The biological phenotype of primary human immunodeficiency virus type 1 (HIV-1) isolates varies according to the severity of the HIV infection. Here we show that the two previously described groups of rapid/high, syncytium-inducing (SI) and slow/low, non-syncytium-inducing (NSI) isolates are distinguished by their ability to utilize different chemokine receptors for entry into target cells. Recent studies have identified the C-X-C chemokine receptor CXCR4 (also named fusin or Lestr) and the CC chemokine receptor CCR5 as the principal entry cofactors for T-cell-line-tropic and non-T-cell-line-tropic HIV-1, respectively. Using U87.CD4 glioma cell lines, stably expressing the chemokine receptor CCR1, CCR2b, CCR3, CCR5, or CXCR4, we have tested chemokine receptor specificity for a panel of genetically diverse envelope glycoprotein genes cloned from primary HIV-1 isolates and have found that receptor usage was closely associated with the biological phenotype of the virus isolate but not the genetic subtype. We have also analyzed a panel of 36 well-characterized primary HIV-1 isolates for syncytium induction and replication in the same series of cell lines. Infection by slow/low viruses was restricted to cells expressing CCR5, whereas rapid/high viruses could use a variety of chemokine receptors. In addition to the regular use of CXCR4, many rapid/high viruses used CCR5 and some also used CCR3 and CCR2b. Progressive HIV-1 infection is characterized by the emergence of viruses resistant to inhibition by -chemokines, which corresponded to changes in coreceptor usage. The broadening of the host range may even enable the use of uncharacterized coreceptors, in that two isolates from immunodeficient patients infected the parental U87.CD4 cell line lacking any engineered coreceptor. Two primary isolates with multiple coreceptor usage were shown to consist of mixed populations, one with a narrow host range using CCR5 only and the other with a broad host range using CCR3, CCR5, or CXCR4, similar to the original population. The results show that all 36 primary HIV-1 isolates induce syncytia, provided that target cells carry the particular coreceptor required by the virus.
More than three-quarters of the HIV- and HCV Ab-positive patients in EuroSIDA showed active HCV replication. Viremia was more frequent in IDUs and, conversely, was less common in HBsAg-positive patients. Of the patients with HCV viremia analyzed, 53% were found to carry HCV genotype 1, and this genotype was associated with greater serum HCV RNA levels.
We report that interleukin 4 (IL-4) inhibits the propagation of non-syncytia-inducing and increases the propagation of syncytia-inducing HIV-1 isolates by two mechanisms. It differentially regulates the two major HIV-1 coreceptors, CCR5 and CXCR4, in human peripheral blood mononuclear cells, increasing CXCR4 and decreasing CCR5 expression in primary CD4(+) T-lymphocytes. In addition, IL-4 stimulates the expression of all HIV-1 isolates via a transcriptional activation mechanism. The combination of these effects results in increased propagation of CXCR4-using and inhibition of CCR5-using HIV-1 strains. IL-4 also activates HIV-1 expression in primary monocytes/macrophages but does not affect CCR5 expression. These results identify IL-4 as an important regulator of HIV-1 and suggest a critical role for this cytokine in the control of viral evolution and in the phenotypic switch from non-syncytia-inducing to syncytia-inducing, which leads to accelerated disease progression.
The evolution of human immunodeficiency virus type 1 (HIV-1) coreceptor use has been described as the acquisition of CXCR4 use linked to accelerated disease progression. However, CXCR4-using virus can be isolated only from approximately one-half of individuals with progressive HIV-1 disease. The other half continue to yield only CCR5-using viruses (R5 phenotype) throughout the course of disease. In the present work, the use of receptor chimeras between CCR5 and CXCR4 allowed us to study the evolution of HIV-1 with the R5 phenotype, which was not revealed by studies of wild-type coreceptor use. All together, 246 isolates (173 with the R5 phenotype) from 31 individuals were tested for their ability to infect cells through receptor chimeras. R5 narrow virus was able to use only wild-type CCR5, whereas R5 broad(1) to R5 broad(3) viruses were able to use one to three chimeric receptors, respectively. Broad use of chimeric receptors was interpreted as an increased flexibility in the mode of receptor use. R5 broad isolates showed higher infectivity in cells expressing wild-type CCR5 than R5 narrow isolates. Also, the increased flexibility of R5 broad isolates was concomitant with a lower sensitivity to inhibition by the CC chemokine RANTES. Our results indicate a close relationship between HIV-1 phenotypic changes and the pathogenic process, since the mode and efficiency of CCR5 use as well as the decrease in the RANTES sensitivities of isolated viruses are significantly correlated with CD4؉ -T-cell decline in a patient. One possible explanation is that ligand competition at the CCR5 receptor or changed CCR5 availability may shape the outcome of HIV-1 infection.
Primary HIV-1 isolates were evaluated for their sensitivity to inhibition by -chemokines RANTES (regulated upon activation, normal T-cell expressed and secreted), macrophage inflammatory protein 1␣ (MIP-1␣), and MIP-1. Virus isolates of both nonsyncytium-inducing (NSI) and syncytium-inducing (SI) biological phenotypes recovered from patients at various stages of HIV-1 infection were assessed, and the results indicated that only the isolates with the NSI phenotype were substantially inhibited by the -chemokines. More important to note, these data demonstrate that resistance to inhibition by -chemokines RANTES, MIP-1␣, and MIP-1 is not restricted to T cell line-adapted SI isolates but is also a consistent property among primary SI isolates. Analysis of isolates obtained sequentially from infected individuals in whom viruses shifted from NSI to SI phenotype during clinical progression exhibited a parallel loss of sensitivity to -chemokines. Loss of virus sensitivity to inhibition by -chemokines RANTES, MIP-1␣, and MIP-1 was furthermore associated with changes in the third variable (V3) region amino acid residues previously described to correlate with a shift of virus phenotype from NSI to SI. Of interest, an intermediate V3 genotype correlated with a partial inhibition by the -chemokines. In addition, we also identified viruses sensitive to RANTES, MIP-1␣, and MIP-1 of NSI phenotype that were isolated from individuals with AIDS manifestations, indicating that loss of sensitivity to -chemokine inhibition and shift in viral phenotype are not necessarily prerequisites for the pathogenesis of HIV-1 infection.
Internet-based cognitive behavior therapy (CBT) has been shown effective for university students with social anxiety disorder (SAD) and public speaking fears. The aim of this study was to investigate whether the promising results can be transferred to high school students suffering from this condition. A total of 19 speech-anxious high school students with SAD were randomized either into 9 weeks of Internet-delivered CBT or to a wait-list control group. Significant improvements were found on measures of social anxiety, general anxiety, and depression. Effects were maintained at 1-year follow-up. The average within- and between-group effect sizes (Cohen's d) for the primary social anxiety scales at posttest were 0.98 and 1.38, respectively. However, the average number of completed modules in the CBT program was low. Although compliance can be improved, the results suggest that Internet-based guided self-help is effective in the treatment of high school students with SAD.
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