2-mercapto N-(azolyl)benzenesulfonamides. VI. Synthesis and anti-HIV activity of some new 2-mercapto-N-(1,2,4-triazol-3-yl)benzenesulfonamide derivatives containing the 1,2,4-triazole moiety fused with a variety of heteroaromatic rings.
(1/994)
A series of 2-mercapto-N-(1,2,4-triazol-3-yl)benzenesulfonamide derivatives containing the triazole moiety fused with a variety of heteroaromatic rings [XVI-XXVIII] was obtained by the reactions of 3-methylthio-1,4-2-benzodithiazine 1,1-dioxide derivatives [Ia-d] with 2-hydrazines [IIa-f]. Some of the intermediate 1,1-dioxide-1,4,2-benzodithiazin-3-ylhydrazines [III-XV] initially formed were also isolated. Preliminary screening data indicated that compounds [XVI-XIX and XXVII] were anti-HIV inactive, whereas other compounds showed a high [XXI and XXIII], fairly high [XXIII and XXVI] or moderate [XX, XXIV, XXV and XXVIII] activity. The compound [XXI] exhibited also high activity against ten selected HIV mutants. (+info)
Human immunodeficiency virus types 1 and 2 differ in the predominant mechanism used for selection of genomic RNA for encapsidation.
(2/994)
Retroviral RNA encapsidation is a highly selective process mediated through recognition by the viral Gag proteins of cis-acting RNA packaging signals in genomic RNA. This RNA species is also translated, producing the viral gag gene products. The relationship between these processes is poorly understood. Unlike that of human immunodeficiency virus type 1 (HIV-1), the dominant packaging signal of HIV-2 is upstream of the major splice donor and present in both unspliced and spliced viral RNAs, necessitating additional mechanisms for preferential packaging of unspliced genomic RNA. Encapsidation studies of a series of HIV-2-based vectors showed efficient packaging of viral genomes only if the unspliced, encapsidated RNA expressed full-length Gag protein, including functional nucleocapsid. We propose a novel encapsidation initiation mechanism, providing selectivity, in which unspliced HIV-2 RNA is captured in cis by the Gag protein. This has implications for the use of HIV-2 and other lentiviruses as vectors. (+info)
Human immunodeficiency virus antibody testing by enzyme-linked fluorescent and western blot assays using serum, gingival-crevicular transudate, and urine samples.
(3/994)
The aim of the present study was to evaluate the possible utilization of saliva and urine as alternative samples to serum for the diagnosis of human immunodeficiency virus (HIV) infection. A total of 302 individuals participated in the study: 187 HIV-infected individuals (106 had Centers for Disease Control and Prevention [CDC] stage II infection, 19 had CDC stage III infection, and 62 had CDC stage IV infection) and 115 noninfected persons (46 of the noninfected persons were blood donors and 69 belonged to a group at high risk of HIV infection). Paired saliva and urine samples were taken from each of the participants in the study. The presence of HIV-specific antibodies was detected by an enzyme-linked fluorescent assay (ELFA), and the result was confirmed by Western blot analysis (WB). The ELFA with saliva gave maximum sensitivity and specificity values, while ELFA had lower sensitivity (95.2%) and specificity (97. 4%) values for detection of HIV antibody in urine samples. WB with all saliva samples fulfilled the World Health Organization criterion for positivity, while only 96.8% of the urine samples were confirmed to be positive by WB. Among the four reactivity patterns found by WB of these alternative samples, the most frequent included bands against three groups of HIV structural proteins (was ENV, POL, and GAG). The reactivity bands most frequently observed were those for the proteins gp160 and gp120. The least common reactivity band was the band for protein p17. The detection of HIV antibodies in saliva samples by means of ELFA with the possibility of later confirmation by WB makes saliva an alternative to serum for possible use in the diagnosis of infection. In contrast, HIV antibody detection in urine samples by the same methodology (ELFA) could be taken into consideration for use in epidemiological studies. (+info)
Viral burden and disease progression in rhesus monkeys infected with chimeric simian-human immunodeficiency viruses.
(4/994)
To determine the role of viral burden in simian-human immunodeficiency virus (SHIV)-induced disease, cellular provirus and plasma viral RNA levels were measured after inoculation of rhesus monkeys with four different SHIVs. These SHIVs included SHIV-HXBc2 and SHIV-89.6, constructed with env, tat, rev, and vpu derived from either cell line-passaged or primary patient isolates of human immunodeficiency virus type 1; the viral quasispecies SHIV-89.6P derived after in vivo passage of SHIV-89.6; and a molecular clone, SHIV-KB9, derived from SHIV-89.6P. SHIV-HXBc2 and SHIV-89.6 are nonpathogenic in rhesus monkeys; SHIV-89.6P and SHIV-KB9 cause rapid CD4(+) T cell depletion and an immunodeficiency syndrome. Relative SHIV provirus levels were highest during primary infection in monkeys infected with SHIV-89.6P, the virus that caused the most rapid and dramatic CD4(+) T cell depletion. However, by 10 weeks postinoculation, provirus levels were similar in monkeys infected with the pathogenic and nonpathogenic chimeric viruses. The virus infections that resulted in the highest peak and chronic viral RNA levels were the pathogenic viruses SHIV-89.6P and SHIV-KB9. SHIV-89. 6P uniformly caused rapid and profound CD4(+) T cell depletion and immunodeficiency. Infection with the SHIV-KB9 resulted in very low CD4(+) T cell counts without seroconversion in some monkeys and a substantial but less profound CD4(+) T cell depletion and rapid seroconversion in others. Surprisingly, the level of plasma viremia did not differ between SHIV-KB9-infected animals exhibiting these contrasting outcomes, suggesting that host factors may play an important role in AIDS virus pathogenesis. (+info)
CD26/dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3.
