摘要:

Summary:Identification of immunodominant T-helper-cell determinants after natural infection is an important step in the design of immunogens for potential use in vaccination. Using cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals and a panel of peptides encompassing the sequence of the regulatory protein vpr from HIV-1, we identified the T-helper determinant QLLFIHFRIGCRHSR, which is active in 37.5% of these individuals. To gain insight on the efficacy of this peptide in helping induce neutralizing antibodies against a B-cell determinant (BD), we synthesized constructs containing B- and T-cell determinants and tested them in BALB/c mice, the highest responders to the T-cell determinant moiety among several strains tested. These immunogens induced antibodies against two chosen B-cell determinants from HIV-1IIIBgp160 (amino acids 310–322 from the V3 loop of gp120 and 736–751 from gp41) that were able to neutralize HIV-1 infectionin vitro.The highest neutralization titer-against HIV-1IIIBwas obtained by immunization with the homopolymer of the construct containing the T-cell epitope from vpr and the B-cell epitope from the V3 loop. We believe that the immunodominant T-cell determinant from vpr is a promising epitope to consider in the design of future peptide vaccines.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Summary:The abnormalities of B lymphocytes in human immunodeficiency virus (HIV) infection usually have been attributed to secondary consequences of disturbed immunoregulation. However, recent work has revealed avid binding of HIV gp120 to a conserved immunoglobulin motif unique to the VH3 gene family and the selective gp120-induced activation of VH3 B cells in vitro. This cross-sectional clinical study tests whether HIV infection is associated with a selective response of VH3 B cells in vivo. Levels of blood B cells and serum immunoglobulins (Ig) expressing the D12 idiotope of the VH3 gene family were measured in subjects of the Multicenter AIDS Cohort Study grouped according to clinical stages of HIV infection. A 3-fold elevation in D12 B cells was observed in HIV seropositive versus seronegative groups. This was selective for the D12 population, since total B cell numbers were identical in the two groups. The levels of D12 B cells and CD4 T cells were significantly correlated, and D12 B cells were markedly reduced in the AIDS group (4− and 10-fold, compared to the seronegative and seropositive groups). Analogous differences were also seen in the levels of serum anti-gp120 D12 Ig. This change in VH3 B cells among groups of HIV-infected individuals provides further evidence identifying gp120 as a VH3 B cell superantigen.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Summary:This study examined the effects of leukemia inhibitory factor (LIF) on human immunodeficiency virus (HIV) replication in mononuclear phagocytes (MNP). LIF induced a dose-dependent increase in p24 antigen production in the chronically infected promonocytic cell line U1. The magnitude and time kinetics of the LIF effects were similar to interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF), other cytokines known to induce HIV replication in this cell line. To characterize mechanisms responsible for these LIF effects, levels of HIV mRNA, activation of the DNA binding protein nuclear factor (NF)-kB, signal transduction pathways, and potential interactions with other cytokines were analyzed. LIF increased steady-state levels of HIV mRNA at 2.0, 4.3, and 9.2 kB. This was detectable by 24 h and persisted until 72 h. The DNA binding protein NF-kB is a central mediator in cytokine activation of HIV transcription. NF-kB levels were higher in unstimulated U1 cells as compared to the parent cell line U937. In both cell lines LIF increased NF-kB activity. Induction of NF-kB and HIV replication by cytokines are at least in part dependent on reactive oxygen intermediates. The oxygen radical scavengerN-acetyl-L-cysteine, but not an inhibitor of nitric oxide synthase, inhibited LIF-induced HIV replication. LIF induces the production of other cytokines in monocytes but its effects on HIV replication were not inhibited by antibodies to IL-1, TNF, or IL-6. These results identify LIF as a stimulus of HIV replication. Its effects are related to increased HIV mRNA production and, NF-kB activation, and it is independent from the production of other cytokines.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Summary:The human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) Tat proteins Tat-1 and Tat-2 stimulate transcription of the viral long terminal repeat (LTR) sequences and are required for efficient viral replication. A class of mutant Tat proteins, termed “transdominant mutants,” has been described that possesses relatively low transactivation activity, yet is able to inhibit the function of wild-type Tat. These mutant proteins contain a nonfunctional TAR RNA-binding domain but apparently retain a functional activation domain. A potential limitation for therapeutic use of transdominant mutants described to date is their low but significant basal level of transactivation for the HIV-1 or HIV-2 LTRs. In order to make an improved transdominant mutant, we have constructed Tat-2 proteins that contain mutations in four contiguous arginines at residues 81 to 84 in the RNA-binding domain. Using purified proteins and in vitro RNA-binding assays, we verified that these mutant Tat-2 proteins are defective for TAR RNA binding. We also verified that these mutant Tat-2 proteins bind to a cellular protein kinase in vitro that we have previously shown to bind specifically to the Tat-1 and Tat-2 activation domain. Using plasmid cotransfection assays, we compared the phenotypes of these mutant Tat-2 proteins with the most potent Tat-1 transdominant mutant described to date. One Tat-2 mutant, named “R81–84A,” was found to be equivalent to the Tat-1 mutant in ability to inhibit wild-type Tat transactivation of HIV-1 and HIV-2 LTRs. Moreover, the R81–84A mutant possessed a significantly lower basal level of transactivation than the Tat-1 mutant. The R81–84A Tat-2 mutant is therefore a promising reagent for future development as an anti-HIV agent. Additionally, our results suggest that wild-type Tat-2 transactivation of the HIV-2 LTR is especially sensitive to inhibition by transdominant mutants.