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)

Although it is known that a single peptide can be recognized by CTL restricted to two MHC class I alleles, there is no direct evidence for presentation of a single peptide by two MHC class I molecules. Furthermore, it is unclear whether such peptides are presented to the same T cell or to different T cells. Our previous study suggested that CTL recognition of the human immunodeficiency virus-1 (HIV-1) Pol HIV-B35-SF2-24 epitope (IPLTEEAEL) occurs via both HLA-B35 and HLA-B51 restriction. Here we provide the first direct evidence that a single CTL clone can recognize this peptide presented by both HLA-B35 and HLA-B51. Furthermore, we directly purified this peptide eluted from both HLA-B*3501 and HLA-B*5101 molecules isolated from target cells infected with HIV-1 recombinant vaccinia virus. These results demonstrate that HIV-B35-SF2-24 is a naturally processed peptide which is presented by both HLA-B*3501 and HLA-B*5101. TCR analysis of one CTL clone suggested that it is a single clone. B*3501-SF2-24-tetrameric complexes inhibited both HLA-B*3501- and HLA-B*5101-restricted recognition of this clone, suggesting that the TCR of this clone cross-recognize the structure of both HLA class I-peptide complexes.
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PMID:A single CTL clone can recognize a naturally processed HIV-1 epitope presented by two different HLA class I molecules. 1100 85

We have recently identified the Nef-associated serine-threonine kinase (NAK) as the p21-activated kinase 2 (PAK2). Here we have taken advantage of the possibility to manipulate the functional properties of NAK by transfecting PAK2 cDNA or its mutant derivatives in order to further characterize the Nef-NAK complex. To exclude the possibility that some Nef variants might interact with PAK1 instead of PAK2, we also examined the identity of NAK complexed with divergent human immunodeficiency virus type 1 HIV-1 Nef proteins. All tested Nef proteins, including SF2, NL4-3, BH10, and HAN-2, associated with PAK2 but not with PAK1. By exchanging different regions between these two PAK proteins, the selective ability of PAK2 to associate with Nef could be mapped to the carboxy-terminal part of its regulatory domain. Binding of PAK2 with the adapter protein Nck or beta-PIX was found to be dispensable for the assembly of the Nef-PAK2 complex, whereas an intact Cdc42-Rac1 interactive binding motif was required. Most importantly, we found that NAK represented a distinct subpopulation of the total cellular PAK2 characterized by a high specific kinase activity. Thus, although only a small fraction of cellular PAK2 could be found in complex with Nef, NAK represented a major part of cellular PAK2 activity.
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PMID:Human immunodeficiency virus type 1 Nef selectively associates with a catalytically active subpopulation of p21-activated kinase 2 (PAK2) independently of PAK2 binding to Nck or beta-PIX. 1116 Jul 19

We have tested for combined anti-HIV-1 effects of a hammerhead ribozyme and antiretroviral drugs and the possibility of reducing the drug burden of patients on highly active antiretroviral therapy (HAART). The antiretroviral compounds used represent the three groups in HAART: nucleoside analogue reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and protease inhibitors. A human T cell line (HUT78), stably expressing a hammerhead ribozyme targeted to nef (hhRz.nef(9016-9029)), was infected with HIV-1(SF2) in the presence of a single drug. The combined effects on HIV-1 replication were measured by p24 antigen determinations over a 2-week period. In the presence of the ribozyme, smaller amounts of antiretroviral drugs were required to reduce the HIV-1 p24 levels equally as much as when only drugs were present. The results support a strategy of combining ribozyme gene therapy with HAART to improve the long-term outcome of anti-HIV-1 therapy.
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PMID:Smaller amounts of antiretroviral drugs are needed when combined with an active ribozyme against HIV-1. 1131 14

HIV-1 env expression from certain subgenomic vectors requires the viral regulatory protein Rev, its target sequence RRE, and a 5' splice site upstream of the env open reading frame. To determine the role of this splice site in the 5'-splice-site-dependent Rev-mediated env gene expression, we have subjected the HIV-1 5' splice site, SD4, to a mutational analysis and have analyzed the effect of those mutations on env expression. The results demonstrate that the overall strength of hydrogen bonding between the 5' splice site, SD4, and the free 5' end of the U1 snRNA correlates with env expression efficiency, as long as env expression is suboptimal, and that a continuous stretch of 14 hydrogen bonds can lead to full env expression, as a result of stabilizing the pre-mRNA. The U1 snRNA-mediated stabilization is independent of functional splicing, as a mismatch in position +1 of the 5' splice site that led to loss of detectable amounts of spliced transcripts did not preclude stabilization and expression of the unspliced env mRNA, provided that Rev enables its nuclear export. The nucleotides capable of participating in U1 snRNA:pre-mRNA interaction include positions -3 to +8 of the 5' splice site and all 11 nt constituting the single-stranded 5' end of U1 snRNA. Moreover, env gene expression is significantly decreased upon the introduction of point mutations in several upstream GAR nucleotide motifs, which are mediating SF2/ASF responsiveness in an in vitro splicing assay. This suggests that the GAR sequences may play a role in stabilizing the pre-mRNA by sequestering U1 snRNP to SD4.
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PMID:The sequence complementarity between HIV-1 5' splice site SD4 and U1 snRNA determines the steady-state level of an unstable env pre-mRNA. 1133 22

