摘要:

ABSTRACTA workshop entitled "Early Phases of HIV-1 Infection" was held to review current research on the immunological and virological aspects of early phases of HIV infection in humans and in animal models, to identify studies for future research, and to foster collaborations among investigators in the biomedical community.In infections of adults, the appearance of cytotoxic T lymphocyte activity, when present, coincides with a decrease in viral load as measured by plasma viremia. In neonatal infections, however, an initial decrease in viral load has been observed months before cytotoxic T lymphocytes are detected. Immunological data, from a limited number of patients, indicated that CD8+cytotoxic T lymphocytes detected early after HIV-1 infection may recognize epitopes in any of several HIV-1 proteins: Env, Gag, Pol, Tat, and Nef. With regard to the humoral antibody response, anti-Env binding antibodies appear before neutralizing antibodies and do not predict the appearance of neutralizing activity. The time at which neutralizing antibody appears is variable and unpredictable. Preliminary data indicate that early viral peak load does not predict disease progression in many cases, and the phenotype or virulence of the virus appears to be a critical variable. However, the quantity of HIV-1 RNA in plasma is a strong CD4+T cell-independent predictor of outcome following HIV-1 seroconversion in homosexual men. Early, high virus load with sustained viremia is often accompanied, in both adults and infants, by the inability to mount an effective immune response, resulting in rapid disease progression.

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.1

年代:1996

数据来源: MAL

摘要:

ABSTRACTBetter surrogate markers need to be developed to evaluate therapy in HIV-infected children. This study evaluated plasma RNA, immune complex-dissociated p24 antigenemia, and unintegrated DNA (uDNA) in HIV-infected pediatric patients. Ten children were followed from initiation of nucleoside antiretroviral therapy at intervals up to 24 months. Prior to initiation of therapy, HIV RNA was detected in 10 of 10 patients (median, 76,000 Eq/ml), p24 antigen was detected in 8 of 10 patients (median, 193 pg/ml), and uDNA was detected in 6 of 7 patients (median, 10% uDNA). After 12 months the RNA decreased in all patients and became undetectable in six. In contrast, p24 antigenemia decreased in 6 of 10 patients, remained undetectable in 1, and increased in 3. HIV uDNA decreased in six of six patients and became undetectable in three. There was no overall change in CD4 cell count. Plasma RNA and uDNA levels are both sensitive markers of nucleoside therapy in children; however, they do not covary strongly.

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.11

年代:1996

数据来源: MAL

摘要:

ABSTRACTThe relationship between CD8 lymphocyte phenotypic alterations and virological parameters was studied in 47 asymptomatic subjects with human immunodeficiency virus type 1 (HIV-1) infection and CD4 T cell counts above 400/μl.CD8 subsets were examined by means of three-color flow cytometry, using an extensive panel of monoclonal antibody combinations. Virological parameters were measured by both end-point dilution culture of peripheral blood mononuclear cells (PBMCs) and plasma and branched-DNA (bDNA) signal amplification of plasma HIV RNA.Whereas HIV-infected patients had a near-normal CD4 cell count (mean, 782 cells/μl), several subsets of activated CD8 cells were markedly expanded relative to values in 23 HIV-seronegative controls. The PBMC cultures were positive in 38 cases and plasma HIV RNA was detected in 31. The percentage of CD4 cells correlated negatively with both cellular viremia and plasma HIV RNA levels. Conversely, a positive correlation was observed between viral load and the percentage of CD8 cells. Among CD8 lymphocytes, the CD38+CD8 and HLA-DR+CD8 subsets correlated best with viral load. Three-color analysis showed that the subpopulations involved in this relationship were CD38+HLA-DR+, CD38+CD28−, HLA-DR+CD28+, HLA-DR+CD57−, CD38+CD57−, CD38+CD45RO+, and HLA-DR+CD45RO+. Our data provide the first evidence that viral load correlates with subsets of activated CD8 lymphocytes in asymptomatic HIV-infected subjects who have near-normal numbers of CD4 lymp

