ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective: To determine HIV-1 genomic RNA and proviral DNA sequences of thethird hypervariable region (V3 loop) of the envelope protein in patients with primaryHIV-1 infection (PHI), and to compare these sequences with sequences from patientswith more advanced HIV-1 infection.Methods: Sera and peripheral blood mononuclear cells were collected from 24patients with PHI living in Geneva. V3 sequences were determined using directsolid-phase sequencing on polymerase chain reaction (PCR) products.Results: A 100% homology rate was observed between HIV-1 genomic RNA andproviral DNA paired nucleotide sequences from the V3 region in the 24 patients.Using a limiting dilution approach for three patients, a unique V3 sequence wasobserved for the genomic RNA. Three out of 24 amino-acid sequences presented thecharacteristic signature sequence QRGPGR, first described for the HIV-1 LAI isolate,which is associated with lymphocytotropism. These three isolates also presented, forthe V3 loop, a characteristic elevated charge (8) at physiological pH in comparisonwith the other isolates (3–5). There was no significant difference in the distribution ofamino acids between the 24 V3 loop sequences from patients with PHI and 245 V3loop sequences of the 6 subtype determined in patients with more advanced HIV-1infection.Conclusion: The paired sequences recovered from HIV-1 genomic RNA and proviralDNA are identical for each of the 24 patients with PHI. Three isolates had the V3 loopcharacteristic signature sequence QRGPGR first described for the HIV-1 LAI isolate.There is no characteristic V3 loop pattern associated with PHI isolates.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo study the binding of human complement proteins to gp41 and gp120 of HIV-1.MethodsThe interaction of complement proteins with gp41 and gp120 and their effect on the gp41-gp120 complex in enzyme-linked immunosorbent assays (ELISA) and on stably transfected Schneider-2 cells expressing a gp41-gp120 complex was investigated. The molecular basis of these interactions was analysed by computer-supported sequence analysis.Resultgp41 strongly binds human complement regulatory proteins factors H and properdin, and weakly binds factors I and B. The binding occurs with recombinant soluble (rs) gp41 fixed on ELISA plates as well as gp41-gp120 complex expressed on Schneider-2 cells. The basis for this binding potential might be an amino-acid (aa) sequence of gp41 displaying homologies to sites in human C3. rgp120 also binds C3(H20), a C3b-like form of C3, and C4b. These binding features of gp120 can be explained by homology of constant region (CR) 4 in gp120 to sites in C4b binding protein. Additionally, CR1 in gp120 exhibits a weak similarity to human properdin. Preincubation of rsgp41 with either factor H or properdin, and of rgp120 with C3b or C4b affected the interaction between rsgp41 and rgp120. Incubation of Schneider-2 cells, expressing a functional gp41-gp120 complex, with factor H reduced the detectable amount of gp120. This effect was similar to that induced by soluble CD4.ConclusionThese results strongly suggest that HIV-1 envelope proteins interact with human complement proteins. Additionally, C3b-like features of gp41 and the C3b/C4b binding structures in gp120 may affect the non-covalent association between gp41 and gp120.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo demonstrate that antibodies against amino acids (aa) 603–622 of the SIV gp41 transmembrane glycoprotein enhance infection of SIVin vivo.DesignA synthetic peptide derived from aa 603–622 of SIVmac251gp41 was synthesized and tested for immunogenicity in rabbits and SIV-infected rhesus macaques. Next, SIV-naive animals were immunized with either a recombinant vaccinia virus expressing the SIV gp160 envelope glycoprotein (Wrgp160) and boosted three times with aa 603–622 (group 1, four animals), wild-type vaccinia virus and boosted with aa 603–622 (group 2, two animals), or VVrgp160 followed by three doses of an irrelevant peptide (group 3, two animals). Animals were challenged with SIVmac251.ResultsPeptide aa 603–622 was immunogenic in rabbits. SIV-infected rhesus monkeys immunized with the peptide developed two-three log increases in antibodies to this peptide and antibodies that could enhance SIV infectionin vitro.SIV-naive rhesus macaques in group 1 had higher levels of antibody to the peptide by enzyme-linked immunosorbent assay and higher levels of enhancing antibodies at the time of SIV challenge than the animals in groups 2 or 3. Following challenge with SIVmac251the group 1 animals had detectable p27 antigen longer than animals in group 2 and 3 and died of simian AIDS before the respective animals in the two control groups (P<0.05 by log-rank test).Conclusionsaa 603–622 of SIV gp41, like aa 579–613 of HIV gp41, can stimulate production of antibodies that enhance SIV and HIV infectionin vitro.Furthermore, immunization with this peptide suppressed beneficial effects of a gp160 vaccine and appeared to enhance SIV infectionin vivo.