摘要:

SummaryTo determine the safety, maximum tolerated dose, and preliminary efficacy of concomitant interferon-α and zidovudine therapy in AIDS-related Kaposi's sarcoma (KS), 56 patients with biopsy-proven KS and documented human immunodeficiency virus type 1 (HIV) infection were enrolled into a phase I study. Interferon-α was given intramuscularly at a dose of 9, 18, or 27 mu once a day and zidovudine was administered as 100 or 200 mg every 4 h for 8 weeks followed by a 48-week maintenance period. The major toxicities were anemia, neutropenia, and hepatotoxicity. Neutropenia was dose limiting with 1,200 mg of zidovudine/day and the lowest dose of interferon-α (9 mu/day). Hepatotoxicity was dose limiting with 27 mu of interferon and 600 mg of zidovudine/day. Cumulative dose-related anemia or neutropenia was not seen during long-term follow-up. The maximum tolerated doses for the combination were defined as 18 mu daily for interferon-α and 600 mg daily for zidovudine. Variable changes in CD4 lymphocytes occurred during the first 8 weeks of therapy. At higher doses of the combination, sustained increases in median CD4 lymphocyte numbers were noted (p< 0.001). In HIV antigenemic patients, progressive antigen suppression was seen with increasing doses of the combination (p< 0.005). The overall antitumor response rate was 47%. Tumor regression was associated with better survival benefits (p< 0.001) and a pre-treatment CD4 cell count ≧200 cells/mm3(p= 0.01). In conclusion, intermediate doses of interferon-α and lower doses of zidovudine appear to be relatively well tolerated and associated with disease improvement, including survival benefits.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryThe safety of continuous i.v. interleukin-2 (IL-2) in conjunction with zidovudine (ZDV) was assessed in asymptomatic patients infected with human immunodeficiency virus. Clinical, immunologic, and viral parameters were monitored in a phase I/II trial with dose escalation and crossover arms. Daily doses of IL-2 from 1.5 to 12 x 106IU/m2were well tolerated and, in the presence of ZDV, did not induce increases in p24 antigenemia. Significant (p< 0.05) but transient increases in CD4 cells were observed midway through infusion of IL-2 at all doses, and increases in natural and lymphokine-activated killer activity were seen at higher doses. Circulating hypodense eosinophils and soluble IL-2 receptors increased more than 10-fold. Of nine patients available for long-term follow up 13–25 months from baseline and 4–21 months after stopping IL-2, six still had improved CD4 counts (versus baseline), and the mean increase (135/mm3) for all nine patients was significant (p< 0.05). Eight of these nine patients were negative for serum p24 at the start of therapy, and none had become p24 antigenemic at long-term follow-up.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryIn this study, we asked whether there is a difference in the number of CD4+and CD4−peripheral blood monocytes as CD4+T cells decrease during HIV-mediated immunodeficiency. Monocytes and T cells from 90 HIV-positive and 43 HIV-negative persons were analyzed by flow cytometry. The 90 HIV-positive patients represented the entire spectrum of CD4+T-cell counts. We report that as CD4+T cells decrease, the number of CD4+monocytes decrease in parallel. Moreover, significantly higher CD4+monocyte counts were observed in persons with early stage HIV disease, i.e., >800 CD4+T cells/mm3, than in HIV-negative persons with >800 CD4+T cells/mm3. Potential implications of these findings are discussed.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryWe used an autonomic nervous system (ANS) testing battery to determine if generalized ANS dysfunction was present in five human immunodeficiency virus-positive (HIV +) patients presenting with severe orthostatic hypotension (OH). All five patients had abnormal ANS testing, which demonstrated both sympathetic and parasympathetic defects, i.e., generalized ANS dysfunction. Treatment with fludrocortisone effectively reversed the OH in four of the five patients. The OH was transient in these four patients. We believe it is important to recognize that OH may be the result of generalized ANS dysfunction in HIV-positive patients and that it can be effectively treated.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryThe gp41 transmembrane protein of human immunodeficiency virus type 1 (HIV-1) contains a hydrophobic membrane-spanning domain that serves to anchor the gp120-gp41 complex on the surface of infected cells and virions. To study the requirements for membrane anchorage, conservative amino acid substitutions in three residues at a time were made within this hydrophobic gp41 region. The complete gp160 precursor as well as the gp120 exterior envelope glycoprotein were exported into the supernatant of expressing cells for two mutants with amino acid substitutions in residues 687–689 and 697–699. The soluble gp160 molecules exhibited a binding ability for CD4 on the surface of SupT1 cells that was 33–36% that of the soluble gp120 glycoproteins. These results implicate residues 687–689 and 697–699 as important components of the stop-transfer signal that anchors the gp160 envelope glycoprotein precursor in the membrane. The data also suggest that characteristics in addition to hydrophobicity are required for stop-transfer signals.