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.17

年代:1996

数据来源: MAL

摘要:

ABSTRACTEosinophils, when stimulated, release a variety of agents that can be toxic to ingested or extracellular targets. Among these systems is one that consists of eosinophil peroxidase (EPO), H2O2, and a halide. We report here that phorbol myristate acetate (PMA)-stimulated human eosinophils are virucidal to HIV-1 in a chloride-containing medium. When the eosinophil concentration is decreased to a level at which the virucidal effect is incomplete, the addition of bromide or iodide restored complete virucidal activity. The virucidal effect of eosinophils, PMA, and bromide under these conditions is inhibited by the peroxidase inhibitor azide and catalase, but not heated catatase or Superoxide dismutase, implicating the EPO–H2O2–halide system. Purified EPO when combined with H2O2in a chloride-containing medium is virucidal to HIV-1. When the EPO concentration is suboptimal, virucidal activity is increased by bromide, iodide, and, in this instance, thiocyanate and the virucidal activity of the bromide-supplemented system is inhibited by azide and catatase. Our findings, together with the demonstration that eosinophils express CD4 on their surface and, under some circumstances, can be productively infected with HIV-1, raise the possibility that biological oxidants formed by eosinophils can influence the pathogenesis of HIV-1 infection by their toxicity to eosinophil-associated or extracellular vi

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.25

年代:1996

数据来源: MAL

摘要:

ABSTRACTPrevious reports demonstrated that alloantigen- or xenoantigen-specific antibodies displayed neutralizing activity toward human or simian immunodeficiency viruses. In the present article we have addressed the question of alloantigen-induced cell-mediated anti-HIV activity. We show that allostimulation resulted in a lymphocyte population (largely of the CD8-positive phenotype) with the capacity to inhibit HIV-1 replication in PHA blasts of homologous and, unexpectedly, also autologous origin. The allostimulated effector cells exerted their activity via a noncytolytic mechanism. Experiments in which direct cell-to-cell contact between allostimulated effectors and HIV-1-infected PHA blasts was prevented by a semipermeable membrane indicated that soluble mediators were involved in inhibition of HIV-1 replication. As such allostimulated effectors not only would have the capacity to prevent viral replication in allogeneic HIV-1-infected cells (known to play an important role in HIV-1 transmissionin vivo), but also might inhibit HIV-1 growth in autologous lymphocytes, the concept of an AIDS vaccine containing both HIV-1 antigens and alloantigens warrants further consideration.

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.31

年代:1996

数据来源: MAL

摘要:

ABSTRACTAcute HIV-1 infection of H9 and C8166 cultures has been shown to be suppressed by certain flavonoids, and evidence for inhibition of HIV-1 protease, integrase, and reverse transcriptase by flavonoids also exists. The present aim was to determine whether flavonoids inhibit HIV-1 activation in models of latent infection. By screening flavonoids from six different classes, three structurally related compounds (chrysin, acacetin, and apigenin) were identified that inhibited HIV expression in TNF-α-treated OM-10.1 cultures. The three compounds had favorable potencies against HIV activation in relation to their growth inhibitory effects (therapeutic index 5–10). Chrysin also inhibited HIV expression in response to PMA in OM-10.1 cells, in ACH-2 cells stimulated with either TNF-α or PMA, and in 8E5 cultures. Furthermore, return to viral latency in OM-10.1 cells previously exposed to TNF-α occurred over a shorter time interval when chrysin was added. The inhibition of HIV activation was not dependent on preincubation with flavonoids relative to TNF, and was characterized by a lack of HIV RNA accumulation by Northern analysis. Gel-shift experiments revealed that NF-κB activation after TNF-α treatment was not inhibited by these agents, suggesting that some other critical factor(s) needed for viral transcription was being affected. These findings indicate that flavonoids inhibit HIV-1 activation via a novel mechanism, and that these agents are potential candidates for therapeutic strategies aimed at maintaining a cellular state of HIV-1 l

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.39

年代:1996

数据来源: MAL

摘要:

ABSTRACTWe have previously demonstrated that human immunodeficiency virus (HIV) envelope glycoproteins have specific carbohydrate-binding properties for mannosyl/N-acetylglucosaminyl residues presented at high density on a carrierin vitro. Here, we investigated whether HIV envelope glycoprotein gp120 was able to interact with surface membrane carbohydrates of CD4+cells by means of such lectin–carbohydrate interactions. CD4-free tryptic glycopeptides, prepared from the membrane of CD4+monocytic U937 cells and partially purified by ConA–agarose affinity chromatography, could be eluted by mannan but not by methyl-α-mannose or methyl-α-glucose, which strongly suggests that they displayed oligomannosidic structures. These glycopeptides bound in a mannosyl-specific manner to radiolabeled recombinant gp120. Deglycosylation withN-glycanase which, as expected, strongly diminished binding of the glycopeptides to concanavalin A also abolished their interaction with gp120. In addition, the glycopeptides inhibited HIV infection of both U937 and CD4+lymphoid CEM cells when preincubated with the virus. These findings indicate that, independently of the binding to CD4, mannosyl structures on CD4+cells may play a role through lectin–carbohydrate interactions in envelope glycoprotein binding to a putative coreceptor(s)

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.47

年代:1996

数据来源: MAL

摘要:

ABSTRACTInhibitors of HIV-1 protease represent a new class of antiretroviral compounds. Here, we report the design and synthesis of two novelC2 symmetry-based inhibitors, MP-134 and MP-167, specifically targeted against HIV-1 variants with reduced sensitivity to another related protease inhibitor, A-77003. In addition, we describe thein vitroselection of viral variants with reduced sensitivity to these two protease inhibitors. An isoleucine-to-valine substitution at residue 84 (I84V) of the HIV-1 protease confers resistance to MP-134, whereas a glycine-to-valine substitution at residue 48 (G48V) confers resistance to MP-167. Testing other protease inhibitors against these variants has revealed specific overlapping patterns of resistance among these agents. These findings have important implications in the design of combination regimens using multiple protease inhibitors and underscore the need to develop non-cross-resistant compounds to be used toward this goal.

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.55

年代:1996

数据来源: MAL

摘要:

ABSTRACTHeparin (Hep) and sulfated polysaccharides (SPs) have been reported to inhibit HIV infectionin vitro.In vivo, anticoagulant activity and reduced bioavailability were found to limit the antiviral effects of Hep. In this investigation, three nonanticoagulant N-acylated Hep conjugates [Ol1:3Hep, Pal1:5Hep, and Pal1:5Hep(SO4)] were compared to Hep for their ability to interact with HIV replication in CD4-positive cell lines and PBMCs. Resulfated palmitoyl-Hep [Pal1:5Hep(SO4)] exhibited the strongest anti-HIV effects. For instance, no provirus HIV DNA was detected in the genome of HIV-1-LAI-infected PBMCs treated with this heparin derivative. Cell-to-cell fusion and RT activity were explored to explain these differences. Hep and Pal1:5Hep(SO4) derivative exerted identical effects on cell-to-cell fusion. On the other hand, Pal1:5Hep(SO4) displayed the strongest inhibitory effects in the acellular RT inhibition assay. This suggests that RT might be a second target for N-acylated Hep, even though SP uptake and the preferential effects of SPs on RT as opposed to DNA polymerase have not yet been demonstrated. Nevertheless, considering the anticoagulant, antiviral, and antiinflammatory effects of N-acylated Hep, the N-acylated Hep derivatives might be excellent candidates as new anti-HIV pharmacological tools.

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.63

年代:1996

数据来源: MAL

ISSN:0889-2229    

DOI:10.1089/aid.1996.12.71

年代:1996

数据来源: MAL