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveDuring HIV-1 infection, CD4+ T lymphocytes migrate to immune-reactive lymphoid organs where they are infected by the virus and/or killed by apoptosis on immunoregulatory stimuli—a potential mechanism underlying fatal CD4+ T-cell depletion observed in AIDS. This study seeks to determine the effects of glucocorticoids (GCC) on the activation-induced T-cell apoptosis triggered by HIV-1.MethodsCD4+ and CD8+ T cells were purified from HIV-negative donor peripheral blood mononuclear cells (PBMC) by positive selection and exposed to HIV-1 (primary isolates). HIV-1-exposed CD4+ and CD8+ T cells as well as PBMC derived from HIV-1-infected patients were cultured with medium alone or anti-CD3 monoclonal antibodies (MAb)/mitogens in the presence or absence of hydrocortisone or prednisolone. Viral infection kinetics were assessed by polymerase chain reaction and viral replication was measured by p24 enzyme-linked immunosorbent assay. Cell survival, apoptosis, T-cell proliferation, blast cell transformation, and interleukin (IL)-2 receptor (CD25) expression were monitored in parallel for each cell population.ResultsFractionated CD4+ T cells acutely infected by HIV-1 underwent apoptotic death on anti-CD3 MAb/mitogen stimulation. This activation-induced apoptotic cell killing was antagonized by pharmacological doses of prednisolone or hydrocortisone added up to 6 h after stimulation. GCC were also found to be capable of inhibiting the accelerated apoptosis in PBMC (including both CD4+ and CD8+ T-cell fractions) from HIV-1-infected patients. This anti-apoptotic action of GCC overbalanced their downregulatory effect on T-cell proliferation, resulting in an overall improvement of CD4+ T-cell survival in patient PBMC. These effects of GCC were abrogated by the anti-GCC RU486 and were not associated with significant suppression of CD25 expression and IL-2-dependent T-cell blast transformation; moreover, GCC had no impact on viral infection and replication.ConclusionGCC exert a receptor-mediated anti-apoptotic activity in mature T cells through both activation-induced and HIV-1-triggered pathways, and could be potent inhibitors of T-cell apoptosis in HIV-1-infected patients.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo demonstrate the safety and enhancement of HIV-1-specific immune responses in HIV-infected asymptomatic patients following treatment with retroviral vector (Retrovector®)-transduced autologous fibroblasts (VTAF) expressing HIV-1IIIBEnv/Rev proteins.DesignA non-placebo-controlled, single arm Phase I study.ParticipantsFour HIV-1-seropositive asymptomatic volunteers were selected based on age (18–50 years), CD4/CD3 lymphocyte counts (> 600 × 106/l or > 40%), and positive delayed-type hypersensitivity test to at least one recall antigen.InterventionsPatients were treated at 2-week intervals with a total of three intramuscular injections of irradiated autologous fibroblasts transduced with a molecularly engineered, non-replicating amphotropic murine retrovector encoding the HIV-1IIIBEnv/Rev proteins.Main outcome measuresThe clinical status of patients was assessed by history, physical examination, serum chemistry and hematology, CD4/CD3 lymphocyte counts, HIV viral burden, and monitored throughout the study to detect potentially treatment-induced toxic or unwanted side-effects. In addition, HIV-1-specific cytotoxic T-lymphocyte (CTL) activity was measured to determine the biological activity of VTAF.ResultsNo acute local or systemic adverse events occurred following three injections with VTAF. Furthermore, a statistically significant increase of CD8+ CTL activity against HIV-1IIIBEnv/Rev-expressing targets was observed in peripheral blood mononuclear cells from two out of four patients.ConclusionsThis is the first report of the administration of a gene transfer treatment to HIV-1-infected patients and provides initial support for the safety and biological activity of retrovector-transduced fibroblasts administered to asymptomatic patients. This treatment resulted in the detection of increased HIV-1IIIBEnv/Rev-specific CTL activity in two HIV-seropositive patients and could provide a better understanding of the role of CTL activity in HIV disease progression.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo evaluate the effect of transmission category and demographic, clinical and immunological characteristics on the progression to AIDS and survival of zidovudine-treated patients.DesignProspective multicentre cohort study of symptomatic non-AIDS patients.SettingEighty-three clinical centres reporting data to the National Zidovudine Registry.PatientsA total of 1468 patients enrolled between July 1987 and January 1991 were analysed.Main outcome measuresThree-year AIDS-free survival probability estimates since therapy start. Cox proportional hazards regression analysis was used to identify independent predictors of progression to AIDS and survival.ResultsFaster progression was associated with increasing age (8% risk increase for a 5-year increase), low baseline CD4+ count (39% risk increase for 100 × 106/l cells decrease), and zidovudine > 1000 mg/day (20% risk increase compared with ≤ 1000 mg/day). Homosexual men had a 33% risk increase compared with other risk groups. The presence of fever and oral candidiasis at enrolment were also independently associated with a higher risk of progression. Differences in the risk of progression were not significant between men and women. Older age, baseline CD4+ count, homosexual behaviour, fever and oral candidiasis were independently associated with a shorter survival.ConclusionsOur results confirm that age and baseline CD4+ count are independent predictors of progression, but do not provide evidence for differences in clinical outcome between the sexes. The higher risk of progression to AIDS and shorter survival for homosexual men appears to be correlated with the higher risk of developing Kaposi's sarcoma.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo examine the role of initial AIDS-defining illness in survival following AIDS and survival trends over time.DesignStates and Territory Health Departments notified new diagnoses of AIDS to the National AIDS Registry. Information on vital status and date of last medical contact was sought annually.MethodsSurvival was calculated for all adult and adolescent AIDS cases (n = 3204) in Australia diagnosed until 1 November 1991 and reported to the National AIDS Registry by 31 March 1994. The Cox regression method was used to identify independent predictors for survival.ResultsAge < 50 years, a CD4+ cell count >100 × 106/l and an initial diagnosis of Kaposi's sarcoma were independently associated with longer survival (P<0.05). Acquisition of HIV through blood transfusion and the AIDS-defining illness non-Hodgkin's lymphoma were significantly associated with shorter survival. Survival improved substantially from 1986 to 1987, but did not improve further thereafter. A further study of initial AIDS-defining illnesses in a subgroup of individuals, i.e., men aged <50 years at diagnosis who acquired HIV infection through homosexual or bisexual contact and diagnosed after 1987, showed that Kaposi's sarcoma,Pneumocystis cariniipneumonia, oesophageal candidiasis and herpes simplex virus as initial AIDS-defining illnesses had a relatively better prognosis than other single illnesses. Furthermore, patients with multiple illnesses did not have a worse prognosis than patients with a single illness, provided all illnesses were those with a better prognosis.ConclusionsInitial AIDS-defining illness, as well as age at diagnosis, year of diagnosis, HIV exposure and CD4+ cell count at diagnosis, plays an important role in survival following AIDS in Australia.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo examine the association of clinical complications and age at diagnosis with survival for a cohort of children and adults with AIDS.DesignA population-based analysis of 734 children and 5584 adults diagnosed with AIDS from 1985 to 1990 in New York State.ResultsThe initial AIDS-defining diagnoses for 68% of children were lymphoid interstitial pneumonitis or infections specified in the Centers for Disease Control and Prevention's (CDC) pediatric AIDS case definition but not the CDC's 1987 adult AIDS case definition. Of opportunistic infections in both case definitions,Pneumocystis cariniipneumonia (PCP) was the most common initial AIDS diagnosis, occurring in 53% of adults, 47% of children aged < 6 months at diagnosis (n = 122) and 14% aged ≥6 months at diagnosis (n = 612). Median survival after AIDS diagnosis was 62 months for all children compared with 11 months for adults. For children initially diagnosed with conditions only in the pediatric case definition, median survival ranged from 27 to 62 months compared with less than 12 months for children and adults with PCP. Compared with children aged 6–54 months, the estimated hazards of death for younger and older children were 2.06 [95% confidence interval (Cl), 1.48–2.86] and 1.54 (95% Cl, 1.10–2.16), respectively.ConclusionChildren survived significantly longer than adults after AIDS diagnosis, but their survival varied by age at diagnosis. Differences in the types of common initial AIDS-defining diagnoses appear to contribute to the observed differences in survival.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo examine long-term changes in psychological symptomatology from 6 to 24 months after notification of HIV serostatus among male injecting drug users (IDU).DesignSelf-report and interview data were collected at 6-month intervals as part of a longitudinal study monitoring HIV infection and risk-associated behaviors among IDU.SettingA community-based methadone-maintenance clinic.ParticipantsNinety-seven male IDU (81 HIV-seronegative, 16 HIV-seropositive), including both methadone-maintained and out-of-treatment IDU.Main outcome measuresAnalyses of long-term changes in psychological symptomatology associated with HIV serostatus among male IDU.ResultsAnalyses of long-term changes in psychological symptomatology between groups revealed no significantly greater levels of overall psychological distress or significant elevations on subscales of the Symptom Checklist-90 for HIV-seropositive compared with HIV-seronegative male IDU. Also, no significantly higher scores on the Beck Depression Inventory or the psychiatric composite score of the Addiction Severity Index were observed between groups.ConclusionsOur results suggest that HIV-seropositive male IDU do not express greater levels of psychological symptomatology from 6 to 24 months following notification of seropositivity compared with HIV-seronegative male IDU. Several explanations for these findings are considered. Future work should examine why male IDU do not report significant and long-term elevations in symptoms post-notification of HIV seropositivity. Also, studies of changes in psychological symptomatology as a function of HIV serostatus among female IDU need to be conducted to assess implications for treatment interventions among this underserved population.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID