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

The wild-type -Phe*Pro- bond located at the N-terminus of the mature aspartic proteinase of HIV-1 was replaced by -Ile-Pro- or -Val-Pro-. By this means, processing at this cleavage junction was prevented and so, extended or precursor forms of HIV-proteinase were generated. These constructs were expressed in Escherichia coli, purified therefrom, and their specificity, activity at different pH values and susceptibility to the potent inhibitor, Ro31-8959, was assessed. A hitherto unobserved cleavage junction (at approximately Ala-Phe*Leu-Gln approximately) in the frame-shift region of the gag-pol viral genome was identified and confirmed by demonstrating cleavage of a synthetic peptide corresponding to this region. The implications for viral replication of self-processing at neural pH by proteinase whilst still present (in a precursor form) as a component of the polyprotein are considered; such reactions, however, are still blocked even at pH values as high as 8.0 by Ro31-8959.
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PMID:Intrinsic activity of precursor forms of HIV-1 proteinase. 146 83

Individuals infected with human immunodeficiency virus type 1 (HIV-1) develop a humoral immune response to the virus's major structural gene products env, gag, and pol. The distribution of antibodies to env, gag, and pol proteins in Central African populations is of interest as they have a high level of immune system activation compared to non-African populations. Using the Western blot technique, we analyzed the isotypic distribution of anti-HIV antibodies in 45 HIV-1-infected individuals from Central Africa that were either symptomatic or asymptomatic. We observed two basic differences between the isotypic profile of individuals from Central Africa and non-African populations. Central African individuals had a strong polyisotypic response to gag and pol, which has only been observed for gag in American and European populations. In addition, individuals from Central Africa had a high frequency of IgG4 to gag and pol, 75 and 51%, respectively, as compared to 29 and 6% in a non-African population. The elevated IgG4 response may result from the high basal level of immune stimulation seen in Africans due to multiple and frequent exposures to viral, bacterial, and parasitic antigens.
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PMID:Isotypic distribution of HIV-1-specific antibodies in individuals from central Africa. 147 77

Synthetic peptide analog inhibitors of human immunodeficiency virus type 1 (HIV-1) protease were used to study the effects of inhibition of polyprotein processing on the assembly, structure, and infectivity of virions released from a T-cell line chronically infected with HIV-1. Inhibition of proteolytic processing of both Pr55gag and Pr160gag-pol was observed in purified virions from infected T cells after treatment. Protease inhibition was evident by the accumulation of precursors and processing intermediates of Pr55gag and by corresponding decreases in mature protein products. Electron microscopy revealed that the majority of the virion particles released from inhibitor-treated cells after a 24-h treatment had an immature or aberrant capsid morphology. This morphological change correlated with the inhibition of polyprotein processing and a loss of infectivity. The infectivity of virion particles purified from these chronically infected cell cultures was assessed following treatment with the inhibitor for 1 to 3 days. Virions purified from cultures treated with inhibitor for 1 or 2 days demonstrated a 95- to 100-fold reduction in virus titers, and treatment for 3 days resulted in complete loss of detectable infectivity. The fact that virions from treated cultures were unable to establish infection over the 7- to 10-day incubation period in the titration experiments strongly suggests that particles produced by inhibitor-treated cells were unable to reactivate to an infectious form when they were purified away from exogenous protease inhibitor. Thus, a block of HIV-1 protease processing of viral polyproteins by specific inhibitors results in a potent antiviral effect characterized by the production of noninfectious virions with altered protein structures and immature morphologies.
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PMID:Human immunodeficiency virus type 1 protease inhibitors irreversibly block infectivity of purified virions from chronically infected cells. 151 Apr 24

HIV-1 replication requires limited proteolysis of gag and gag-pol encoded precursor proteins by a specific viral proteinase (PR). Sequences of 20 different HIV-1 strains were compared in order to determine regions of conservation and variability within the PR gene. Viral strains included: (a) five new ones derived from New Orleans patient isolates, (b) four established ones grown in our laboratory, (c) eight, whose sequences were published in the Los Alamos Data Base (1990), (d) one Ugandan, and (e) two Brazilian isolates. In the first two groups, HIV proviral DNA extracted from infected lymphocytes was grown in tissue culture and directly amplified by PCR using specific primers flanking the PR gene. Amplified DNA was directly sequenced using a modified di-deoxy sequencing procedure. Sequence data showed a 25% variation among the 20 different HIV strains studied at the amino acid level, including 8% nonconservative changes and 17% conservative changes. Moreover, five noncontiguous regions were able to be delineated in which the PR showed no amino acid changes. These areas included amino acids (I) 1-9 (amino terminal sequence); (II) 21-32 (sequence around the active site); (III) 47-56 (top of the flap); (IV) 78-88; and (V) 94-99 (carboxy terminal sequence). Our results are consistent with those obtained from X-ray crystallography studies as well as single site mutational analysis.
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PMID:PCR amplification of HIV-1 proteinase sequences directly from lab isolates allows determination of five conserved domains. 152 22

The gag-pol coding region of the HIV-2BEN genome was expressed in CV-1 cells infected with four recombinant vaccinia viruses (VV). These recombinant VV encoded either the whole gag-pol region or the gag gene including the protease-coding region of the pol gene or the gag gene truncated at its 3'-end or only the pol gene. The HIV-2BEN gag precursor p55, its mature cleavage products p24 and p17 as well as the pol reverse transcriptase (RT) p66 were detected in VV-infected CV-1 cells. The p55 and two intermediate cleavage products p40 and p35 were myristilated. Comparison to lysates of permanently HIV-2BEN-infected Molt 4 clone 8 cells revealed that several additional gag and pol proteins were present in the VV-infected CV-1 cells. Deletion of the gag and pol overlapping region coding for the viral protease prevented cleavage of the recombinant gag precursor. Electron microscopy of VV-infected CV-1 cells revealed budding structures and immature as well as mature retroviral particles formed by the recombinant gag proteins. Striking differences in the ability to form complete particles were observed between the different recombinant VV. Expression of the truncated gag gene led to the formation of budding structures, but completely budded circular particles were not detectable. Such particles were produced by expression of the whole gag gene and the protease. Mature virions with an internal core structure were only detected in VVgagpol-infected cells. From these findings we conclude that the 3'-end of the gag gene coding for the p16 protein is essential for the formation of complete HIV-2 particles and that the pol proteins support the assembly of the viral core.
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PMID:Morphogenesis of recombinant HIV-2 gag core particles. 152 43

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is the viral protein required for integration of the HIV-1 genome into host cell DNA. A series of clones expressing portions of IN as lambda cII fusion proteins has been constructed in an Escherichia coli expression system; a Southwestern procedure was used to examine binding of the expressed proteins to DNA oligonucleotides. Proteins expressed by clone pHIP106, encoding the entire IN protein but no other pol sequence, and pKNA101, which expresses an IN fusion protein containing 23 amino acids of HIV-1 reverse transcriptase at its amino terminus, exhibited similar levels of oligonucleotide binding. Little DNA sequence specificity was associated with binding activity and there was a preference for Mn2+ over Mg2+ and Ca2+. Interestingly, the protein expressed by an N-terminal clone containing nucleotides coding for IN amino acids 1-141 (including a conserved His-Cys box) was unable to bind oligonucleotide, whereas the protein expressed by a C-terminal clone containing nucleotides coding for amino acids 142-288 exhibited binding equivalent to that of full-length IN. The C-terminal protein was unreactive with a MAb to the lambda cII leader peptide and with an antipeptide serum directed against amino acids 141-158. These results are consistent with the previously reported internal initiation of IN protein synthesis in E. coli at met 154, and indicate that the C-terminal clone does not express IN amino acids 142-153. These amino acids represent part of a conserved region termed D(35)E, containing amino acids 116-152, which has been implicated in IN DNA binding.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization of DNA binding activity of HIV-1 integrase to the C-terminal half of the protein. 154 Apr 16

Patients infected with human immunodeficiency virus type 1 (HIV-1) develop a renal syndrome characterized by proteinuria, renal failure, and focal segmental glomerulosclerosis. By using a noninfectious HIV-1 DNA construct lacking the gag and pol genes, three transgenic mouse lines have been generated that develop a syndrome remarkably similar to the human disease. In the present study, we have characterized in detail one of these lines, Tg26. In Tg26 mice, proteinuria was detectable at approximately 24 days of age, followed by severe nephrotic syndrome and rapid progression to end-stage renal failure. Renal histology showed focal segmental glomerulosclerosis and microcystic tubular dilatation. Indirect immunofluorescence studies demonstrated increased accumulation of the basement membrane components laminin, collagen type IV, and heparan sulfate proteoglycan. The viral protein Rev was present in sclerotic glomeruli. Northern blot analysis of total renal RNA showed expression of viral genes prior to the appearance of histologic renal disease, with greatly diminished viral gene expression late in the disease course. Kidneys from transgenic mice expressed increased steady-state levels of collagen alpha 1(IV) mRNA when glomerulosclerosis was present. We conclude that the presence of HIV-1 genes is associated with progressive renal dysfunction and glomerulosclerosis in transgenic mice.
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PMID:Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes. 154 49

To understand the role of the HIV-1 envelope protein in the assembly of virus, we constructed a proviral clone of HIV-1 where the methionine initiator codon of the env gene was substituted with a translational stop codon. Upon DNA transfection into permissive cells in culture, this clone produces virus-like particles similar in size to parental virus but are noninfectious in human T-cells, promonocytic cells, and primary macrophages. This mutant readily recombines with a deletion mutant provirus lacking the entire gag-pol region producing a recombinant virus that is infectious. Substitution of the same initiator methionine codon with valine results in a leaky missense mutant provirus capable of a low level of Env protein synthesis that leads to a productive infection. Thus, the prototype initiation codon AUG is dispensable for virus infectivity. Further, the expression of the envelope protein is not a prerequisite for the assembly of the virus particles in the HIV-1 system. These noninfectious envelope-less particles revert readily to wild-type phenotype upon cotransfection with Env-producing plasmid DNAs.
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PMID:Biological characterization of noninfectious HIV-1 particles lacking the envelope protein. 154 56

HIV-2 infections are rare in North America, with less than 30 cases identified since 1988. We conducted a surveillance for HIV-2 seroprevalence by re-evaluating 457 HIV-1 indeterminate serology specimens submitted to the Maryland Department of Health Laboratories from January 1, 1988 to July 15, 1991. All indeterminates were screened using a combination HIV-1/HIV-2 synthetic peptide EIA. The presence of HIV-2-specific antibodies in initially reactive sera was confirmed utilizing a selective HIV-2 synthetic peptide EIA and Western blotting. Eight sera from four adult males attending public health clinics in suburban Washington, D.C. were found to be specifically reactive for HIV-2 antibodies. One is a native West African; the others remain anonymous. All eight sera demonstrated a gag (core) and pol (polymerase) only pattern of reactivity on HIV-1 Western blots. Targeting selected groups of HIV-1 indeterminate sera from patients attending public health clinics may represent a more appropriate strategy to monitor the spread of HIV-2 in North America than testing similar samples from the blood donor population.
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PMID:Identifying HIV-2-seropositive individuals by reevaluating HIV-1 indeterminate sera. 845 Apr 10

The human retroviruses human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type I (HTLV-I) are characterized by complex regulation of gene expression. Each virus encodes a posttranscriptional regulator, the 19-kDa HIV-1 Rev protein and the 27-kDa HTLV-I Rex protein, which is required for viral replication. Expression of these trans activators results in the cytoplasmic accumulation of unspliced or singly spliced viral mRNA which encode the gag, pol, and env gene products. The finding that the HTLV-I Rex protein is able to functionally substitute for the Rev protein of HIV-1 indicates that HIV-1 Rev and HTLV-I Rex may interact with the same component of a cellular pathway involved in either mRNA splicing or transport. In this study, we have generated functional Rev/Rex hybrid proteins by domain exchange. We have defined, using in vivo and in vitro analyses, the activation domains of Rev and Rex which are the putative targets of a common host cell factor(s) required for Rev and Rex function.
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PMID:Definition of the human immunodeficiency virus type 1 Rev and human T-cell leukemia virus type I Rex protein activation domain by functional exchange. 154 84


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