ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective:To identify novel major histocompatibility complex (MHC) class I‐restricted cytotoxic T‐lymphocyte (CTL) epitopes conserved in HIV‐1.Methods:Potential conserved CTL epitopes were selected using a predictive computer algorithm based on a human leukocyte antigen (HLA)‐A*0201 peptide‐binding motif and tested for actual binding to the human processing defective cell line 174.CEM T2 (T2). Hence, the amino‐acid sequences of 14 full‐length sequenced HIV‐1 strains were analysed. Anin vitroprimary peptide‐specific human CTL response was induced with responding lymphocytes of an HIV‐1‐seronegative donor. Responding T cells were cloned by limiting dilution and tested for their ability to recognize naturally processed antigen in a51Cr‐release assay using recombinant vaccinia‐HIV protein‐infected B‐lymphoblastoid cells (B‐LCL) as target cells.Results:The analysis of peptides bearing the HLA‐A*0201 motif for conservation resulted in one peptide of Env, three of Gag and 12 of Pol. Only Gag340‐348, Pol83‐92, Pol267‐277and Pol960‐968showed binding properties to T2 comparable with those of known CTL epitopes Gag76‐84SLYNTVATL and Pol468‐476ILKEPVHGV. A successful primary MHC class I‐restricted CTL response was induced against Pol468‐476and Pol267‐277VLDVGDAYFSV, a peptide in a functional sequence of reverse transcriptase (RT). The resulting CD8+ CTL clones were peptide‐specific and able to specifically lyse recombinant vaccinia‐HIV‐1 RT‐infected HLA‐A*0201‐matched B‐LCL.Conclusion:The method used to screen proteins sequences for potential CTL epitopes, test selected peptides for binding to MHC class I and induction of anin vitroprimary response against optimal binding peptides resulted in the identification of at least one novel conserved CTL epitope. The novel epitope is located in an area crucial for RT activity. This study demonstrates the feasibility of identifying highly conserved HIV‐1‐derived peptides capable of eliciting novel anti‐HIV‐1 CTL responses.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective:To establish whether the steroid hormone retinoic acid (RA) was able to modulate the activity of the HIV‐1 promoter.Design:The effect of RA and nuclear factor (NF)‐&kgr;B on HIV‐1 promoter activity was investigated using HIV‐1 long terminal repeat (LTR)‐based reporter constructs.Methods:The activity of wild type and mutant LTR sequences was compared in a variety of stably and transiently transfected human cell lines.Results:It was shown that RA treatment inhibits both the basal activity of the HIV‐1 LTR and its stimulation by phorbol ester treatment. This inhibition is observed in both HeLa cells (in the presence of exogenously supplied RA receptors) and the naturally RA‐responsive U937 monocyte cell line. RA can also inhibit the stimulation of the HIV‐1 LTR by overexpression of NF‐&kgr;B subunits, while linkage of the NF‐&kgr;B sites in the HIV promoter to a heterologous promoter results in its inhibition by RA.Conclusions:The data presented clearly demonstrate a negative effect of RA on HIV‐1 LTR activity that may contribute to its effect on viral replication.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective:To investigate the induction of cytokines as a possible mechanism for the neurotoxicity of the HIV‐1 envelope protein gp120.Design:The gp120 protein was tested directly on primary human brain cultures to examine its ability to induce cytokines and its neurotoxicity on human neural cells because gp120 is known to be toxic to rodent ganglion cultures, and neural cells such as astrocytes and microglia produce cytokines when stimulated.Methods:Primary cultures of human brain cell aggregates, astrocytes and macrophages were exposed to HIV‐1 recombinant (r) gp120SF2. Induction of cytokines was assayed by enzyme‐linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT‐PCR); neurotoxicity of rgp120SF2and interleukin (IL)‐6 on human brain cultures was examined by electron microscopy.Results:ELISA and RT‐PCR studies revealed that rgp120SF2induced IL‐6 and tumor necrosis factor (TNF)‐&agr; in brain cultures; IL‐6 could also be induced by TNF‐&agr; added to brain cultures. Both IL‐6 and TNF‐&agr; were upregulated in astrocytes and macrophage cultures on rgp120SF2treatment. Ultrastructural studies demonstrated that IL‐6 treatment for 72h induced large cytoplasmic vacuoles in neural cells with morphology consistent with neurons; rgp120SF2treatment for 7 days resulted in chromatin condensation along the inner margins of nuclear envelopes of neural cells.Conclusions:Our results demonstrated that HIV‐1 rgp120SF2can upregulate at least two known neurotoxic cytokines, IL‐6 and TNF‐&agr;, which may injure neural cells and contribute to the neuropathology observed in AIDS dementia patients.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective:Quantify and study cofactors of long‐term survival without AIDS in HIV‐1‐infected individuals with CD4+ cell counts < 200 × 106/l.Design:Comparison of 579 participants who could be longitudinally evaluated for at least 3 years after the earliest date of first reaching a CD4+ cell count < 200 × 106/l or an AIDS‐defining illness (1987 Centers for Disease Control and Prevention definition).Setting:Ongoing 9‐year cohort study with data collected at 6‐month intervals.Patients:HIV‐1‐infected homosexual men.Measurements and main results:Of the men, 20% did not develop an AIDS illness within 3 years following a confirmed CD4+ cell count < 200 × 106/l; 29 and 28% were diagnosed with a first clinical AIDS illness from 1‐3 and < 1 years, respectively, beyond their first CD4+ cell count < 200 × 106/l; 23% were diagnosed with a clinical AIDS illness prior to their first CD4+ cell count < 200 × 106/l. Slower decline of CD4+ cell count (P<0.001) and presence of higher body‐mass index during the period prior to the first CD4+ cell count < 200 × 106/l (P< 0.001) predicted longer time to an AIDS illness once this threshold was reached. Most men had rapid loss of CD4+ cells, total T cells, and hemoglobin during the period after CD4+ cells declined below 200 × 106/l. However, those remaining free of AIDS illnesses the longest arrested their decline in CD4+ cell counts and hemoglobin levels and increased total T cells during this period. Although antiretroviral therapy andPneumocystis cariniiprophylaxis extend AIDS‐free survival, 45% of the group who were AIDS‐free ≥ 3 years after CD4+ cells fell below 200 × 106/l had not used these treatments.Conclusions:Significant numbers of individuals remain free of illnesses and AIDS symptoms ≥ 3 years after CD4+ cell counts drop below 200 × 106/l. This occurs even in the absence of treatment. The associations seen here suggest that host and viral factors play important roles. Thus, further studies are needed to determine the biological basis of long‐term survival without AIDS illnesses in HIV‐1‐immunosuppressed patients.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective:Improved therapy for AIDS dementia and related encephalopathies may be achieved through enhanced delivery of effective antiretroviral agents to the central nervous system (CNS).Design:A novel chemical delivery system (CDS) was used, which utilized redox trapping of drugs in the brain. This study was aimed at defining the pharmacokinetics of a zidovudine (ZDV)‐CDS as well as establishing itsin vitroantiviral efficacy against HIV in both lymphocytes and in a neural cell line.Results:ZDV‐CDS administered parenterally to rats produced significantly higher brain levels of ZDV [area under the curve (AUC), 425 &mgr;g × min/g] than equimolar ZDV (AUC, 13.5 &mgr;g × min/g). Native ZDV uptake was minimal after 1h when analyzed in CEM lymphocytes and in SKNMC neuroblastoma cell line. By contrast, marked uptake of ZDV‐CDS was followed by biochemical conversion of ZDV‐CDS to its main metabolites (ZDV‐CDS quaternary salt, ZDV‐Q+, and native ZDV). These improved uptake profiles were associated with greaterin vitrovirucidal effect. ZDV‐CDS at 0.5 &mgr;M was 80% more effective than ZDV in suppressing p24 production in a lymphocyte culture infected with 6000 median tissue culture infective doses (TCID50) of the HIV N1T strain and 50% more effective at 0.05 &mgr;M. Furthermore, syncytia formation was completely suppressed at a ZDV‐CDS dose of 0.5 &mgr;M (600TCID50) but native ZDV at the same dose was ineffective. Finally, while ZDV (at 0.5 &mgr;M) is not active in reducing viral replication in an SKNMC neural cell line, the ZDV‐CDS complex significantly suppressed p24 synthesis.Conclusion:The ZDV‐CDS complex is capable of delivering higher ZDV doses to lymphocytes and neural cells, with improved antiretroviral activity.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective:To evaluate whether early changes in viraemia in response to didanosine (ddl) predict death and occurrence of new AIDS‐defining events.Methods:Forty‐three patients were followed during ddl treatment with sequential determinations of serum viraemia, mutations associated with drug resistance, CD4 counts and clinical evaluation. Patients were stratified into two groups of equal size, responders and nonresponders, using the median of individual changes in viraemia 1 month after initiation of ddl therapy.Results:After 1 month of ddl, mean viraemia decreased by 0.35 log RNA copies/ml of serum (P<0.001) in the population. A significant difference in survival (median, 14 and 35 months in nonresponders and responders, respectively; log rank,P=0.004) and in the delay to the occurrence of new AIDS‐defining events (median, 8 and 33 months in nonresponders and responders, respectively; log rank,P=0.018) was observed. After stratification for presence of AIDS before starting ddl, viraemia response at 1 month remained predictive of both overall and AIDS‐defining event‐free survival (log rank,P=0.0006 andP=0.01). After a similar stratification for initial CD4, viraemia response still predicted overall survival (log rank,P=0.009), but its predictive value for AIDS‐defining event‐free survival did not reach statistical significance (P=0.12). High initial levels of HIV RNA, presence of mutation 215 or previous duration of zidovudine therapy were not predictive of survival.Conclusions:In patients treated with ddl, changes in viraemia at 1 month predict survival independently of initial AIDS diagnosis and initial CD4 counts.