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryAn early host defense against infection by RNA or DNA viruses is the induction, within infected cells, of tumor necrosis factor-α (TNF-α) gene transcription. The protein product of the TNF-α gene alone, or together with different types of interferons, inhibits viral propagation in diverse cell types. In this study, the effect of acute and chronic human immunodeficiency virus type 1 (HIV-1) infection on the transcription of the TNF-α and interferon-β (IFN-β) genes was examined in susceptible monocyte and T-cell lines as well as in primary human mononuclear phagocytes. Although Sendai virus, a prototypic inducer of TNF-α and IFN-β mRNA. induced the transcription of both genes in the monocyte cell lines and TNF-α in the T-cell line and in primary mononuclear phagocytes, transcription of these genes was not inducible by HIV-1. Therefore, HIV-1 was able to infect these cells without triggering the transcription of genes encoding proteins important in immediate antiviral cellular defenses. These results may explain in part how HIV-1 is able to establish persistent intracellular infections and escape acute host responses that have evolved to combat viral infection.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryInhibitors of glycoprotein processing, such as castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine), have been shown previously to inhibit human immunodeficiency virus type 1 (HIV-1) with acceptable toxicity in cultured human cells. In prior experiments, we have tested the toxicity and antiviral efficacy of castanospermine in mice infected with the Rauscher murine leukemia virus (RLV). When compared with 3‘-azido-3’-deoxythymidine (AZT, zidovudine), castanospermine was less effective and more toxic. Since the 6-O-butanoyl analog of castanospermine was previously found to have a more favorable activity profile than the parent compound against HIV-1 in cultured cells, we compared the antiviral efficacy of both compounds in parallel in vitro and in vivo in the RLV system. Plaque formation in the XC assay was inhibited with a 50% inhibitory concentration (IC50) of 2.4 μMfor the 6-O-butanoyl analog of castanospermine, as compared to 9 μM for castanospermine. For both compounds, concentrations resulting in significant cytotoxicity were about ten times higher. Both compounds significantly decreased HIV-1env-induced syncytium formation in a novel in vitro assay. In RLV-exposed mice, the 6-O-butanoyl analog showed no advantage over the parent compound: both curves for toxicity as well as antiviral efficacy were super-imposable. We conclude that the 6-O-butanoyl analog of castanospermine as well as castanospermine itself are active antiviral agents in mice and that prolonged oral administration is tolerable. However, in comparison to AZT, their antiviral activity profiles are less favorable.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryPhysical contact between latent HIV-infected monocytes and epithelial cells appears to trigger rapid assembly and release of HIV into the enclosed space between donor and acceptor cells. During this process, monocytes form microvilli that intimately associate with epithelial membrane. HIVs sequestered in these sites are then internalized in the epithelial cells within phagocytic endosomes. Morphological evidence suggests that parts of virions fuse with the endosomal membrane and escape into the cytoplasm of the epithelium before endosome-lysosome fusion. In addition, virions in the lysosomal compartment are not necessarily degraded and may cause dissolution of phagolysosome membrane before HIV is damaged. This is reflected in the observation of free coated virions in the epithelial cytoplasm. Apart from the phagocytic mode of HIV entry, two other less common routes of HIV penetration were observed. One resembles direct HIV fusion with host membrane, which is similar to the entry mode of virus into CD4 lymphocytes. The second mode of entry resembles receptor-mediated endocytosis characterized by small pits and endosomes. Cell contact-mediated viral shedding and the diversity of HIV entry mechanisms are described for an in vitro model.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryAdministration of zidovudine (ZDV or azidothymidine) to pregnant women with HIV infection may be of benefit to both the mother and her unborn child. Since pregnancy can have a substantial effect on the pharmacokinetics of a drug, the effect of pregnancy on the pharmacokinetics of ZDV (10 mg/kg, i.v. bolus) was studied in the macaque (Macaca nemestrina). The plasma clearance, steady-state volume of distribution, and terminal half-life of ZDV were found not to be significantly affected by pregnancy. Based on these findings, we predict that the pharmacokinetics of ZDV in women will not be affected by pregnancy. If this prediction is found to be correct, the dose of ZDV need not be adjusted when the drug is administered to pregnant women.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryData from a cohort study of 1,637 homosexual men in Los Angeles are used to estimate the distribution of times from HIV infection to AIDS, and to detect any changes in the distribution. We find weak, but not statistically significant, evidence that the incubation period is lengthening. When the incubation period distribution is assumed not to have changed, we estimate that the proportion developing AIDS within 6 years of HIV infection is 27%, with a 95% confidence interval of (23%, 31%). However, if we assume that the incubation period distribution began to change in July 1987, then we estimate that for individuals infected in the first half of 1979, 28% develop AIDS within 6 years, and for those infected in the first half of 1983, 25% develop AIDS in 6 years. Four different hypotheses are suggested for a lengthening of the incubation period; these are a treatment hypothesis, a cofactor hypothesis, a better health care hypothesis, and a changing virus and disease hypothesis. The statistical method used is semiparametric modeling of the joint distribution of the date of infection and the incubation period for the participants in the study. These methods, although computationally intensive, are an attractive way of analyzing data from a prevalent cohort because only minimal parametric assumptions are made.

ISSN:0894-9255    

出版商:OVID    

年代:1991

数据来源: OVID