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Objectives The aim of the study was to assess the impact of rapid and sustained viral control produced by combination antiretroviral therapy (c ART) on HIV-associated immune activation and inflammation. Methods In this longitudinal observational study, we examined changes in interleukin-6 ( IL-6), interferon-γ-inducible protein-10 ( IP-10), monokine induced by interferon-γ ( MIG) and soluble CD14 (s CD14) levels during 2 years of effective first-line c ART. Biomarker levels before and after c ART were compared with those observed in healthy subjects, using the Wilcoxon signed rank test. Elevated biomarker levels were defined with respect to values for healthy subject (mean + 2 standard deviations). Factors associated with persistently elevated biomarker levels after 2 years of c ART were identified by logistic regression. Results We included in the study 139 patients with a median HIV-1 RNA level of 4.8 log10 HIV-1 RNA copies/mL and a median CD4 cell count of 294 cells/μL at c ART initiation [day 0 ( D0)]. At D0, all biomarker levels were higher than in healthy subjects ( P < 0.05). After 2 years of c ART, IL-6, IP-10 and MIG levels fell significantly, by a median of 0.54, 420 and 1107 pg/mL, respectively (all P < 0.001), and were no longer elevated in > 75% of patients. In contrast, s CD14 levels did not change significantly (0.18 × 106 pg/mL; P = 0.102) and remained elevated. Older age was associated with elevated levels of IP-10 [odds ratio ( OR) 1.60 per 10 years older; P = 0.047] and MIG ( OR 1.92 per 10 years older; P = 0.007) after 2 years of c ART. Conclusions The rapid and sustained viral suppression produced by first-line c ART reduced IL-6, IP-10 and MIG to normal levels, while s CD14, a marker of monocyte activation, remained elevated. High levels of IP-10 and MIG tended to persist in older patients. [ABSTRACT FROM AUTHOR]

We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in ≤4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype. [ABSTRACT FROM AUTHOR]

A double-blinded, controlled study of vaccination of untreated patients with chronic human immunodeficiency virus type 1 (HIV-1) infection with 3 doses of autologous monocyte-derived dendritic cells (MD-DCs) pulsed with heat inactivated autologous HIV-1 was performed. Therapeutic vaccinations were feasible, safe, and well tolerated. At week 24 after first vaccination (primary end point), a modest significant decrease in plasma viral load was observed in vaccine recipients, compared with control subjects (P = .03). In addition, the change in plasma viral load after vaccination tended to be inversely associated with the increase in HIV-specific T cell responses in vaccinated patients but tended to be directly correlated with HIV-specific T cell responses in control subjects. [ABSTRACT FROM AUTHOR]

INITIO is an open-labelled randomized trial evaluating first-line therapeutic strategies for human immunodeficiency virus-1 (HIV-1) infection. In an immunology substudy a tetanus toxoid booster (TTB) immunization was planned for 24 weeks after initiation of highly active antiretroviral therapy (HAART). All patients had received tetanus toxoid immunization in childhood. Generation of proliferative responses to tetanus toxoid was compared in two groups of patients, those receiving a protease inhibitor (PI)-sparing regimen ( n = 21) and those receiving a PI-containing ( n = 54) regimen. Fifty-two participants received a TTB immunization [PI-sparing ( n = 15), PI-containing ( n = 37)] and 23 participants did not [PI-sparing ( n = 6) or PI-containing ( n = 17)]. Cellular responses to tetanus antigen were monitored by lymphoproliferation at time of immunization and every 24 weeks to week 156. Proportions with a positive response (defined as stimulation index ≥ 3 and Δ counts per minute ≥ 3000) were compared at weeks 96 and 156. All analyses were intent-to-treat. Fifty-two participants had a TTB immunization at median 25 weeks; 23 patients did not. At weeks 96 and 156 there was no evidence of a difference in tetanus-specific responses, between those with or without TTB immunization ( P = 0·2, P = 0·4). There was no difference in the proportion with response between those with PI-sparing or PI-containing regimens at both time-points ( P = 0·8, P = 0·7). The proliferative response to tetanus toxoid was unaffected by initial HAART regimen. Anti-tetanus responses appear to reconstitute eventually in most patients over 156 weeks when treated successfully with HAART, irrespective of whether or not a TTB immunization has been administered. [ABSTRACT FROM AUTHOR]

Background. Kaposi sarcoma (KS) occurs mainly in immunocompromised patients and is strongly associated with infection with human herpesvirus 8 (HHV-8; also known as 'KS-associated herpesvirus'). We hypothesized that KS is linked to deficiencies in specific anti-HHV-8 T cell immunity. Methods. We studied asymptomatic HHV-8 carriers coinfected with human immunodeficiency virus (HIV; n=23) and patients with HIV-related or classic KS (n=29). We used an interferon-gamma enzyme-linked immunospot assay with 56 specific peptides distributed on 6 HHV-8 proteins (glycoprotein [gp] B, gpH, gp35/37, latent nuclear antigen 1 [LANA-1], K12, and K15) to detect HHV-8-specific T cell responses. Results. We found that patients with KS responded to these peptides less often and had much lower HHV-8-specific T cells counts than did asymptomatic HHV-8 carriers (P=.001 and P=.0004, respectively), regardless of CD4 T cell count or HHV-8 load. The frequency of Epstein-Barr virus-specific T cells was similar in both groups. Conclusions. Our results suggest that HIV-related and classic KS are associated with a lack of HHV-8-specific T cells. Also, we have described 8 new HHV-8 T cell epitopes in LANA-1, K12, and K15, including 2 CD4 T cell epitopes. These data provide new insight into HHV-8 cellular immunity. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Bioterrorism is defined by the intentional or threatened of microorganisms or toxins derived from living organisms to cause death or diseases in humans, animals or plants on which we depend. The other major point is to generate fear in the population. More than 180 pathogens have been reported to be potential agents for bioterrorism. The following is an overview of several agents that could be involved in a biological attack. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTLs) play an essential role in the control of viral replication during human immunodeficiency virus (HIV) infection. However, the efficacy of the CTL response varies between individuals. We tested the hypothesis that genetic polymorphisms in the lytic effector molecule perforin could influence the progression of HIV infection. The perforin gene was screened for single nucleotide polymorphisms (SNPs) by denaturing high-performance liquid chromatography (dHPLC). Correlations were sought between perforin genotype, perforin expression and lytic function of CD8+ T lymphocytes from HIV-positive patients. Association of perforin genotype with disease progression was investigated in 426 seroconverters enrolled in the French SEROCO cohort. AIDS-free survival curves were constructed using the Kaplan–Meier method and compared using the log-rank test. Three SNPs were found in the proximal promoter region of the perforin gene: 63G (allelic frequency 0.029), 112G (allelic frequency 0.071) and 1012T (allelic frequency 0.070). The presence of the 1012T genotype correlated with fewer perforin+ cells among circulating CD8+ CTL. However, CTL lines from HIV-positive individuals heterozygous for the perforin 1012T SNP displayed normal lysis of target cells, and within the SEROCO cohort, patients heterozygous for the 1012T SNP showed normal disease progression. However, 1012T/T homozygotes showed a tendency towards slower disease progression ( P = 0.08). In conclusion, polymorphism in the perforin gene is limited, and although the 1012T genotype appears to influence perforin expression, it was not conclusively associated with disease progression in HIV infection. [ABSTRACT FROM AUTHOR]

Leukemic T-LGL (large granular lymphocyte) composed of clonal CD3+ TCR alphabeta+ CD8+ CD57+ cells were compared with oligoclonally CD3+ CD8hi+ CD57- lymphocytes expanded after BMT. Leukemic CD3+ CD8hi+ CD57+ LGL showed several phenotypic differences such as an upregulation of CD16 and adhesion molecules (mainly CD11c, CD58 and CD54), activation markers and an exclusive CD45RA isoform expression. Unstimulated CD3+ CD8+ CD57+ LGL from both leukemic and BMT donors spontaneously developed an ex vivo CTL-like CD3-redirected cytotoxicity but no NK cell activity. Different stimuli (PHA, PMA or rhIL-2) induced similar cytotoxic profiles after a 6-day culture involving a CD3-redirected lysis predominating over a low NK cell activity. However, culture of leukemic LGL with these stimuli allowed either a 2 week persistence (PMA or rhIL-2) of CD8+ CD57+ LGL or their disappearance after 3 days (PHA). Furthermore, leukemic CD8hi+ CD57+ T lymphocytes produced an inhibitor of cytotoxic functions as previously described for BMT recipients' CD8+ CD57+ cells. Thus, despite some phenotypic differences between both cell sources, leukemic CD57+ T-LGL display the same functional characteristics of cytotoxic effector and immunoregulatory T cells as CD8+ CD57+ T cells from BMT recipients which might represent their normal counterpart. [ABSTRACT FROM AUTHOR]

Our previous studies on the human specific B- and T-cell responses against diptheria toxoid (DT) had shown that the B- and T-cell antigenic determinants were mostly assembled topographic sites with large intra-molecular cross-reactivities. In order to characterize further the B-cell responses against DT, and to investigate these cross-reactivities, we have produced 54 murine monoclonal antibodies (moAbs) against the native DT. Determination of their antigenic specificity showed that (i) 25 moAbs recognized conformational determinants on the native DT, (ii) 20 moAbs reacted against the A fragment (DTA) of the toxin, and (iii) nine moAbs reacted with at least three distinct highly purified CNBr peptides of the B fragment (DTB); some of them simultaneously recognized two or three purified CNBr peptides of DTB. As shown by cross-inhibition studies, the epitopes cross-reacting with those moAbs were distinct. Previously described sequence data indicated that these epitopes were not induced by repetitive amino-acid sequences. Finally, (iv) a cross-reactive idiotype was shared by moAbs specific for the CB1 and the CB3 peptides of DTB. Altogether, these data indicate that anti-DT moAbs are mostly directed against conformational determinants, and may cross-react with several DTB CNBr peptides. [ABSTRACT FROM AUTHOR]

Mice homozygous for a SCID mutation (SCID mice) are severely deficient in T and B lymphocytes. The absence of effector T and B cells has encouraged investigators to attempt engraftement of SCID mice with human fetal tissues, mature lymphocytes, hematopoietic progenitors and tumors. SCID mice can be reconstituted with human lymphocytes and are of interest for studying normal and abnormal lymphocyte development and function. SCID mice are also providing an in vivo model of infectious diseases. In addition, SCID mice readily support normal and pathologic human hematopoiesis differentiation and is useful for testing innovative hematological disease therapy. SCID mice with a fully functionnal human immune or hematopoietic system therefore seem to be extremely valuable for biomedical research. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell (HSC) transplantation, whatever its conditions, is associated with an increased risk of infections and tumoral complications, because of a delayed immune reconstitution. T-cell regeneration has been mostly investigated and appears to come more from graft and/or host mature T-cells, rather than from the differentiation/maturation of reinfused progenitors. In allogeneic setting, the immune defect is enhanced by the immune host/donor conflict and the use of prophylactic or curative immunosuppressive therapy. The tools used for studying post-transplant immunity are the following: immunophenotyping (kinetics and alterations of lymphocyte subset reconstitution), functional studies of T cell proliferation, cytokine production, cytotoxicity and signal transduction, as well as studies of T cell repertoire diversity. The CD4/CD8 cell immunophenotyping might be enough for routine clinical evaluation, allowing an adapted prophylaxis of opportunistic infections in those immune-suppressed patients, while functional assays might be useful to evaluate the persistence overtime of defects in immune reconstitution. These overall assays are useful both for basic and clinical research and allow better understanding in the mechanisms for T cell regeneration in the diverse types of HSC transplants performed nowadays particularly after graft of purified HSC where immune reconstitution remains a key question. [ABSTRACT FROM AUTHOR]

Major expansions of CD8hi+CD57+ T lymphocytes frequently occur during human immunodeficiency virus (HIV) infection and after transplantation. To investigate mechanisms of such cell expansion, we compared the activation and functional status of CD8hi+CD57+ and CD57- peripheral blood lymphocytes (PBL) from normal, bone marrow transplantation (BMT) and HIV+ donor. The CD8hi+CD57+PBL from BMT and HIV+ donors preferentially displayed CD38 and HLA-DR activation markers without correlation between CD8hi+CD57+ percentages and HIV load, the CD45RA+ isoform in all ex vivo conditions but acquired CD45RO after in vitro expansion, CD11b and CD11c in BMT and HIV+ donors but decreased expression of CD62-L, VLA-2 and VLA-6. The CD8hi+CD57+ cells were positive for perforin and granzyme B and spontaneously mediated cytolytic activity in a CD3-redirected assay. In contrast the inhibitor of cytolytic functions (ICF) produced by CD8hi+CD57+ cells down-modulated the CD3-redirected cytolytic activity but only at low levels of CD3 cross-linking. While CD3-triggering induced a low, if any, short-term proliferation of CD8+CD57+ cells, this subset could be amplified after long-term stimulation either with mitogens or with HIV antigens, thereby enriched in HIV-specific T cells producing tumor necrosis factor-α. Altogether these data suggest that CD8hi+CD57+ cells represent a terminal differentiation state of activated effector cytotoxic T lymphocytes which are enriched in antigen-specific T cells and down-modulate their own cytolytic potential, thus participating in a negative control of effector cell functions during persistent viral infections or transplantations. [ABSTRACT FROM PUBLISHER]

The aim of this study was to investigate the peripheral blood lymphocyte (PBL) phenotypes and T cell repertoire in patients with HCV infection, with or without mixed cryoglobulinaemia (MC). The patients were: Group 1, 23 patients with HCV infection and MC; Group 2, 14 patients with HCV infection but without MC; Group 3, 10 patients with symptomatic essential MC. Twenty healthy blood donors were used as controls. Blood lymphocyte counts were determined, and flow cytometry was used to measure proportions of B cells (CD19+), natural killer (NK) cells (CD16+ CD56+), T cells (CD3+), CD4+ T cell subsets (memory CD4+ CD45RO+; naive CD4+ CD45RO-; Th0/Th2 CD4+ CD7-; activated CD4+ CD25+), and CD8+ T cell subsets (immunoregulatory CD8+ CD57+; cytotoxic CD8+ S6F1+, activated CD8+ CD25+). Bias in the usage of T cell receptor (TCR) Vβ chains was studied in a subgroup of 10 representative patients of Group 1 using a polymerase chain reaction (PCR) analysis of the Vβ segments with a series of 20 oligonucleotides specific for the Vβ families. The three groups were comparable for blood lymphocyte counts, and we observed no abnormal repartition of the following PBL subsets: T cells (CD3+), CD4+ and CD8+ subpopulations, B cells (CD19+), and the NK cells (CD16+ 56+). In none of the groups could we observe lymphocyte ex vivo activation as assessed by the normal expression of the activation cell markers: CD25 on CD4+ or CD8+ T cells, or CD5 on B cells. The repartition of naive and memory (CD45RO-/RO+) CD4+ T cells was normal and we did not observe any amplification of the CD4+ CD7- T cell subset differentiated in... [ABSTRACT FROM AUTHOR]

The European collaborative study of HIV-infected pregnant women in Europe now indicates a 13% risk of fetal HIV infection (originally thought to be about 30%, and possibly higher in some countries)- Several reports suggest transplacental passage. However, the detailed mechanisms associated with such vertical transmission have not yet been clarified. We have examined the possibility that HIV enters placental tissue from maternal blood via binding to CD4 and Fc receptors (FcR) at the trophoblast level, allowing intraplacental infection. Here we report the detection of several FcR with distinct localization in the placental villus as well as CD4 surface expression on human trophoblast cells. In addition, we show that trophoblastic cells interact specifically with the gp120/gp160 viral envelope protein. By their tissue localization, these receptors could be responsible or the entry of HIV into the fetal placental cells. Furthermore, purified placental cells can be directly infected by HIV in vitro, and the infection is inhibited by soluble CD4. This suggests a crucial role of the CD4 receptor but an additional way of entry cannot be excluded. Such an in vitro model may be suitable for further studies concerning placental HIV transmission and its prevention. [ABSTRACT FROM AUTHOR]

The γ/δ T cell receptor is expressed on 1-15% of normal human peripheral blood lymphocytes (PBL). This subpopulation is recognized by anti-TcR-δ1 MoAb which is functionally defined as a pan-δ MoAb. Two other antibodies, anti-Ti-γA and anti-δ-TcS1 are directed at variable determinants of either the γ or the δ chain, respectively. In normal individuals anti-Ti-γA characterizes two thirds of the TcR-δ1+ subpopulation whereas anti-delta TcS1 reacts with most of the δ-TcR1+, Ti-γA- cells. In the present study, we have used these three MoAbs to characterize the TcR γ/ δ+ peripheral lymphocytes during HIV infection. Fifty patients at three distinct clinical stages (SPC/PGL, ARC, AIDS) of the infection have been studied. The Ti-γA+ subset in the whole group accounted for 3.45% of PBL and did not differ from controls; it was also unchanged when the three groups were analysed separately. The Ti-γA circulating cells were in a resting state as assessed by the absence of surface- expressed activation markers. In contrast, in some patients the proportion of circulating TcR-δ1+, Ti-γA-, δTcS1+ cells was increased (4.75%) leading to an inversion of the Ti-γA/δ-TcS1 ratio. Altogether, those data suggest a conservation of the Ti-γA+ subset during HIV infection, contrasting with an increase of the δ-TcS1+, Ti-γA- fraction in some cases. [ABSTRACT FROM AUTHOR]

Objective: To identify the cause of a hypersensitivity pneumonitis and to determine its pathogenesis.Design: Case study.Setting: Intensive care unit of a referral hospital.Patient: A 51-year-old man with chronic bronchitis who developed a hypersensitivity pneumonitis within 1 month after exposure to minocycline, amoxicillin, and erythromycin.Intervention: Sequential bronchoalveolar lavages after reexposure to minocycline and amoxicillin.Measurements: Immunologic analysis of the phenotype and function of alveolar lymphocytes.Results: Reexposure to minocycline but not to amoxicillin was followed by an interstitial pneumonitis. Sequential bronchoalveolar lavages showed a transient rise of eosinophils and neutrophils and a persistent alveolar lymphocytosis. Alveolar lymphocytes consisted predominantly of CD8+ but also CD4+ cells. Two CD8+ lymphocyte subsets were identified: CD8+ D44+ cytotoxic T cells that increased rapidly after the drug was resumed and CD8+ CD57+ suppressor T cells that predominated 11 days after the drug's withdrawal. In-vitro assays showed the presence of a lymphocyte-mediated specific cytotoxicity against minocycline-bearing alveolar macrophages.Conclusion: These results support the hypothesis of a central role of T lymphocytes in the pathogenesis of drug-related hypersensitivity pneumonitis. [ABSTRACT FROM AUTHOR]

Systemic capillary leak syndrome (SCLS) is a rare disorder of unknown etiology, characterized by recurrent hypovolemic shock attacks associated in most cases with a serum monoclonal immunoglobulin. Prophylactic therapy is usually disappointing and the outcome is often fatal. We report on a patient with recurrent hypovolemic shocks consistent with the diagnosis of SCLS associated with severe serum panhypogammaglobulinemia but no detectable monoclonal immunoglobulin or B cell proliferation. Attacks were often preceded by severe respiratory infections. Both infections and attacks were successfully prevented by i.v. gammaglobulin replacement. Further evaluation is needed to assess the efficacy of i.v. gammaglobulins in patients with SCLS but without hypogammaglobulinemia. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Cellular immune responses and changes in VL after a Dendritic Cells (DC)-based therapeutic vaccine in cART treated chronic HIV-infected patients with CD4 T cells above 450/mm," by A. C. Guardo and colleagues are presented.