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective:To examine the involvement of cognitive function in HIV‐seropositive drug users (DU) in a pre‐AIDS state.Design:Fifty‐six HIV‐positive DU were prospectively evaluated. They belonged to groups II, III and IV (subgroups A, C2 and E) of the 1987 Centers for Disease Control and Prevention classification, with anamnesis negative for neurological pathology. HIV‐negative DU (n = 19) and non‐DU (n = 27) were used as controls. Infection with HIV and use of toxic drugs were considered variables of influence on cognitive function.Method:Subjects underwent neuropsychological evaluation by tests designed to explore cortical and subcortical function.Results:HIV‐positive DU showed worse performance scores at the psychometric tests than HIV‐negative non‐DU, but there was no difference when compared with HIV‐negative DU. Ex‐DU showed better performance than active DU. No difference with regard to degree of disease evolution was observed among HIV‐positive individuals (i.e., groups II and III versus group IV).Conclusions:There was no evidence of cognitive deficits in HIV‐positive individuals in non‐AIDS phases to indicate early involvement by HIV at the cerebral level. Progression of the disease, prior to the AIDS phase, did not determine a worsening of intellectual performance. Instead, cognitive function was affected by the chronic and current use of toxic substances. In HIV‐positive DU, a decline in cognitive function was found to be attributable to the chronic use of toxic substances rather than HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objectives:To assess the risks for HIV infection and sexually transmitted diseases (STD) among young northern Thai men who have sex with men (MSM), and to examine the possible role of male same‐sex behavior in the northern Thai HIV/AIDS epidemic.Methods:Two cohorts of northern Thai military conscripts and one cohort of recently discharged conscripts, a total of 2047 men, were studied. Data were collected by interview on behavioral risk factors, and sera were examined for syphilis and HIV‐1 antibodies. Univariate and multiple logistic regression analyses were used to determine risk factors associated with HIV and STD, and to assess the frequency and patterns of same‐sex behaviors among these men.Results:Of 2047 men, 134 (6.5%) reported one or more male lifetime sex partners. Of these MSM, 130 (97.0%) also had female partners, and four (3.0%) had exclusively male partners. Compared with men who reported only female sex partners, MSM had a higher number of lifetime sex partners, a higher mean number of female sex partners, more female and male commercial sex worker (CSW) partners, and were more likely to be married. MSM were significantly more likely than exclusively heterosexual men to report having had any STD [odds ratio (OR), 2.72], gonorrhea (OR, 2.05), syphilis (OR, 3.17), non‐gonococcal urethritis (OR, 4.54) and penile discharges (OR, 6.24). They were at borderline increased risk for HIV infection [OR, 1.51; 95% confidence interval (Cl), 0.95‐2.41]. Men with more than one lifetime male sex partner compared with those with only one partner were significantly more likely to be HIV‐infected (OR, 2.81; 95% Cl, 1.09‐7.19).Conclusions:Northern Thai MSM are a high‐risk population for STD, including HIV. Reported same‐sex behavior in this population appears to vary considerably with data collection techniques. HIV and STD prevention strategies aimed at changing unsafe sexual practices may need to be targeted to the general population of young Thai men.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective:To measure HIV seroprevalence trends associated with sexually transmitted diseases (STD) causing ulcerative lesions [genital ulcer disease (GUD)], such as syphilis, chancroid and genital herpes, in New York City between 1990 and 1992.Design:Unlinked HIV‐1 serosurvey using remnant serum drawn originally for routine syphilis screening.Setting and patients:Consecutive sample of patients presenting to New York City Department of Health STD clinics for STD examination (n = 41 678).Main outcome measure:Serologic evidence of antibody to HIV‐1.Results:Although overall HIV seroprevalence and GUD incidence declined between 1990 and 1992, seroprevalence in patients with GUD increased from 10 to 16%. In contrast, seroprevalence in patients with non‐ulcerative STD decreased. The most dramatic changes in seroprevalence associated with GUD occurred in patients using crack cocaine and injecting drugs.Conclusions:Despite declining HIV seroprevalence and GUD incidence, the association between GUD and HIV infection has strengthened over time in New York City STD clinics. Longitudinal incidence studies are needed to elucidate the biological, behavioral and temporal associations between GUD and HIV. Timely diagnosis and treatment of acute STD and more intensive risk reduction strategies at the clinics and associated testing sites, with a particular focus on GUD patients, are indicated.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID