摘要:

SummaryThe human T-cell leukemia type I (HTLV-I) virus is associated with two different diseases, adult T-cell leukemia (ATL) and tropical spastic para-paresis/HTLV-I-associated myelopathy (TSP/HAM). We have compared the viral envelopes originating from TSP/HAM and ATL patients, using the capacity of infected cells to form syncytia with receptor-expressing cells. We show that like the ATL cell lines, the TSP/HAM ones can form syncytia with a large panel of human target cells, including a variety of hematopoietic cell lines, as well as cell lines of neuroectodermal origin. None of the target cell lines tested was able to discriminate between TSP/HAM- and ATL-infected cell lines. When infected cells of TSP/HAM origin are cocultivated with cells of ATL origins, syncytia are never observed. This interference phenomenon suggests that the viruses expressed by the different cell lines utilize the same receptor.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryDespite its shortcomings as a disease model, the chimpanzee is still the most relevant animal model for human immunodeficiency virus type 1 (HIV-I) infection. Previous studies have revealed qualitative differences between human and chimpanzee anti-HIV-1 responses. In this study, the development of specific anti-HIV-1 antibody-dependent cellular cytotoxic (ADCC) reactivities was evaluated in chronically infected chimpanzees and compared to the human response, because anti-HIV-1 ADCC represents a major component of anti-envelope cytolytic response found in infected patients. Ten HIV-1-infected chimpanzees up to 5 years after the infection were investigated. Anti-HIV-1 ADCC-directing antibodies were detectable in only three of 10 infected chimpanzees, and in these animals, activity was apparent only several months after the HIV infection. In some of the infected animals, ADCC reactivity against infected cells preceded reactivity against gp120-coated targets. When anti-gp120 ADCC-directing antibodies were apparent, they exhibited the same broad reactivity described in humans against different HIV isolates. The pattern of ADCC reactivities in infected chimpanzees is completely different from the well-characterized anti-gp120 cytotoxic reactivities present in HIV-1-infected patients. It is a relatively rare and late-occurring event that may have an important bearing on the lack of virus-induced pathogenesis in the chimpanzee model.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryUsing human monoclonal antibodies (HuMAbs) r(1)-447 (L-736,523) and 19b to the V3 region of HIV-1 gp120, we have explored epitope presentation on V3-peptides and on the corresponding gp120 proteins. HuMAb r(1)-447 binds strongly to the MN and SF-2 peptides and gp120 proteins. In contrast, while this HuMAb binds equally avidly to both the HxB2 and the BRU/BH10 peptides, it binds but weakly to the HxB2 V3 loop on gp120 and fails to bind at all to BH10 gp120. Thus, the solid-phase peptide binding assay can falsely predict reactivity of an MAb with a gp120 protein. Conversely, HuMAb 19b fails to bind to a peptide from the V3 loop of HIV-1 AD-6 in solid-phase assays, but binds to the same peptide in solution and also to AD-6 gp120. Thus, the solid-phase peptide binding assay can fail to predict reactivity of an MAb with a gp120 protein. Furthermore, serum antibodies from individual AD-6 do not react well with the AD-6 V3-peptide in a solid-phase assay, but react strongly with the corresponding MN V3-peptide. On the basis of peptide binding assays, we had assumed that the AD-6 virus was “MN-like” with a prototypic North American/European subtype B GPGR motif at the crown of the V3 loop. However, direct sequencing demonstrates that the AD-6 V3 loop contains a variant GPGK motif. This highlights a limitation of V3-peptide-based assays for serotyping viruses.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryHuman immunodeficiency virus type 1 (HIV-1) gp-120 potentially plays an important role in inducing functional suppression and depletion of CD4 lymphocytes following infection with HIV. In order to further understand the mechanisms involved in HIV-induced immunosuppression, we have studied the effects of recombinant HIV-1 gp120/SF2 and anti-gp120/SF2 antibodies on T cell receptor (TCR)-mediated proliferation of peripheral blood mononuclear cells (PBMCs) and isolated lymphocyte subsets from HIV-seronegative donors. In a dose-dependent manner, gp120 significantly reduces the proliferative responses of unfractionated PBMCs and highly enriched CD4 T lymphocytes when they are polyclonally stimulated through the TCR using WT31 (anti-αβ Ti chains) and anti-Leu 4 (anti-CD3) in the presence of autologous accessory cells. The addition of divalent anti-gp120/SF2 to lymphocytes previously incubated with gp120 further reduces the proliferation to the levels seen after pretreating cells with divalent anti-CD4 (anti-Leu 3a). CD8 T lymphocytes, on the other hand, show no change in TCR-mediated proliferation following preincubation with either anti-CD4 or gp120/anti-gp120. We find no evidence for significant cell death by apoptosis using methods of DNA analysis or flow cytometry and DNA-specific dyes to account for the loss of CD4 lymphocyte proliferation. Interleukin-2 restores the proliferation suppressed by gp120/anti-gp120 suggesting the induction of reversible functional anergy.