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

The mechanisms involved in the incorporation of viral glycoproteins into virions are incompletely understood. For retroviruses, incorporation may involve interactions between the Gag proteins of these viruses and the cytoplasmic domains of the relevant envelope (Env) glycoproteins. Recent studies have identified within the cytoplasmic tail of the human immunodeficiency virus type 1 (HIV-1) Env protein a tyrosine-containing internalization motif similar to those found in the cytoplasmic domains of certain cell surface proteins that undergo rapid constitutive endocytosis in clathrin-coated pits. Given that surface expression of the HIV-1 Env protein is essential for the production of infectious virus, the presence of this internalization motif is surprising. We show here that in contrast to the rapid rate of Env protein internalization observed in cells expressing the Env protein in the absence of other HIV-1 proteins, the rate of internalization of Env protein from the surfaces of HIV-1-infected cells is extremely slow. The presence of the Pr55gag precursor protein is necessary and sufficient for inhibition of Env protein internalization, while a mutant Pr55-gag that is incapable of mediating Env incorporation into virions is also unable to inhibit endocytosis of the Env protein. The failure of the Env protein to undergo endocytosis from the surface of an HIV-1-infected cell may reflect the fact that the proposed interaction of the matrix domain of the Gag protein with Env during assembly prevents the interaction of Env with host adaptin molecules that recruit plasma membrane molecules such as the transferrin receptor into clathrin-coated pits. When the normal ratio of Gag and Env proteins in the infected cells is altered by overexpression of Env protein, this mechanism allows removal of excess Env protein from the cell surface. Taken together, these results suggest that a highly conserved system to reduce surface levels of the Env protein functions to remove Env protein that is not associated with Gag and that is therefore not destined for incorporation into virions. This mechanism for the regulation of surface levels of Env protein may protect infected cells from Env-dependent cytopathic effects or Env-specific immune responses.
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PMID:Human immunodeficiency virus type 1 envelope protein endocytosis mediated by a highly conserved intrinsic internalization signal in the cytoplasmic domain of gp41 is suppressed in the presence of the Pr55gag precursor protein. 879 89

The human genome contains a wide variety of endogenous retrovirus-like sequences. The human endogenous retrovirus type K (HERV-K) family comprises 30-50 members per haploid genome in humans and is highly conserved in Old World monkeys and apes. Some proviruses are displaying open reading frames (ORF) with coding capacity for viral particles. HERV-K sequences most likely code for the previously described human teratocarcinoma-derived virus (HTDV) and correlated expression of HERV-K Gag has been demonstrated by immunoelectron microscopy studies. Protease, but not yet reverse transcriptase (RT), enzymatic activity was demonstrated for recombinant HERV-K proteins. However, an ultrasensitive RT assay revealed specific polymerase activity associated with the HTDV particles. HERV-K transcription is specifically regulated by viral long terminal repeats and RNA is expressed at low steady-state levels in a variety of human tissues and tumours. In teratocarcinoma cell lines, HERV-K is highly expressed in a complex pattern showing full-length as well as subgenomic envelope (env) and two alternatively spliced small transcripts. The doubly spliced 1.8-kb mRNA codes for cORF protein which resembles Rev of HIV-1 and is located in the nucleolus. In addition, the cORF sequence acts as a leader and is essential for effective expression of glycosylated HERV-K Env protein. Although HERV-K sequences code for all necessary retroviral proteins, infectious particles could not yet be demonstrated. The putative implication of HERV sequences in pathophysiological processes, for example, testicular malignancies, remains to be elucidated.
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PMID:HERV-K: the biologically most active human endogenous retrovirus family. 879 33

We selected HIV-1-LAI variants with the ability to induce syncytium formation of C8166 cells in the presence of a monoclonal antibody (MAb), 5A8, to domain 2 of CD4. Five biologically cloned variants with at least 60-fold greater resistance than wild type to 5A8-mediated inhibition of syncytium formation were obtained. The variants exhibited reduced relative sensitivity to inhibition of syncytium formation and virus infection, not only by the selecting anti-domain 2 MAb, but also by MAbs to domains 1 and 3 of CD4. By contrast, the sensitivity of these variants to neutralization by soluble CD4 and bivalent CD4-IgG was greater than for the parental clone. The affinities of soluble CD4 for Env protein, in either solubilized or membrane-anchored form, did not differ significantly between the variants and LAI. Analyses of sCD4-induced exposure of the transmembrane protein at 4 and 37 degrees C suggested, however, that the variants had acquired an increased susceptibility to the triggering of conformational changes in their Env oligomers at 37 degrees C. This may represent a mechanism of both the increased resistance to the CD4 MAbs and the enhanced sensitivity to soluble CD4.
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PMID:Altered CD4 interactions of HIV type 1 LAI variants selected for the capacity to induce membrane fusion in the presence of a monoclonal antibody to domain 2 of CD4. 882 17

The authors isolated and characterized a new HIV-1 variant (HIV-1[IbNg]) from the peripheral blood mononuclear cells (PBMCs) of a person living in Nigeria. The virus is highly cytopathic to PBMCs in culture, replicates in primary human T cells and macrophages/monocytes as well as in established human T cell and monocytic cell lines, and it does not induce syncytia in MT-2 cells. Using cytoplasmic RNA from HIV-1[IbNg]-infected PBMCs, five overlapping DNA fragments were amplified through reverse transcriptase-polymerase chain reaction (RT-PCR) and cloned into pBluescript II SK(+). DNA sequencing of those fragments indicated that the entire HIV-1[IbNg] genome consists of 9201 nucleotides. Phylogenetic analysis of the variant's env gene sequence showed that the virus clustered with HIV-1 strains belonging to HIV-1 clade A. The following genetic features are unique to this virus: a 16-bp insert in the primer-binding site, a large Rev open reading frame, a Rev-responsive element which is predicted to form a different secondary structure than described for clade B viruses, the potential to encode a heavily glycosylated Env protein, and a frameshift resulting in a stop codon in the tat gene.
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PMID:Genomic structure and nucleotide sequence analysis of a new HIV type 1 subtype A strain from Nigeria. 889 49

A mutant human immunodeficiency virus (HIV-1) provirus encoding an envelope (Env) protein with a truncated transmembrane protein cytoplasmic domain was defective for replication. Coexpression of the mutant with a wild-type (wt) HIV-1 provirus potently inhibited the production of infectious virus. The maximum inhibitory effect was reached when the ratio of mutant to wt proviral DNA was 2:1. This transdominant defect in infectivity conferred by the mutant Env did not appear to involve the late steps of virus replication, since the synthesis, precursor processing, and intracellular transport of the Env proteins were not blocked; nor did it prevent the incorporation of the envelope proteins into virions or the subsequent release of the virus. Although the mutant Env protein still retained syncytia-forming ability, the truncated protein was unable to mediate cell-to-cell transmission of the virus. Moreover, coexpression with the mutant effectively inhibited the ability of the wt Env to mediate cell-to-cell transmission. The mutant Env protein formed a complex with the wt protein when they were coexpressed, producing heterooligomeric structures which appeared to be severely defective in an early, post-CD4 binding step of the virus life cycle despite the inclusion of wt Env in the complexes.
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PMID:Characterization of an envelope mutant of HIV-1 that interferes with viral infectivity. 895 46

The biologically relevant form of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein is oligomeric, with the major points of contact between oligomeric partners located in the ectodomain of gp41. To identify and map conserved epitopes and regions in gp41 where structure is influenced by quaternary interactions, we used a panel of 38 conformation-dependent and 9 conformation-independent anti-gp41 monoclonal antibodies (MAbs) produced by immunization of mice with oligomeric Env protein. By cross-competition experiments using these MAbs and several others previously described, six distinct antigenic determinants were identified and mapped. Three of these determinants are conformational in nature and dependent in part on Env oligomeric structure. MAbs to two of these determinants were broadly cross-reactive with Env proteins derived from primary virus strains. The prevalence of antibodies in HIV-1-positive human sera to the antigenic determinants was determined by the ability of such sera to block binding of MAbs to Env protein. Strong blocking activity that correlated with cross-reactivity was found.
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PMID:Epitope map of human immunodeficiency virus type 1 gp41 derived from 47 monoclonal antibodies produced by immunization with oligomeric envelope protein. 906 Jun 20

Human immunodeficiency virus type 1 (HIV-1) can readily accept envelope (Env) glycoproteins from distantly related retroviruses. However, we previously showed that the HIV-1 Env glycoprotein complex is excluded even from particles formed by the Gag proteins of another lentivirus, visna virus, unless the matrix domain of the visna virus Gag polyprotein is replaced by that of HIV-1. We also showed that the integrity of the HIV-1 matrix domain is critical for the incorporation of wild-type HIV-1 Env protein but not for the incorporation of a truncated form which lacks the 144 C-terminal amino acids of the cytoplasmic domain of the transmembrane glycoprotein. We report here that the C-terminal truncation of the transmembrane glycoprotein also allows the efficient incorporation of HIV-1 Env proteins into viral particles formed by the Gag proteins of the widely divergent Moloney murine leukemia virus (Mo-MLV). Additionally, pseudotyping of a Mo-MLV-based vector with the truncated rather than the full-length HIV-1 Env allowed efficient transduction of human CD4+ cells. These results establish that Mo-MLV-based vectors can be used to target cells susceptible to infection by HIV-1.
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PMID:Truncation of the human immunodeficiency virus type 1 envelope glycoprotein allows efficient pseudotyping of Moloney murine leukemia virus particles and gene transfer into CD4+ cells. 906 Jul 7