This study evaluated the association between reactivity of maternal antibody to human immunodeficiency virus type 1 (HIV-1) V3 loop peptides and perinatal transmission in Uganda. Plasma from 40 HIV-1-infected mothers (20 transmitting and 20 nontransmitting mothers) and 31 uninfected mothers in Uganda were tested for reactivity and antibody titer to synthetic peptides representing V3 loop sequences from HIV-1 strains MN, SF2, LAI, ZR6, and CM235 and consensus peptides CA, CB, and CD. No significant differences were found between 20 transmitting mothers and 20 nontransmitting mothers in terms of percent reactivity or titer of antibody to any of the V3 loop peptides tested. Use of a multivariable logistic model to adjust for beta-2 microglobulin level as a confounding variable of stage of infection did not help demonstrate an association except possibly for the ZR6 peptide. These data suggest that neither reactivity nor maternal antibody titer to V3 loop peptides are protective against perinatal transmission of HIV-1 in Uganda.
Pediatr AIDS HIV Infect 1994 Dec
PMID:Lack of association between anti-V3 loop antibodies and perinatal transmission of HIV-1 in Kampala, Uganda. 1136 76

HIV-1 SF13 emerged in a patient with immunity to HIV-1 SF2. This study determined the effect of antibodies raised to HIV-1 SF2 on the replication of the later variant. Antisera in rats were raised previously to a complete set of overlapping, synthetic 15mer peptides following the sequence of HIV-1 SF2 gp120. These sera have now been used in neutralization and enhancement assays against viruses derived from molecular clones of both variants. The sets of peptides inducing neutralizing antibodies to the two variants overlap. Antibodies to the third variable region of HIV-1 SF2 only neutralize the homologous virus whereas those to the second and fourth variable regions neutralize both variants. In contrast, the sets of major epitopes involved in enhancement do not overlap. Epitopes for both variants form two clusters when superimposed on the conformation of the conserved regions. To determine if antibodies with the potential to enhance or neutralize HIV-1 SF2 change over time in infected individuals sera from chimpanzees were used because no material was still available from the original patient. Antibodies to HIV-1 SF2 neutralizing epitopes and HIV-1 SF13 enhancing epitopes were present in the circulation of chimpanzees infected with HIV-1 SF2. Once antibodies to the neutralizing epitopes were induced they persisted whereas antibodies to the enhancing epitopes varied with time after infection. Conditions may therefore exist within individual hosts where not only neutralizing but also enhancing antibodies have the potential to contribute to the selection pressure operating on the circulating population of polymorphic variants.
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PMID:Antibodies raised to short synthetic peptides with sequences derived from HIV-1 SF2 gp120 can both neutralize and enhance HIV-1 SF13: a later variant isolated from the same host. 1142 6

The Nef protein of the simian and human immunodeficiency viruses (SIV and HIV) is regarded as one of the critical determinants of the pathogenicity of HIV-1 in vivo. The positive effect of Nef on viral replication is examined most easily in vitro by the use of indicator cells such as HeLa-CD4-LTR-beta-gal cells (MAGI) or MAGIC5 cells, which are MAGI-derived, CCR5-expressing cells. However, Nef increases the infectivity of many HIV-1 strains no more than 10-fold in these indicator cells. It was noted that MAGI cells expressing a lower level of CD4 enabled us to discriminate more clearly between wild-type and Nef-defective virions. A MAGIC5-derived cell line, MAGNEF, which stably expressed a low level of CD4, was established. The infectivity of the Nef-defective HIV-1 NL4-3 strain was consistently less than one-twentieth of that of the wild type in MAGNEF cells. By using MAGNEF cells, it was shown that Nef enhanced the infectivity of a subtype C HIV-1, Indie-C1 strain, although the effect of Nef on Indie-C1 was significantly less than that on the subtype B strains NL4-3 and SF2. These results validate the versatility of MAGNEF cells for use in the simple and sensitive assay for the level of Nef dependence of various HIV-1 isolates.
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PMID:Establishment of a MAGI-derived indicator cell line that detects the Nef enhancement of HIV-1 infectivity with high sensitivity. 1148 25

HGP-30, a 30 amino acid synthetic peptide homologous to a conserved region of HIV-1(SF2) p17 (aa86-115), has previously been shown to elicit both cellular and humoral immune responses when conjugated to KLH and adsorbed to alum. However, the free HGP-30 peptide is not immunogenic in animals. In order to improve the immunogenicity of HGP-30, peptide conjugates consisting of a modified HGP-30 sequence (m-HGP-30/aa82-111) and a peptide segment, residues 38-50, of the MHC I accessory molecule, human beta-2-microglobulin (beta-2-M), referred to as Peptide J, or a peptide from the MHC II beta chain (peptide G) were evaluated in mice. The effects of carriers and adjuvants on serum antibody titers, specificities to various HIV-1 clade peptides similar to HGP-30 and isotype patterns were examined. Peptides J or especially G conjugated to modified-HGP-30 (LEAPS 102 and LEAPS 101, respectively) generated comparable or better immune responses to modified HGP-30 than KLH conjugates as judged by the induction of: (1) similar antibody titers; (2) broader HIV clade antigen binding; and (3) antibody isotype response patterns indicative of a TH1 pathway (i.e. increased amounts of IgG2a and IgG2b antibodies). The ISA 51 and MPL(R)-SE adjuvants induced higher antibody responses than alum, with the ISA 51 being more potent. Immune responses to LEAPS 102, as compared to LEAPS 101, were weaker and slower to develop as determined by antibody titers and cross clade reactivity of the antibodies induced. Compared to KLH conjugates which induced significant anti-KLH antibody titers, minimal antibody responses were observed to peptide G, the more immunogenic conjugate, and peptide J. These results suggest that modified HGP-30 L.E.A.P.S. constructs may be useful as HIV vaccine candidates for preferential induction of TH1 directed cell mediated immune responses.
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PMID:Induction of cross clade reactive specific antibodies in mice by conjugates of HGP-30 (peptide analog of HIV-1(SF2) p17) and peptide segments of human beta-2-microglobulin or MHC II beta chain. 1153 26

Three macaques infected with SHIV-IIIB and expressing the shared 1F7-idiotypic marker on antibodies against HIV-1 gp120, were injected intravenously with 1F7 monoclonal antibodies (MoAb). As controls, a SHIV-IIIB-infected macaque was injected with a HIV-unrelated mouse monoclonal isotype antibody (TEPC-183) and two healthy, noninfected macaques were injected with MoAb 1F7. 1F7-id-expressing antibodies against gp120-IIIB decreased in two of the three MoAb 1F7-treated macaques and then rebounded. Importantly, antibodies binding to envelope proteins of heterologous HIV-1 strains MN, CM, and SF2, which were low or not detectable before the MoAb 1F7 treatment, increased rapidly following MoAb inoculations in all three 1F7 MoAb treated macaques, but not in the macaque injected with control MoAb TEPC-183. Newly arising antibodies reacting with heterologous virus, i.e. HIV-1 gp120-MN, SF2, and CM did not express 1F7-id. Surprisingly, significant increases of antibodies were also observed in the 1F7-inoculated macaques' antibodies directed to non-HIV antigens (DNP, peptides and BSA). The noninfected control animals did not produce antibodies to these antigens despite MoAb 1F7 treatment. These data show that the MoAb 1F7 injections of chronically SHIV-IIIB-infected macaques resulted in idiotype-specific clonal suppression with broadening the antibody response to HIV envelope proteins.
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PMID:Stimulation of antiviral antibody response in SHIV-IIIB-infected macaques. 1155 5

Splicing of a single HIV-1 primary transcript into more than 30 different mRNAs is regulated by a combination of suboptimal splice sites, cis-acting RNA splicing enhancers and silencers, and trans-acting factors. We have studied the splicing of the second tat intron (SD4 to SA7) and find that activation of splicing by SF2/ASF is mediated by a degenerate exon splicing enhancer (ESE3), consisting of at least three functionally independent sub-elements. One of these sub-elements appears to have both enhancing and silencing properties, depending on the context. SF2/ASF stimulates U2AF65 binding to the suboptimal tat polypyrimidine tract in an ESE3-dependent manner, whereas the exon splicing silencer (ESS3) that is located downstream of the ESE3 inhibits this step. Truncated SF2/ASF protein without the RS domain binds specifically to the ESE3 and retains almost full capacity to stimulate U2AF65 binding and activate splicing. This suggests that SF2/ASF can stimulate the recruitment of U2AF65 by an RS domain-independent mechanism.
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PMID:SF2/ASF binds to a splicing enhancer in the third HIV-1 tat exon and stimulates U2AF binding independently of the RS domain. 1157 21


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