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryWe wished to determine whether antiretroviral therapy with zidovudine first received when a person is diagnosed with AIDS was associated with diminished or increased direct health resource utilization. As a measure of health resource utilization, we examined all Medicaid-administered health care charges to adult Maryland residents diagnosed with AIDS from 1987 to 1989 who were part of the Human Immunodeficiency Virus Information System. We specifically compared those persons who first received zidovudie therapy either prior to or within 60 days of diagnosis of AIDS (n = 101) with those who never received zidovudine therapy (n = 279). Median survival time after diagnosis of AIDS in those who received zidovudine was 605 days and in those who did not receive zidovudine 235 days. After diagnosis of AIDS, median per-person lifetime direct health care charges to Medicaid were $66,200 in those who received zidovudine and $31,300 in those who did not receive zidovudine. The median incremental charge per year of life gained in zidovudine users was $34,600 compared with nonusers. Adjusting by proportional hazards regression for age, gender, race/ethnicity, HIV transmission risk group, AIDS-defining diagnosis, and length of follow-up, lifetime Medicaid charges were higher in zidovudine receivers. Compared with patients who did not receive zidovudine, patients who first received zidovudine at the time AIDS was diagnosed incurred higher cumulative lifetime charges, associated principally with longer survival time. The rate of resource utilization was not decreased by zidovudine use.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryTreatment with zidovudine has been standard therapy for patients with advanced HIV infection, but intolerance is common. Previously, management of intolerance has consisted of symptomatic therapy, dose interruption/discontinuation, and, when appropriate, transfusion. The availability of new antiretroviral agents such as didanosine as well as adjunctive recombinant hematopoietic growth factors makes additional strategies possible for the zidovudine-intolerant patient. Because all of these agents are costly, we evaluated the cost implications of these various strategies for the management of zidovudine-intolerant individuals within a population of persons with advanced HIV disease. We performed a decision analysis using iterative algorithmic models of 1 year of antiretroviral care under various strategies. The real costs providing antiretroviral therapy were estimated by deflating medical center charges by specific Medi-Cal (Medicaid) charge-to-payment ratios. Clinical data were extracted from the medical literature, product package inserts, investigator updates, and personal communications. Sensitivity analysis was used to test the effect of error in the estimation of parameters. The models predict that a strategy of dose interruption and transfusion for zidovudine intolerance will provide an average of 46 weeks of therapy per year to the average patient at a cost of $5,555/year of therapy provided (1991 U.S. dollars). The models predict that a strategy of adding hematopoietic growth factors to the regimen of appropriate patients would increase the average amount of therapy provided to the average patient by 3 weeks (6%) and the costs attributable to therapy by 77% to $9,805/year of therapy provided. Finally, they predict that a strategy of switching intolerant patients to didanosine would increase the average amount of therapy provided to the average patient by 5 weeks (9%) and decrease costs attributable to therapy by 13% to $4,844/year of therapy provided. Increases in overall cost for strategies using hematopoietic growth factors were driven by large drug costs, while savings for strategies using crossover to didanosine were driven by savings on toxicity management and monitoring. A strategy of adding hematopoietic growth factors to the regimen of appropriate zidovudine-intolerant patients in a population would result in a modest increase in the total amount of antiretroviral therapy provided to that population but would also greatly increase overall costs. Crossing such patients over to didanosine yields a greater increase in the amount of therapy provided to the population under care and a decrease in overall costs. This occurs because use of growth factors in the zidovudine-intolerant patients