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein was expressed by a vaccinia vector that encodes the late promotor P11. The envelope protein synthesized mediated syncytia formation with SupT1 cells and was efficiently cleaved to produce mature gp120 and gp41 in CV-1 cells. gp 160 precursor processing was neither affected by a change in culture medium nor by a heterologous vesicular stomatitis virus coinfection. These results suggest that the proteolytic cleavage of gp160 is an efficient process and that coinfection with other viruses may not affect precursor processing of the HIV-1 Env protein.
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PMID:Expression and processing of the human immunodeficiency virus type 1 envelope glycoprotein. 907 65

Recombinant vaccinia virus (VV) vectors that express the envelope (Env) protein of the human immunodeficiency virus-type 1 (HIV-1) have been previously shown to elicit HIV-specific cytotoxic T-lymphocyte (CTL) and weak antibody responses in non-human primate studies and clinical trials. In first clinical trials, single Env proteins were presented to the immune system by VV recombinants and other vectors, but individuals were not protected against later exposures to heterologous HIV. It is likely that the generation of protective immune responses against diverse HIV will require that vaccines encompass proteins from not just one, but multiple distinct HIV isolates. Here is described the simple construction of numerous new VV, each expressing a unique, truncated, Env protein (VVenv). Mouse experiments were performed to evaluate the ability of these VVenv to elicit immune responses. HIV-1-specific antibodies appeared within one month following one intraperitoneal inoculation of mice with single or mixed VVenv, reaching plateau levels by 4 months. The magnitude of antibody production was poor at the dose of 10(5) p.f.u. VVenv per animal, but improved with increasing doses of VVenv up to 10(7) p.f.u. per animal. The subcutaneous route of VV immunization, previously proven safe in human trials, was also effective for administering VVenv. These results highlight the strengths of recombinant VV constructs as vehicles for the presentation of multiple HIV-1-Env proteins to the naive immune system.
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PMID:Eliciting HIV-1 envelope-specific antibodies with mixed vaccinia virus recombinants. 913 84

A HeLa T4 cell line containing a defective human immunodeficiency virus type 1 (HIV-1) DNA (HD4) was isolated. After transactivation with Tat, the HD4 DNA was transcribed into a single 3.7-kb mRNA that encodes a chimeric CD4/Env protein and a multitarget-ribozyme directed against multiple sites within the gp120 coding region of HIV-1 RNA (Chen et al., 1992). Early steps in HIV infection such as entry, reverse transcription, and proviral DNA formation were not affected in HD4 cells, and HD4 was efficiently transactivated after either HIV-1 or HIV-2 infections. HIV-2, which lacks all of the HIV-1-specific ribozyme target sites, replicated to high levels in HD4 cells whereas HIV-1 replication was selectively inhibited. Despite a reduced accumulation of all HIV-1 transcripts, transactivation of HD4 was efficient. Surprisingly, the most abundant, multiply spliced mRNAs were reduced even though they lack all of the ribozyme target sites. These results strongly suggest that the ribozyme co-localizes with unspliced HIV-1 pre-mRNA and/or genomic HIV-1 RNA in the nucleus. Cleavage of these precursor RNAs explains the reduction of all spliced and unspliced HIV-1 RNAs. Cleavage of genomic RNA probably contributed to the three-fold reduction in the infectivity of viral progeny. Thus, the HD4 ribozyme RNA functioned as a ribozyme in the nucleus and as a mRNA for a chimeric CD4/Env protein in the cytoplasm. Its unusual large size for a ribozyme (3.7 kb) indicates that, in the future, other antiviral proteins, like negative transdominant mutant HIV-1 proteins, may also be encoded to increase its antiviral potential in a gene therapy approach.
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PMID:Defective HIV-1 provirus encoding a multitarget-ribozyme inhibits accumulation of spliced and unspliced HIV-1 mRNAs, reduces infectivity of viral progeny, and protects the cells from pathogenesis. 918 69


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