(5/994)
Chemokines attract and activate distinct sets of leukocytes. The CC chemokine eotaxin has been characterized as an important mediator in allergic reactions because it selectively attracts eosinophils, Th2 lymphocytes, and basophils. Human eotaxin has a penultimate proline, indicating that it might be a substrate for dipeptidyl-peptidase IV (CD26/DPP IV). In this study we demonstrate that eotaxin is efficiently cleaved by CD26/DPP IV and that the NH2-terminal truncation affects its biological activity. CD26/DPP IV-truncated eotaxin(3-74) showed reduced chemotactic activity for eosinophils and impaired binding and signaling properties through the CC chemokine receptor 3. Moreover, eotaxin(3-74) desensitized calcium signaling and inhibited chemotaxis toward intact eotaxin. In addition, HIV-2 infection of CC chemokine receptor 3-transfected cells was inhibited to a similar extent by eotaxin and eotaxin(3-74). Thus, CD26/DPP IV differently regulates the chemotactic and antiviral potencies of eotaxin by the removal of two NH2-terminal residues. This physiological processing may be an important down-regulatory mechanism, limiting eotaxin-mediated inflammatory responses. (+info)
Potent inhibition of human immunodeficiency virus type 1 (HIV-1) gene expression and virus production by an HIV-2 tat activation-response RNA decoy.
(6/994)
Tat activation-response region (TAR) decoys have been developed for use in gene therapy for people infected with human immunodeficiency virus type 1 (HIV-1). When a TAR RNA decoy is overexpressed, it will bind Tat, thus leaving less of this crucial protein to bind to and activate the natural transcriptional promoter of HIV-1. Previous TAR decoy constructs have used HIV-1 TAR. However, recent epidemiological and biological data began to suggest that the TAR region from the human immunodeficiency virus type 2 (HIV-2) may suppress HIV-1 transcription and hence replication. We created a vector which overexpresses TAR-2 under the control of the human U6 small nuclear RNA gene promoter and here show that the U6-TAR-2 decoy construct potently inhibits both HIV-2 and HIV-1 gene expression. Further, this decoy construct is able to markedly suppress HIV-1 replication. Thus, we have directly proven that TAR-2 can suppress HIV-1 replication and suggest that the HIV-2 TAR decoy may prove useful for combating HIV-1 infection. (+info)
Human immunodeficiency virus type 2 produces a defect in CD3-gamma gene transcripts similar to that observed for human immunodeficiency virus type 1.
(7/994)
T cells are central players in the immune response to infectious disease, with the specificity of their responses controlled by the T-cell receptor (TCR)/CD3 complex on the cell surface. Impairment of TCR/CD3-directed CD4(+) T-cell immune responses is frequently observed in individuals infected with human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Virus replication is also regulated by T-cell activation factors, with HIV-1 and HIV-2 responding to different TCR/CD3-directed cellular pathways. We previously demonstrated that HIV-1 infection of the human interleukin-2-dependent CD4(+) T-cell line WE17/10 abrogates TCR/CD3 function and surface expression by a specific loss of CD3-gamma gene transcripts. In this study, we show that HIV-2 provokes the same molecular defect in CD3-gamma gene transcripts, resulting in a similar but delayed progressive loss of TCR/CD3 surface expression after infection. (+info)
An orphan G protein-coupled receptor, GPR1, acts as a coreceptor to allow replication of human immunodeficiency virus types 1 and 2 in brain-derived cells.
(8/994)
Twelve G protein-coupled receptors, including chemokine receptors, act as coreceptors and determinants for the cell tropisms of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). We isolated HIV-1 variants from T-cell-line (T)- and macrophage (M)-tropic (i.e., dualtropic) (R5-R3-X4) HIV-1 strains and also produced six HIV-1 mutants carrying single-point amino acid substitutions at the tip of the V3 region of the Env protein of HIV-1. These variants and three mutants infected brain-derived CD4-positive cells that are resistant to M-, T-, or dualtropic (R5, X4, or R5-X4) HIV-1 strains. However, a factor that determines this cell tropism has not been identified. This study shows that primary brain-derived fibroblast-like cell strains, BT-3 and BT-20/N, as well as a CD4-transduced glioma cell line, U87/CD4, which were susceptible to these HIV-1 variants and mutants and the HIV-2ROD strain, expressed mRNA of an orphan G protein-coupled receptor (GPCR), GPR1. When a CD4-positive cell line which was strictly resistant to infection with diverse HIV-1 and HIV-2 strains was transduced with GPR1, the cell line became susceptible to these HIV-1 variants and mutants and to an HIV-2 strain but not to T- or dualtropic HIV-1 strains, and numerous syncytia formed after infection. These results indicate that GPR1 functions as a coreceptor for the HIV-1 variants and mutants and for the HIV-2ROD strain in vitro. (+info)