bundle formation of the gp41 transmembrane (TM) domain may contribute to the process of virus-cell membrane fusion in HIV-1 infection. In this study, molecular dynamics is used to analyze and compare the conformations of monomeric and trimeric forms of the TM domain in various solvent systems over the course of 4 to 23-ns simulations. The trimeric bundles of the TM domain were stable as helices and remained associated in a hydrated POPE lipid bilayer for the duration of the 23-ns simulation. Several stable inter-chain hydrogen bonds, mostly among the three deprotonated arginine residues located at the center of each of the three TM domains, formed in a right-handed bundle embedded in the lipid bilayer. No such bonds were observed when the bundle was left-handed or when the central arginine residue in each of the three TM helices was replaced with isoleucine (R_I mutant), suggesting that the central arginine residues may play an essential role in maintaining the integrity of the three-helix bundle. These observations suggest that formation of the three-helix bundle of the TM domain may play a role in the trimerization of gp41, thought to occur during the virus-cell membrane fusion process.
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PMID:Molecular dynamics studies of the transmembrane domain of gp41 from HIV-1. 1954 Aug 28

In most human immunodeficiency virus type 1 (HIV-1)-infected individuals who achieve viral loads of <50 copies/ml during highly active antiretroviral therapy (HAART), low levels of plasma virus remain detectable for years by ultrasensitive methods. The relative contributions of ongoing virus replication and virus production from HIV-1 reservoirs to persistent low-level viremia during HAART remain controversial. HIV-1 vaccination of HAART-treated individuals provides a model for examining low-level viremia, as immunizations may facilitate virus replication and sequence evolution. In a phase 1 trial of modified vaccinia virus Ankara/fowlpox virus-based HIV-1 vaccines in 20 HIV-infected young adults receiving HAART, we assessed the prevalence of low-level viremia and sequence evolution, using ultrasensitive viral load (<6.5 copies/ml) and genotyping (five-copy sensitivity) assays. Viral evolution, consisting of new drug resistance mutations and novel amino acid changes within a relevant HLA-restricted allele (e.g., methionine, isoleucine, glutamine, or arginine for leucine at position 205 of RT), was found in 1 and 3 of 20 subjects, respectively. Sequence evolution was significantly correlated with levels of viremia of between 6.5 and <50 copies/ml (P = 0.03) and was more likely to occur within epitopes presented by relevant HLA alleles (P < 0.001). These findings suggest that ongoing virus replication contributes to low-level viremia in patients on HAART and that this ongoing replication is subject to CD8(+) T-cell selective pressures.
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PMID:Identification of ongoing human immunodeficiency virus type 1 (HIV-1) replication in residual viremia during recombinant HIV-1 poxvirus immunizations in patients with clinically undetectable viral loads on durable suppressive highly active antiretroviral therapy. 1960 90

Tetherin (BST-2/CD317) is an interferon-inducible antiviral protein that restricts the release of enveloped viruses from infected cells. The HIV-1 accessory protein Vpu can efficiently antagonize this restriction. In this study, we analyzed mutations of the transmembrane (TM) domain of Vpu, including deletions and substitutions, to delineate amino acids important for HIV-1 viral particle release and in interactions with tetherin. The mutants had similar subcellular localization patterns with that of wild-type Vpu and were functional with respect to CD4 downregulation. We showed that the hydrophobic binding surface for tetherin lies in the core of the Vpu TM domain. Three consecutive hydrophobic isoleucine residues in the middle region of the Vpu TM domain, I15, I16 and I17, were important for stabilizing the tetherin binding interface and determining its sensitivity to tetherin. Changing the polarity of the amino acids at these positions resulted in severe impairment of Vpu-induced tetherin targeting and antagonism. Taken together, these data reveal a model of specific hydrophobic interactions between Vpu and tetherin, which can be potentially targeted in the development of novel anti-HIV-1 drugs.
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PMID:Polarity changes in the transmembrane domain core of HIV-1 Vpu inhibits its anti-tetherin activity. 2167 66

Identification of vulnerability in the HIV-1 envelope (Env) will aid in Env-based vaccine design. We recently found an HIV-1 clade C Env clone (4-2.J45) amplified from a recently infected Indian patient showing exceptional neutralization sensitivity to autologous plasma in contrast to other autologous Envs obtained at the same time point. By constructing chimeric Envs and fine mapping between sensitive and resistant Env clones, we found that substitution of highly conserved isoleucine (I) with methionine (M) (ATA to ATG) at position 424 in the C4 domain conferred enhanced neutralization sensitivity of Env-pseudotyped viruses to autologous and heterologous plasma antibodies. When tested against monoclonal antibodies targeting different sites in gp120 and gp41, Envs expressing M424 showed significant sensitivity to anti-V3 monoclonal antibodies and modestly to sCD4 and b12. Substitution of I424M in unrelated Envs also showed similar neutralization phenotype, indicating that M424 in C4 region induces exposure of neutralizing epitopes particularly in CD4 binding sites and V3 loop.
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PMID:A single amino acid substitution in the C4 region in gp120 confers enhanced neutralization of HIV-1 by modulating CD4 binding sites and V3 loop. 2185 58

The recently described anti-human immunodeficiency virus type 1 (HIV-1) human mAb PG9 and PG16 are cross-clade broadly neutralizing. Therefore, it can be postulated that the targeted epitope(s) are highly conserved among variants of the entire group M. We analysed the sensitivity to PG9 and PG16 of pseudotyped viruses carrying envelope glycoproteins from the viral quasispecies of three HIV-1 clade CRF01_AE-infected patients. The broad heterogeneity in sensitivity to PG9 and PG16, despite closely genetically related envelope glycoproteins issued from single individuals, allowed us to identify two gp120 cross-clade conserved residues, a lysine at position 168 in the V2 loop and an isoleucine at position 215 in the C2 region, whose substitutions were associated with resistance to PG9 and PG16. By site-directed mutagenesis, we confirmed both in clades B and CRF01_AE that the substitutions K168E and I215M have a major impact on PG9 and PG16 neutralization sensitivity of pseudotyped viruses.
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PMID:Naturally occurring substitutions of conserved residues in human immunodeficiency virus type 1 variants of different clades are involved in PG9 and PG16 resistance to neutralization. 2249 17


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