Loss of CD4 + T cells in the gut is necessary but not sufficient to cause AIDS in animal models, raising the possibility that a differential loss of CD4 + T-cell subtypes may be important. We found that CD4 + T cells that produce interleukin (IL)-17, a recently identified lineage of effector CD4 + T-helper cells, are infected by SIV mac251 in vitro and in vivo, and are found at lower frequency at mucosal and systemic sites within a few weeks from infection. In highly viremic animals, Th1 cells predominates over Th17 T cells and the frequency of Th17 cells at mucosal sites is negatively correlated with plasma virus level. Because Th17 cells play a central role in innate and adaptive immune response to extracellular bacteria, our finding may explain the chronic enteropathy in human immunodeficiency virus (HIV) infection. Thus, therapeutic approaches that reconstitute an adequate balance between Th1 and Th17 may be beneficial in the treatment of HIV infection.
T-cell-mediated immune effector mechanisms play an important role in the containment of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication after infection. Both vaccination-and infection-induced T-cell responses
Programmed death-1 (PD-1) is a critical mediator of virus-specific CD8 ؉ T-cell exhaustion. Here, we examined the expression of PD-1 on simian immunodeficiency virus (SIV)-specific CD8 ؉ T cells and its possible involvement in regulation of cytokine production, proliferation, and survival of these cells. The majority of SIV-specific CD8 ؉ T cells expressed a PD-1 high phenotype, independent of their differentiation status, in all tissues tested. PD-1 expression gradually declined on CD8 ؉ T cells specific for SIV-derived epitopes that had undergone mutational escape, indicating that antigen-specific TCR stimulation is the primary determinant of PD-1 expression. SIV-specific PD-1 high CD8 ؉ T cells produced IFN-␥, TNF-␣, and IL-2 under cognate peptide stimulation. While CD8 ؉ T cells that proliferated in response to antigen had a PD-1 high phenotype, it was determined that there was a reduced proliferative capacity of PD-1 high compared with PD-1 low SIVspecific CD8 ؉ T cells. PD-1 high SIV-specific CD8 ؉ T cells were highly susceptible to IntroductionVirus-specific CD8 ϩ T cells are the predominant effectors through which the immune system controls viral infections. 1,2 While several lines of evidence indicate that human immunodeficiency virus (HIV)-specific CD8 ϩ T cells are involved in the control of HIV replication, 3-10 several reports have focused on intrinsic defects in these cells to explain their failure to clear the virus, thereby leading to progression to acquired immunodeficiency syndrome (AIDS) in all infected individuals. [11][12][13][14] Similarly, simian immunodeficiency virus (SIV)-specific CD8 ϩ T cells contribute substantially to the partial control of viremia in rhesus macaques; depletion of CD8 ϩ T cells results in increased viremia in SIV-infected animals, 15,16 while viral escape at targeted epitopes accelerates disease progression and death in vaccinated animals. 4 Furthermore, in acute SIV infection, cytotoxic SIV-specific CD8 ϩ T cells appear concurrently with the waning of early viremia. 17 As in human infection with HIV, functional defects in SIV-specific CD8 ϩ T cells have been reported, potentially explaining why virtually all SIV-infected rhesus macaques progress to simian AIDS and death despite a readily measurable CD8 ϩ T-cell response. [17][18][19][20] Therefore, understanding factors that regulate the function(s) of SIV-and HIV-specific CD8 ϩ T cells is critical in the fight against AIDS.Chronic viral infection with ongoing antigenic stimulation often results in exhaustion of virus-specific CD8 ϩ T cells. 21,22 Chronically stimulated virus-specific CD8 ϩ T cells express only low levels of receptors for IL-7 and IL-15 23 and lose the ability to maintain homeostatic proliferation. In addition, they lose the ability to produce key cytokines that are critical for the maintenance of CD8 ϩ T-cell memory. 24 In humans, the function and phenotype of chronically stimulated CD8 ϩ T cells differ among viral infections. HIV-specific CD8 ϩ T cells are less polyfunctional and more sensitive ...
The importance of chronic immune activation in progression to AIDS has been inferred by correlative studies in HIV-infected individuals and in nonhuman primate models of SIV infection. Using the SIVmac251 macaque model, we directly address the impact of immune activation by inhibiting CTLA-4, an immunoregulatory molecule expressed on activated T cells and a subset of regulatory T cells. We found that CTLA-4 blockade significantly increased T cell activation and viral replication in primary SIVmac251 infection, particularly at mucosal sites, and increased IDO expression and activity. Accordingly, protracted treatment with anti-CTLA-4 Ab of macaques chronically infected with SIVmac251 decreased responsiveness to antiretroviral therapy and abrogated the ability of therapeutic T cell vaccines to decrease viral set point. These data provide the first direct evidence that immune activation drives viral replication, and suggest caution in the use of therapeutic approaches for HIV infection in vivo that increase CD4+ T cell proliferation.
Macaques infected with the SIV strain SIVmac251 develop a disease closely resembling human AIDS characterized by high viremia, progressive loss of CD4+ T cells, occurrence of opportunistic infection, cachexia, and lymphomas. We report in this study that vaccination with the genetically attenuated poxvirus vector expressing the structural Ags of SIVmac (NYVAC-SIV-gag, pol, env) in combination with priming with DNA-SIV-gag, env resulted in significant suppression of viremia within 2 mo after mucosal exposure to the highly pathogenic SIVmac251 in the majority of vaccinated macaques. The control of viremia in these macaques was long lasting and inversely correlated to the level of both pre- and postchallenge Gag-specific lymphoproliferative responses, as well as to the level of total SIV-specific CD4+ T lymphocyte responses at the peak of acute viremia as detected by intracellular cytokine-staining assay. Viremia containment also correlated with the frequency of the immunodominant Gag181–189CM9 epitope-specific CD8+ T cells present before the challenge or expanded during acute infection. These data indicate, for the first time, the importance of vaccine-induced CD4+ Th cell responses as an immune correlate of viremia containment. The results presented in this work also further demonstrate the potential of a DNA-prime/attenuated poxvirus-boost vaccine regimen in an animal model that well mirrors human AIDS.
Abstract:Acinetobacter baumannii is an opportunistic pathogen which play the more and more greater role in the pathogenicity of the human. It is often attached with the hospital environment, in which is able easily to survive for many days even in adverse conditions. Acinetobacter baumannii is the species responsible for a serious nosocomial infections, especially in the intensive care units. Option of surviving in natural niches, and in the hospital environment could also be associated with the efflux pump mechanisms. Mechanisms of efflux universally appear in all cells (eukaryotic and prokaryotic) and play the physiological important role. In prokaryote, the main functions are evasion of such naturally produced molecules, removal of metabolic products and toxins. These pumps could also be involved in an early stage of infection, such as adhesion to host cells and the colonization. Importantly, they remove commonly used antibiotics from the cell in therapy of infections caused by these bacteria. Efflux pumps exemplify a unique phenomenon in drug resistance: a single mechanism causing resistance against several different classes of antibiotics. In Acinetobacter baumannii, the AdeABC efflux pump, a member of the resistance-nodulation-cell division family (RND), has been well characterized. Aminoglicosides, tetracyclines, erythromycin, chloramphenicol, trimethoprim, fluoroquinolones, some β-lactams, and also recently tigecycline, were found to be substrates for this pump. Drugs, as substrates for the AdeABC pump, can increase the expression of the AdeABC genes, leading to multidrug resistance (MDR). From this reason, treatment failure and death caused by Acinetobacter baumannii infections or underlying diseases are common. Because the AdeABC pump is widespread in Acinetobacter baumannii, similarly to other pumps in Gram-negative and Gram-positive bacteria, exists a need of searching a new therapeutic solutions. Specific efflux inhibitors of pumps (EPIs), including AdeABC inhibitors, could be suppress the activity of pumps and restore the sensitivity of such important bacteria as Acinetobacter baumannii to commonly used antibiotic.
A cohort of rhesus macaques with long-standing SIVmac251 infection (≥5 mo) was treated with continuous antiretroviral therapy (ART). A group of eight macaques was vaccinated with or without simultaneous administration of low dose IL-2 with the highly attenuated poxvirus vector (NYVAC) vaccine candidate expressing the SIVmac structural gag-pol-env (gpe) genes and a novel chimeric fusion protein derived from the rev-tat-nef (rtn) regulatory genes. Control groups consisted of mock-vaccinated macaques or animals treated only with IL-2. Vaccination significantly expanded both virus-specific CD4+ and CD8+ T cell responses, and IL-2 further increased the vaccine-induced response to an immunodominant Gag epitope. Following antiretroviral treatment interruption, the viral set point was significantly lower in vaccinated than in control macaques for at least 4 consecutive mo, and viral containment was inversely correlated with vaccine-induced, virus-specific CD4+ and CD8+ T cell responses. These data provide the proof of concept that therapeutic vaccination before cessation of ART may be a feasible approach in the clinical management of HIV-1 infection.
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