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Summary:Simultaneous measurements of phenotypically defined memory CD4+cells and in vitro proliferation to three recall antigens (Ags; tetanus toxoid, influenza, andCandida albicans) were performed in 53 HIV-seropositive subjects and 39 HIV-seronegative controls. The results indicate that the low proliferative responses to recall Ags of those who were HIV infected could be partly, but not fully, explained by a decrease of phenotypically defined memory CD4+cells. This is, to our knowledge, the first report of experiments that simultaneously measured memory CD4+cell numbers and function and then examined whether the low responses observed in seropositive subjects could be explained by low numbers of phenotypically defined memory CD4+cells. A central finding of the study, which argues against prevailing dogma, was that within the CD4+lymphocyte population, the proportion of cells displaying the memory phenotype was not selectively decreased in HIV-seropositive subjects as compared with the proportion of these cells in seronegative homosexual controls. An entirely new finding of the study was that AIDS patients, many of whom were unresponsive to all three recall Ags tested, actually had a significant increase in the proportion of CD4+cells with the memory phenotype, and this fraction approached 100% in subjects with CD4+cell humbers that were near zero. A final observation of the study, possible because some patients were on zidovudine (ZDV), was that there was no evidence that ZDV treatment led to an increased proliferative response to recall Ags in vivo. An in vitro study also found no effect of ZDV, dideoxycytidine (ddC), or azido-dideoxyuridine (AZU) on proliferative responses to recall Ags.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Summary:To ascertain whether immune complex dissociation (ICD) improves the value of p24 antigen as a prognostic marker for progression of HIV infection, 53 patients were followed over a 3-year period, including at least one visit per year. All had CD4+counts at entry >400/mm3; progressors (n = 18) were defined as having CD4+counts <200/mm3and nonprogressors (n = 35) as having CD4+counts still >400/mm3at the end of follow-up. Serum specimens were collected at each annual visit and assayed for p24 antigen with and without ICD treatment. At entry, the percentage of progressors positive for ICD p24 antigen was significantly higher than the percentage of positive nonprogressors (39% versus 3%,p< 0.01). The sensitivity of p24 antigen over all visits in terms of predicting the progression increased from 61% before ICD to 83% after. The specificity of p24 antigen in terms of predicting progression decreased from 97% before ICD to 89% after. The relative risk of progression in individuals positive for p24 antigen was 6.7 before ICD and increased after ICD to 12.7. When evaluating the respective prognostic value of the p24 antigen and of the ICD p24 antigen, only ICD p24 was significant (RR 10.2,95% CI 2.2–46.9). ICD p24 antigen appears to be a marker of progression that may be detected earlier than p24 antigen without ICD.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Summary:Infection with the human immunodeficiency virus type 1 (HIV-1) in man is associated with an increase in the incidence of Kaposi's sarcoma (KS). The biological and clinical characteristics of these patients differ from those of subjects with other HIV-associated diseases. Here we report that levels of serum-soluble intercellular adhesion molecule 1 (sICAM 1) are increased in HIV-1-positive patients with KS, but not in patients belonging to other CDC classification groups. KS patients with elevated levels of serum sICAM 1 had a significant lowering of CD4 cell counts during the follow-up period compared with those KS subjects whose sICAM 1 levels were only moderately higher. We suggest that increased sICAM 1 levels may have a pathogenetic role in the development of HIV-associated immunodeficiency in KS patients and may also be considered an important prognostic factor.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Summary:We employed a nested case-control study design to evaluate the efficacy of bleach-cleaning of needles and syringes among injecting drug users (IDUs) as a means of preventing human immunodeficiency virus (HIV) infection. Sixteen HIV-seroconverters who responded to bleach use questions and who reported injecting with shared or used equipment in the 6 months prior to their first positive visit were compared with 89 controls. Controls had remained HIV-seronegative at two or more visits, reported injecting with shared or used equipment, responded to bleach-cleaning questions, and were seen at recall visits ± 6 months from the date of seroconversion of the index case. Risk factors associated with HIV seroconversion in univariate analyses were a history of sexual intercourse with an HIV-infected partner and the frequency of speedball (mixed heroin and cocaine) injections. After adjusting for confounders, we found no evidence that bleach use protected against HIV infection.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Summary:Using lookback procedures and other methods, we identified and then prospectively followed human immunodeficiency virus type 1 (HIV-1)-infected transfusion recipients and their sex partners to determine AIDS incidence and risks of heterosexual transmission of HIV-1. At enrollment, 7 of 32 (21.9%) female partners of male recipients were themselves infected with HIV-1, as compared with none of 14 male partners of female recipients (p = 0.08). No additional episodes of transmission were observed. The prevalence of advanced immunodeficiency at enrollment was similar in male and female recipients. Male recipients with advanced immunodeficiency (CD4+ lymphocyte count ≤0.20 × 109/L or a history of clinical AIDS) at enrollment were more likely to have infected their female partners (odds ratio = 7.9; p = 0.03) than men with neither condition. Similarly, AIDS-free survival, as estimated by the product-limit method, was lower among male transmitters than among male nontransmitters (p = 0.01). Transmission was not associated with frequency of unprotected vaginal intercourse. Our data suggest that HIV-1-infected men who develop immunodeficiency rapidly are more likely to infect their sex partners and that the greater efficiency of male-to-female HIV-1 transmission is not explained by a greater number of sexual contacts or more advanced immunodeficiency in index subjects.

ISSN:0894-9255    

出版商:OVID    

年代:1994

数据来源: OVID