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Human immunodeficiency virus type 1 (HIV-1) can be isolated from lymphocytes and tissues of symptomatic and asymptomatic seropositive subjects. However, in some individuals, virus isolation is not always positive, especially in asymptomatics. In this paper we report the results of HIV-1 DNA detection by means of polymerase chain reaction (PCR), a new technique that permits the amplification of specific DNA sequences. PCR was carried out to amplify two highly conserved env regions on samples from 20 normal individuals used as controls, 20 seropositive patients at different stages of HIV disease and 25 seronegative individuals at high risk for infection, such as sexual partners of seropositive patients and intravenous drug addicts. Eighteen out of 20 seropositive subjects were positive by PCR while among seronegatives HIV DNA was detected in 7/25 individuals. Virus isolation was positive only in 2/7. These subjects, followed for HIV antibody production for a period of 10-12 months, remained seronegative except one case who seroconverted after a few weeks. Long latency of HIV infection without detectable antibodies seems prevalent in these subjects. PCR assay represents a useful technique for identifying proviral sequences in seronegative high-risk individuals, to confirm the infection during its early phases and during the follow-up of patients with HIV disease.
Mol Cell Probes 1990 Apr
PMID:Proviral sequences detection of human immunodeficiency virus in seronegative subjects by polymerase chain reaction. 236 63

Human immunodeficiency virus type 1 (HIV-1) pre-mRNA splicing is regulated in order to maintain pools of unspliced and partially spliced viral RNAs as well as the appropriate levels of multiply spliced mRNAs during virus infection. We have previously described an element in tat exon 2 that negatively regulates splicing at the upstream tat 3' splice site 3 (B. A. Amendt, D. Hesslein, L.-J. Chang, and C. M. Stoltzfus, Mol. Cell. Biol. 14:3960-3970, 1994). In this study, we further defined the element to a 20-nucleotide (nt) region which spans the C-terminal vpr and N-terminal tat coding sequences. By analogy with exon splicing enhancer (ESE) elements, we have termed this element an exon splicing silencer (ESS). We show evidence for another negative cis-acting region within tat-rev exon 3 of HIV-1 RNA that has sequence motifs in common with a 20-nt ESS element in tat exon 2. This sequence is juxtaposed to a purine-rich ESE element to form a bipartite element regulating splicing at the upstream tat-rev 3' splice site. Inhibition of the splicing of substrates containing the ESS element in tat exon 2 occurs at an early stage of spliceosome assembly. The inhibition of splicing mediated by the ESS can be specifically abrogated by the addition of competitor RNA. Our results suggest that HIV-1 RNA splicing is regulated by cellular factors that bind to positive and negative cis elements in tat exon 2 and tat-rev exon 3.
Mol Cell Biol 1995 Aug
PMID:Presence of exon splicing silencers within human immunodeficiency virus type 1 tat exon 2 and tat-rev exon 3: evidence for inhibition mediated by cellular factors. 756

Human immunodeficiency virus type 1 (HIV-1) and other lentiviridae demonstrate a strong preference for the A-nucleotide, which can account for up to 40% of the viral RNA genome. The biological mechanism responsible for this nucleotide bias is currently unknown. The increased A-content of these viral genomes corresponds to the typical use of synonymous codons by all members of the lentiviral family (HIV, SIV, BIV, FIV, CAEV, EIAV, visna) and the human spuma retrovirus, but not by other retroviruses like the human T-cell leukemia viruses HTLV-1 and HTLV-II. In this article, we analyzed A-bias for all codon groups in all open reading frames of several lentiviruses. The extent of lentiviral codon bias could be related to host cellular translation. By calculating codon bias indices (CBIs), we were able to demonstrate an inverse correlation between the extent of codon bias and the rate of translation of individual reading frames in these viruses. Specifically, the shift toward A-rich codons is more pronounced in pol than in gag lentiviral genes. Since it is known that Gag synthesis exceeds Pol synthesis by a factor of 20 due to infrequent ribosomal frame-shifting during translation of the gap-pol mRNA molecule, we propose that the aminoacyl-tRNA availability in the host cell restricts the lentiviral preference for A-rich codons. In addition, less A-nucleotides were found in regions of the viral genome encoding multiple functions; e.g., overlapping reading frames (tat-rev-env) or in genes that overlap regulatory sequences (nef-LTR region).(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Evol 1995 Aug
PMID:The tendency of lentiviral open reading frames to become A-rich: constraints imposed by viral genome organization and cellular tRNA availability. 766 42

Human immunodeficiency virus type 1 activates the complement cascade via the classical pathway by direct binding of C1q through specific sites in the TM surface protein, gp41. In this paper we investigated the divalent cation dependence of the interaction between HIV-1 gp41 and C1q or gp120. A solid phase radioimmunoassay was used to investigate the interaction between a recombinant soluble form of HIV-1 gp41 (rsgp41) and C1q and an enzyme linked immunoassay was used to investigate the interaction between rsgp41 and gp120. The interaction between C1q and rsgp41, but not between C1q and immune complexes, was dependent upon the presence of calcium. Calcium could not be replaced by larger cations such as strontium, barium, lead or smaller ions such as magnesium and manganese. Zinc increased binding to 22% of binding achieved with calcium. The interaction between rsgp41 and gp120 was not dependent upon the presence of divalent ions. Thus, calcium is required for the interaction between rsgp41 and C1q, whereas the interaction between rsgp41 and gp120 is independent of divalent cations.
Mol Immunol 1995 Apr
PMID:HIV-1 rsgp41 depends on calcium for binding of human c1q but not for binding of gp120. 773 75

Human immunodeficiency virus type 1 (HIV-1)-infected CEM cells were treated (as single agents or in combination) with (minus)-2', 3'-dideoxy-3'-thiacytidine (3TC) and the following HIV-1-specific non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs): 2', 5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5'-(4'-amino-1',2'-oxathi ole)-2',2'-dioxide derivative of 3-methylthymidine (TSAO-m3T), the thiocarboxanilides UC10 and UC42, bis(heteroaryl)piperazine (BHAP) derivative U90152, and the 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivative 5-isopropyl-1-ethoxymethyl-6-benzyluracil (MKC-442). When used individually, the compounds led to the emergence of HIV-1 strains containing the following mutations in the RT: Glu138 to lysine for TSAO-m3T, Met184 to valine for 3TC, Lys103 to threonine/asparagine for the thiocarboxanilides, and Tyr181 to cysteine for BHAP and MKC-442. When 3TC was combined with TSAO-m3T, UC10, UC42, BHAP, or MKC-442, breakthrough of virus was markedly delayed or even suppressed. For these drug combinations, the concentrations of the individual drugs could be lowered by > or = 25-50-fold to suppress virus breakthrough compared with the individual use of the compounds. The concomitant presence of the Lys138 and Ile/Val184 mutations was found in the RT of the mutant viruses that emerged with combination therapy of the lowest concentrations of 3TC with either the lowest concentrations of TSAO-m3T or UC10 (approximately 0.5-3-fold the EC50 value). These virus strains retained high sensitivity to other NNRTIs such as BHAP or HEPT. The virus mutants that arose in the presence of combinations of the lowest concentrations of 3TC with either BHAP or HEPT predominantly contained the Cys181 mutation in the RT. In one case, the Ile181 mutation was found. The latter mutations, particularly the Ile181 mutation, resulted in markedly decreased sensitivity to the NNRTIs but not to 3'-azido-2', 3'-dideoxythymidine or 3TC.
Mol Pharmacol 1996 May
PMID:Marked inhibitory activity of non-nucleoside reverse transcriptase inhibitors against human immunodeficiency virus type 1 when combined with (-)2',3'-dideoxy-3'-thiacytidine. 862 38

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is an important target for chemotherapeutic agents used in the treatment of AIDS; the TIBO compounds are potent non-nucleoside inhibitors of HIV-1 RT (NNRTIs). Crystal structures of HIV-1 RT complexed with 8-Cl TIBO (R86183, IC50 = 4.6 nM) and 9-Cl TIBO (R82913, IC50 = 33 nM) have been determined at 3.0 A resolution. Mutant HIV-1 RT, containing Cys in place of Tyr at position 181 (Tyrl81Cys), is highly resistant to many NNRTIs and HIV-1 variants containing this mutation have been selected in both cell culture and clinical trials. We also report the crystal structure of Tyrl81Cys HIV-1 RT in complex with 8-Cl TIBO (IC50 = 130 nM) determined at 3.2 A resolution. Averaging of the electron density maps computed for different HIV-1 RT/NNRTI complexes and from diffraction datasets obtained using a synchrotron source from frozen (-165 degrees C) and cooled (-10 degrees C) crystals of the same complex was employed to improve the quality of electron density maps and to reduce model bias. The overall locations and conformations of the bound inhibitors in the complexes containing wild-type HIV-1 RT and the two TIBO inhibitors are very similar, as are the overall shapes and volumes of the non-nucleoside inhibitor-binding pocket (NNIBP). The major differences between the two wild-type HIV-1 RT/TIBO complexes occur in the vicinity of the TIBO chlorine substituents and involve the polypeptide segments around the beta5-beta6 connecting loop (residues 95 to 105) and the beta13-beta14 hairpin (residues 235 and 236). In all known structures of HIV-1 RT/NNRTI complexes, including these two, the position of the beta12-beta13 hairpin or the "primer grip" is significantly displaced relative to the position in the structure of HIV-1 RT complexed with a double-stranded DNA and in unliganded HIV-1 RT structures. Since the primer grip helps to position the template-primer, this displacement suggests that binding of NNRTIs would affect the relative positions of the primer terminus and the polymerase active site. This could explain biochemical data showing that NNRTI binding to HIV-1 RT reduces efficiency of the chemical step of DNA polymerization, but does not prevent binding of either dNTPs or DNA. When the structure of the Tyr181Cys mutant HIV-1 RT in complex with 8-Cl TIBO is compared with the corresponding structure containing wild-type HIV-1 RT, the overall conformations of Tyr181Cys and wild-type HIV-1 RT and of the 8-Cl TIBO inhibitors are very similar. Some positional changes in the polypeptide backbone of the beta6-beta10-beta9 sheet containing residue 181 are observed when the Tyr181Cys and wild-type complexes are compared, particularlty near residue Val179 of beta9. In the p51 subunit, the Cys181 side-chain is oriented in a similar direction to the Tyr181 side-chain in the wild-type complex. However, the electron density corresponding to the sulfur of the Cys181 side-chain in the p66 subunit is very weak, indicating that the thiol group is disordered, presumably because there is no significant interaction with either 8-Cl TIBO or nearby amino acid residues. In the mutant complex, there are slight rearrangements of the side-chains of other amino acid residues in the NNIBP and of the flexible dimethylallyl group of 8-Cl TIBO; these conformational changes could potentially compensate for the interactions that were lost when the relatively large tyrosine at position 181 was replaced by a less bulky cysteine residue. In the corresponding wild-type complex, Tyr181 iin the p66 subunit has significant interactions with the bound inhibitor and the position of the Tyr181 side-chain is well defined in both subunits. Apparently the Tyr181 --> Cys mutation eliminates favorable contacts of the aromatic ring of the tyrosine and the bou
J Mol Biol 1996 Dec 20
PMID:Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant. 900 Jun 32

Protein import into the nucleus is generally considered to involve specific nuclear localization signals (NLS) though it is becoming increasingly clear that efficient and well controlled import of proteins which lack a canonical NLS also occurs in cells. Human immunodeficiency virus type 1 (HIV-1) Vpr is one such protein which does not have an identifiable canonical NLS and yet efficiently localizes to the nuclear compartment. Here, we use confocal microscopy to demonstrate that mutations in the putative central hydrophobic helix of Vpr result in the retention of the protein in highly localized ring-like structures around the nuclear periphery with striking impairment in their ability to enter the nuclear interior. By characterizing other biological activities associated with this protein, such as its ability to incorporate into budding virions and its ability to arrest cells in G2, we show that this helical domain is specific for the nuclear translocation of the protein with very little effect on these other functions. Interestingly, however, perturbation of this helical motif also perturbs the protein's ability to augment viral replication in primary human macrophages indicating that the integrity of this secondary structure is essential for optimal infection in these non-dividing cells.
J Mol Biol 1998 Apr 24
PMID:Human immunodeficiency virus type 1 Vpr localization: nuclear transport of a viral protein modulated by a putative amphipathic helical structure and its relevance to biological activity. 957 Oct 31

Human immunodeficiency virus type-1 (HIV-1) transcription is dependent on the interaction of host-cell transcription factors with cis-regulatory DNA elements within the viral long terminal repeat (LTR). Much attention has focused on the series of sequence elements upstream of the transcriptional initiation site in the U3 region of the LTR including the Sp1 and NF-kappaB binding sites. Recent studies, however, demonstrate that the transcribed 5'-untranslated leader region (5'-UTR) also contains important transcriptional elements. These regulatory elements situated downstream of transcription interact with constitutive and inducible transcription factors, mediate transmission of cellular activation signals, and are important for efficient HIV-1 transcription and replication. The 5'-UTR contains binding sites for the transcription factors AP-1, NF-kappaB, NF-AT, IRF, and Sp1. Mutations in these binding sites can interfere with the viral response to cell activation signals, decrease LTR transcription, and inhibit viral replication. The 5'-UTR also interacts with a specific nucleosome that is rapidly displaced during transcriptional activation of the latent provirus. We propose that the inducible transcription factor binding sites in the 5'-UTR comprise a downstream enhancer domain that can function independent of, or in concert with, the LTR promoter to rapidly increase latent proviral transcription in response to cell activation signals. In this review, we describe the host-cell transcription factors that interact with the 5'-UTR and discuss their role in the transcriptional regulation of HIV-1 gene expression.
Int J Mol Med 1998 May
PMID:Human immunodeficiency virus type-1 transcription: role of the 5'-untranslated leader region (review). 985 10

Human immunodeficiency virus type 2 (HIV-2) is known to be one of the agents that causes acquired immunodeficiency syndrome (AIDS). It has been present in West Africa since the 1960s and is currently epidemic there. Compared with human immunodeficiency virus type 1 (HIV-1), HIV-2 is genomically different. Furthermore, it is less prevalent worldwide than HIV-1. In West Africa, seropositive rates of HIV-2 are higher in urban versus rural communities, however, there are no gender differences. Sexual contact and vertical transmission are known modes of infectivity, though HIV-2 is less contagious than HIV-1.
Int J Mol Med 1998 Nov
PMID:Infection with the human immunodeficiency virus type 2: epidemiology and transmission (Review). 985 54

Human immunodeficiency virus type 1 (HIV-1) uses host tRNA as a primer for reverse transcription of its viral RNA. The 3' terminal 18 nucleotides of human tRNALys3 are complementary to the primer binding site on the viral RNA. A secondary structure model for the HIV-1 RNA/tRNALys3 initiation complex has been proposed that includes additional base-pairing between the tRNA and the HIV-1 RNA beyond the 18 nucleotides of the primer binding site. Included in these interactions is base-pairing between the anticodon of tRNALys3 and an A-rich loop in the HIV-1 secondary structure. The tRNA and HIV-1 RNA are significantly unfolded from their native structures in order to form the initiation complex proposed in this model. We have found several problems with the proposed secondary structure in our efforts to build a three-dimensional model that is compatible with it. The additional interactions between the tRNA and viral RNA cause the structure to be topologically knotted. This poses a problem for folding of the initiation complex and transcription by reverse transcriptase. We have also not been able to build any all-atom models based on known RNA structures that follow the secondary structure model in the extended tRNA/HIV-1 RNA complex. Finally, beyond the primer binding site interaction, subsequent biochemical and genetic studies have given further insight into the structure of the initiation complex. These results call into question some of the extended HIV-1 RNA/tRNA interactions that have been proposed.
J Mol Biol 1999 Jan 15
PMID:Exploring three-dimensional structures of the HIV-1 RNA/tRNALys3 initiation complex. 987 19


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