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryTo determine whether human immunodeficiency virus (HIV) viral load has short term stability, eight clinically stable subjects infected with HIV and having CD4 counts ranging between 10–600/mm3, had blood samples taken at 0800 and 1700 on 3 consecutive days and then weekly at 0800 for 1 month (8–10 observations/subject). Plasma HIV RNA, peripheral blood mononuclear cell (PBMC) proviral DNA, serum p24 antigen levels, and mononuclear cell subsets were measured at each time point. Mean plasma HIV RNA, PBMC HIV DNA, and p24 antigen [both regular and immune complex dissociated (ICD)] levels did not change significantly between mornings and afternoons or on successive days or weeks. CD4+, CD8+, and CD56+number demonstrated a diurnal variation in those subjects with > 200 CD4 cells/mm3. We conclude that HIV viral load demonstrates short-term stability in clinically stable subjects. This stability has important implications for monitoring HIV disease progression or antiretroviral therapy.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryTwenty-four asymptomatic, HIV-1-seropositive subjects with CD4 cell counts of ≥400/μl participated in a Phase I/II, dose escalation trial of intravenous L-2-oxothiazolidine-4-carboxylic acid (OTC: Procysteine). Four groups of six subjects each were consecutively assigned to receive OTC at an initial dose of 3, 10, 30, or 100 mg/kg, followed by the same dose given twice weekly for 6 weeks. Increases in whole-blood glutathione were observed in the highest dosage group after 6 weeks of therapy. No effects on changes in CD4 cell counts, viral load, or proviral DNA frequency were observed among the four dosage groups, although a decline in β2-microglobulin levels was apparent in the highest dosage group. One subject withdrew due to headaches; other probable adverse events including rash, flushing, pruritus, lightheadedness, and diminished concentration were self-limited.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryWestern blot with a time-dependent enhanced chemiluminescence immunodetection method (ECL-WB) was shown to be 100-fold more sensitive than standard commercial colorimetric Western blots (WB) for detecting serum IgG to human immunodeficiency virus type I (HIV-1). ECL-WB was then used to test rectal secretions from 15 HIV-1 infected subjects (HIV +) and 7 uninfected subjects (HIV-) to document local IgG, IgA, and secretory component-associated immunoglobulin (SC-Ig) to HIV-1 proteins. Fourteen of 15 HIV+ subjects had rectal IgA to at least 1 HIV-1 protein, most often to gp41 (80%) or p24 (60%) and 14 (93%) had IgG to gp160, gp120, or gp41. Of seven HIV - subjects, none had detectable bands to HIV-1 proteins. SC-Ig to HIV-1 proteins was detected in all five rectal samples tested. However, the antibody profiles differed from those of rectal IgA, suggesting more than one source of rectal IgA to HIV. ECL-WB requires individual optimization and interpretation for each specimen as well as expensive reagents and is, therefore, not currently applicable to screening assays. However, the method offers promise as a sensitive method to characterize low-level immune responses (IgG, IgA, and SC-Ig) to HIV-1 proteins at local sites such as rectal mucosae.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryThe purpose of this study was to characterize quantitative changes in circulating infected cells over the natural history of human immunodeficiency virus (HIV) disease in relation to clinical/immunological outcome. HIV-1gagDNA polymerase chain reaction (PCR) and peripheral blood mononuclear cell (PBMC) co-cultures were performed on limiting dilutions of cryopreserved PBMC from specimens collected at enrollment and after 5 years of follow-up from nine seropositive subjects classified as rapid progressors, nine intermediate progressors, and 10 nonprogressors. Limiting dilution PCR was also performed on serial pre/postseroconversion specimens from 18 seroconvertors. By quantitative DNA PCR analysis, the infected cell burden was significantly higher at enrollment in the RP [mean of 330 PCR units (PCRU)/106PBMCs] than in the IP (160 PCRU/106PBMCs) and NP (73 PCRU/106PBMCs) groups (p = 0.05). When results were analyzed on an individual level with proportional hazard regression, baseline PCRU (p = 0.05) and CD4 slope (p = 0.0007) were significantly associated with developing acquired immune deficiency syndrome (AIDS) in 5 years, but baseline tissue culture infectious units (TCIU) was not. The increase in PCR-positive cells after 5 years was modest in all three groups (two- to fivefold), whereas the proportion of PCR-positive cells that yielded virus in culture increased significantly (21− to 31-fold) over time in all three groups. Infected cell burden in postseroconversion specimens was relatively stable within each subject, but varied greatly (from 1.6 to 1,024 PCRU/106PBMCs) among subjects. Decline in CD4 cell count during the 4 years following seroconversion was significantly greater for subjects who stabilized at higher (>50 PCRU/106) infected cell burdens following initial infection (p = 0.001). The concentration of circulating infected cells is determined to a great extent at seroconversion and remains relatively stable over the ensuing course of infection. Host response to initial infection may be critical in determining extent of early viral dissemination and subsequent disease course.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID