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

Human immunodeficiency virus type 1 (HIV-1) isolates classified as syncytium-inducing (SI) or non-SI (NSI) in the MT-2 T-cell line exhibit characteristic sequence differences in the V1-V2 and V3 regions of the env gene. Seven HIV-1 isolates were phenotyped as NSI or SI in the MT-2 cell line. Unexpectedly, all four NSI viruses induced large syncytia 4 to 8 days postinoculation in a panel of five primary CD4+ T-cell lines (including two clones) generated from the peripheral blood of normal donors by exposure to infectious HIV-1, inactivated HIV-1, or Epstein-Barr virus. The primary T-cell lines yielded neither HIV-1 provirus nor infectious HIV by PCR analysis or exhaustive coculture with phytohemagglutinin-treated blast cells. Three isolates (TC354, PK1, and PK2) were biologically cloned and retained their SI or NSI phenotypes in MT-2 and primary T-cell lines. The biologically cloned provirus DNA was also used to clone and sequence the relevant V2 and V3 regions of the env genes. The amino acid sequences of the V2 and V3 regions were characteristic of patterns already reported for the NSI, switch NSI, and SI phenotypes, respectively. This evidence precludes the possibility that these results were due to contamination of the NSI isolates with SI virus. The results unequivocally indicate that HIV-1 isolates with the NSI genotype and phenotype in MT-2 cells may actively induce syncytia in cloned CD4+ T cells in vitro and support the view that direct cytopathic effects may contribute to the steady decline in CD4+ T cells in asymptomatic HIV-1-seropositive patients without detectable SI virus.
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PMID:Syncytium induction in primary CD4+ T-cell lines from normal donors by human immunodeficiency virus type 1 isolates with non-syncytium-inducing genotype and phenotype in MT-2 cells. 747 29

We examined the replicative properties of a series of sequential isolates and biological clones of human immunodeficiency virus type 1 (HIV-1) obtained from an individual who progressed from seroconversion to AIDS in approximately 5 years. HIV-1 isolated soon after seroconversion replicated slowly and to low levels in cultures of peripheral blood mononuclear cells; however, subsequent isolates obtained during asymptomatic infection showed a marked increase in replication kinetics. This was examined in more detail by using a panel of 35 biological clones of HIV-1 generated from sequential patient peripheral blood mononuclear cell samples. Each clone was evaluated for replication in primary macrophages and CD4+ T lymphocytes and for the ability to induce syncytium formation in MT-2 cell cultures. Consistent with earlier observations, we found that all of the clones isolated just after seroconversion were slowly replicating and non-syncytium inducing (NSI). However, NSI variants with increased replication kinetics in macrophages were identified soon thereafter. These variants preceded the appearance of NSI and syncytium-inducing variants, with rapid replication in both macrophages and CD4+ T lymphocytes. To determine whether changes in the rate of replication could be traced to the early stages of the virus life cycle, PCR assays were used to evaluate entry and reverse transcription of selected biological clones in macrophages and CD4+ T lymphocytes. We found there was no inherent block to entry or reverse transcription for the slowly replicating variants; however, this does not preclude the possibility that small differences in the rate of entry may account for larger differences in the replication kinetics over many cycles. Overall, our results demonstrate that rapidly replicating variants of HIV-1 emerge during the asymptomatic period in a patient who subsequently progressed clinically, suggesting that these variants may play an important role in HIV-1 pathogenesis.
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PMID:Human immunodeficiency virus type 1 variants with increased replicative capacity develop during the asymptomatic stage before disease progression. 751 72

The third variable region (V3) of the envelope protein of human immunodeficiency virus type 1 (HIV-1) contains group- and type-specific epitopes for neutralizing antibodies and contains determinants involved in viral tropism and syncytium-inducing (SI) activity. We studied the in vivo relationship between V3 sequences and viral phenotypes in 24 perinatally HIV-1-infected children. To avoid in vitro selection of intrapatient minor variants, genetic studies were performed directly on uncultured peripheral blood mononuclear cells (PBMC), and the tropisms of HIV-1 isolates were evaluated by culturing patients' PBMC directly with monocyte-derived macrophages, lymphocytes, and MT-2 cells. According to their phenotypes, we could define five types of primary isolates: (i) non-syncytium-inducing (NSI) macrophagetropic, (ii) NSI macrophage-lymphotropic, (iii) NSI lymphotropic, (iv) SI lympho-T-cell line-tropic, and (v) SI pleiotropic. The SI viral phenotype was correlated with a more advanced status of disease. Genetic analysis of intrapatient molecular variants revealed that no relationship between the degree of intrapatient V3 variability and the pattern of viral tropism existed; moreover, within a single patient, the values for V3 variability between CD4+ lymphocytes and CD14+ monocytes were similar, thus suggesting that in vivo variability of the monocytotropic variants is more extensive than previously appreciated. A comparison between the intrapatient major variants and the phenotype of primary isolates disclosed that a negatively charged amino acid at residue site 25 was associated with an NSI macrophage- and macrophage-lymphotropic viral phenotype. Finally, by comparing the V3 sequences derived from our study population with those of several prototypes, we observed that the majority of isolates circulating in Italy are related to the North American subtype B macrophagetropic isolates.
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PMID:Relationship between the V3 loop and the phenotypes of human immunodeficiency virus type 1 (HIV-1) isolates from children perinatally infected with HIV-1. 752 89

Foscarnet (phosphonoformic acid) is a pyrophosphate analog that inhibits the replication of human immunodeficiency virus type 1 (HIV-1) in vitro and in patients with AIDS. HIV-1 resistance to foscarnet has not been reported despite long-term foscarnet therapy of AIDS patients with cytomegalovirus disease. We therefore attempted to select foscarnet-resistant HIV-1 in vitro by serial endpoint passage of virus in 400 microM foscarnet. After 13 cycles of passage in MT-2 cells, virus exhibiting > or = 8.5-fold foscarnet resistance was isolated. The reverse transcriptase (RT) from resistant virions exhibited a similar level of foscarnet resistance in enzyme inhibition assays (approximately 10-fold resistance). Foscarnet-resistant virus showed increased susceptibility to 3'-azido-3'-deoxythymidine (90-fold) and to the HIV-1-specific RT inhibitors TIBO R82150 (30-fold) and nevirapine (20-fold). DNA sequence analysis of RT clones from resistant virus revealed the coexistence of two mutations in all clones: Gln-161 to Leu (CAA to CTA) and His-208 to Tyr (CAT to TAT). Sequence analysis of six clinical HIV-1 isolates showing reduced susceptibility to foscarnet revealed the Tyr-208 mutation in two, the Leu-161 mutation in one, and a Trp-88-to-Ser or -Gly mutation in four isolates. Site-specific mutagenesis and production of mutant recombinant viruses demonstrated that the Leu-161, Ser-88, and Tyr-208 mutations reduced HIV-1 susceptibility to foscarnet 10.5-, 4.3-, and 2.4-fold, respectively, in MT-2 cells. In the crystal structure of HIV-1 RT, the Gln-161 residue lies in the alpha E helix beneath the putative deoxynucleoside triphosphate (dNTP) binding site. The Gln-161-to-Leu mutation may affect the structure of the dNTP binding site and its affinity for foscarnet. The location of the Trp-88 residue in the Beta5a strand of HIV-1 RT suggest that the Ser-88 mutation affects template-primer binding, as do several mutations that affect RT susceptibility to nucleoside analogs.
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PMID:Novel mutations in reverse transcriptase of human immunodeficiency virus type 1 reduce susceptibility to foscarnet in laboratory and clinical isolates. 754 60

The biological properties and amino acid sequences of the third variable domain (V3 loop and flanking regions) of the env region of 34 HIV-1 isolates obtained from Romanian children were analyzed. Unambiguous nucleic acid sequences were obtained from 31 isolates. The derived V3 amino acid sequences were highly homologous (93-100%) and clustered with the HIV-1 subtype F Romanian consensus. Five of the 31 isolates presented a syncytium-inducing phenotype in MT-2 cells and established continuous viral replication in various CD4+ cell lines (rapid/high phenotype). The V3 sequence from one of these isolates showed a slightly lesser degree of homology with the consensus sequence. The presence of positively charged amino acids at positions 306 and 320 has been strongly associated with the ability to induce syncytia in MT-2 cells, whereas negatively or uncharged amino acids at these positions are present in non-syncytium-inducing isolates (slow/low phenotype). There was, however, no correlation between phenotype and amino acid sequence in the five syncytium-inducing isolates; negatively or uncharged amino acids were conserved at positions 306 and 320 for all 31 isolates in sequences obtained from PBMCs. A tendency toward a more positive net charge in the V3 loop of syncytium-inducing isolates was noted. These data confirm the recent observations that HIV-1 isolates from Romania not only cluster in subtype F, but also show a high degree of interpatient homogeneity in the V3 region.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of HIV type 1 from Romanian children: lack of correlation between V3 loop amino acid sequence and syncytium formation in MT-2 cells. 757 16

The dynamics leading to the emergence of a zidovudine-resistant mutation at codon 215 of the reverse transcriptase coding region was investigated in a cohort of HIV-infected individuals who received early zidovudine therapy. Clinical implications and the role of the resistance mutation at codon 41 were also assessed. Thirty-eight initially asymptomatic HIV-infected patients with a CD4+ cell count above 400 cells/mm3 were followed for a mean period of 121 weeks (20 received zidovudine and 18 matching placebo). Specific mutations in the HIV-1 reverse transcriptase coding region conferring resistance to zidovudine were detected using a selective polymerase chain reaction. During the follow-up period a mutation at codon 215 was detected in eight (40%) of the individuals in the zidovudine group, and in two of these eight subjects, a mutation at codon 41 was found. During the study, disease progression occurred in seven of the eight (88%) patients with a mutation at codon 215, compared with 7 of 18 (39%) patients assigned to the placebo group and 3 of the 12 (25%) patients receiving zidovudine treatment who did not develop a 215-mutant strain (p < 0.05). At entry, none of the patients harbored MT-2 tropic virus. Therefore, the emergence of a zidovudine-resistant mutation at codon 215 is associated with subsequent disease progression in asymptomatic HIV-infected patients who receive zidovudine monotherapy. This association suggests that the mutation at codon 215 is involved in a loss of therapeutic efficacy and, therefore, patients should be monitored during treatment with zidovudine.
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PMID:Emergence and clinical relevance of mutations associated with zidovudine resistance in asymptomatic HIV-1 infected patients. 758 24

Primary human immunodeficiency virus type 1 (HIV-1) isolates were obtained from 22 patients with AIDS from northern Thailand, where HIV-1 is transmitted primarily through the heterosexual route. Viral sequences were determined for the 22 patients with AIDS, and all were subtype E HIV-1 on the basis of sequence analysis of a region from the envelope protein gp120. Syncytium-inducing (SI) viruses were detected for 16 of 22 patients with AIDS by using MT-2 cells. Characteristics of amino acid sequences in V3 which have not been reported previously for subtype B SI HIV-1 were associated with the subtype E HIV-1 SI phenotype. The SI viruses from our study population contain predominantly a GPGR or GPGH motif at the tip of the V3 loop, in contrast to the previously described subtype E HIV-1 from Thailand which contained predominantly GPGQ. All the SI viruses lost a potential N-linked glycosylation site in V3 which is highly conserved among previously described subtype E HIV-1 isolates from asymptomatic patients from Thailand. HIV-1 envelope sequences including V3 from some patients with AIDS were significantly more divergent than viruses from asymptomatic patients in Thailand characterized 2 years ago or earlier. These results suggest that emergence of subtype E SI HIV-1 variants is associated with the development of AIDS, as it is for subtype B HIV-1. The divergence of subtype E HIV-1 in patients with AIDS as the disease progresses, and the divergence of subtype E HIV-1 in the infected population as the epidemic continues in Thailand, may have important implications for vaccine development.
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PMID:Phenotypic and genotypic characteristics of human immunodeficiency virus type 1 from patients with AIDS in northern Thailand. 760 29

Among 75 consecutive human immunodeficiency virus type 1 (HIV-1)-infected patients with moderate and advanced immunosuppression, those harboring syncytium-inducing (SI) HIV-1 had a lower CD(4+)-cell count (145 versus 278 cells per microliter, P < 0.001) and 10-fold-higher virus titers than patients with non-SI HIV-1 (398 versus 39 infectious units per 10(6) CD4+ lymphocytes; P < 0.001). In patients with SI virus, the mean titer of SI virus, determined with a quantitative MT-2 cell assay, was 135 SI infectious units per 10(6) CD4+ lymphocytes. Virus titer correlated inversely with CD(4+)-cell count in patients with SI (r = -0.67) but not non-SI (r = -0.29) virus.
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PMID:Quantitative analysis of syncytium-inducing and non-syncytium-inducing virus in patients infected with human immunodeficiency virus type 1. 769 44

The relationship was investigated between a viral infectious titer in peripheral blood mononuclear cells (PBMC) and plasma on the replicative and syncytium-inducing capacity of human immunodeficiency virus type 1 (HIV-1) isolates. The replicative capacity was defined as the minimum time required for p24 antigen to become positive in PBMCs or plasma of HIV-1 infected individuals, cocultured with PBMCs of healthy donors. Syncytium induction was determined by the MT-2 cell assay and defined as the presence of giant multinucleated cells. The replicative capacity of HIV-1 in PBMCs of healthy donors correlated with the infectious viral titer in PBMCs, but not in the plasma of HIV-1 positive patients. Syncytia formation in MT-2 cells was not related to the infectious viral titer in PBMCs or plasma of HIV-1 positive patients. These findings suggest that syncytium formation, not replicative capacity, is an intrinsic HIV-1 phenotype.
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PMID:Infectious virus titer, replicative and syncytium-inducing capacity of human immunodeficiency virus type 1. 771 95

Human immunodeficiency virus type 1 (HIV-1) Nef protein causes the loss of cell surface CD4 and interleukin-2 (IL-2) receptor (Tac) from peripheral blood mononuclear cells (PBMC) and CD4+ T-cell lines. As both CD4 and the IL-2 receptor play crucial roles in antigen-driven helper T-cell signalling and T-cell proliferation, respectively, the role of Nef in the viral life cycle may be to perturb signalling pathways emanating from these receptors. However, the intracellular targets for Nef that result in receptor down-regulation are unknown. Using a recombinant glutathione S-transferase-full-length 27 kDa Nef (Nef27) fusion protein, produced in Escherichia coli by translation from the first start codon of HIV-1 nef clone pNL4-3, as an affinity reagent to probe cytoplasmic extracts of MT-2 cells and PBMC, we have shown interaction with at least seven host cell protein species ranging from 24 to 75 kDa. Immunoblotting identified four of these proteins as p56lck, CD4, p53, and p44mapk/erk1, all of which are intimately involved in intracellular signalling. To assess the relevance of these interactions and further define the biochemical activity of Nef in signal transduction pathways, highly purified Nef27 protein was introduced directly into PBMC by electroporation. Nef27-treated PBMC showed reduced proliferative responsiveness to exogenous recombinant IL-2. Normally, stimulation of T-cells by IL-2 or phorbol 12-myristate 13-acetate provokes both augmentation of p56lck activity and corresponding posttranslational modification of p56lck. These changes were also inhibited by treatment of PBMC with Nef, suggesting that Nef interferes with activation of p56lck and as a consequence of signalling via the IL-2 receptor. Further evidence for Nef interfering with cell proliferation was the decreased production of the proto-oncogene c-myb, which is required for cell cycle progression, in Nef-treated MT-2 cells. In contrast to the binding characteristics and biological effects of Nef27, the alternate 25-kDa isoform of Nef (Nef25) produced by translation from the second start codon of HIV nef pNL4-3 (57 nucleotide residues downstream) was shown to interact with only three cellular proteins of approximately 26, 28, and 56 kDa from PBMC and MT-2 cells, one of which was identified as p56lck. Also, proliferation and posttranslational modification of p56lck in response to IL-2 stimulation were not profoundly affected by treatment of PBMC with Nef25 compared with Nef27.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines. 785 25

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