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      Co-infection by human immunodeficiency virus type 1 (HIV-1) and human T cell leukemia virus type 1 (HTLV-1): does immune activation lead to a faster progression to AIDS?

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          Abstract

          Background

          Recent data have shown that HTLV-1 is prevalent among HIV positive patients in Mozambique, although the impact of HTLV-1 infection on HIV disease progression remains controversial. Our aim was to determine the phenotypic profile of T lymphocytes subsets among Mozambican patients co-infected by HIV and HTLV-1.

          Methods

          We enrolled 29 patients co-infected by HTLV-1 and HIV (co-infected), 59 patients mono-infected by HIV (HIV) and 16 healthy controls (HC), respectively.

          For phenotypic analysis, cells were stained with the following fluorochrome-labeled anti-human monoclonal antibodies CD4-APC, CD8-PerCP, CD25-PE, CD62L-FITC, CD45RA-FITC. CD45RO-PE, CD38-PE; being analysed by four-colour flow cytometry.

          Results

          We initially found that CD4 + T cell counts were significantly higher in co-infected, as compared to HIV groups. Moreover, CD4 + T Lymphocytes from co-infected patients presented significantly higher levels of CD45RO and CD25, but lower levels of CD45RA and CD62L, strongly indicating that CD4 + T cells are more activated under HTLV-1 plus HIV co-infection.

          Conclusion

          Our data indicate that HTLV-1/HIV co-infected patients progress with higher CD4 + T cell counts and higher levels of activation markers. In this context, it is conceivable that in co-infected individuals, these higher levels of activation may account for a faster progression to AIDS.

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          Most cited references58

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          Molecular mechanisms of cellular transformation by HTLV-1 Tax.

          The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since it transforms and immortalizes rodent fibroblasts and human T-lymphocytes. Through CREB, NF-kappaB and SRF pathways Tax transactivates cellular promoters including those of cytokines (IL-13, IL-15), cytokine receptors (IL-2Ralpha) and costimulatory surface receptors (OX40/OX40L) leading to upregulated protein expression and activated signaling cascades (e.g. Jak/STAT, PI3Kinase, JNK). Tax also stimulates cell growth by direct binding to cyclin-dependent kinase holenzymes and/or inactivating tumor suppressors (e.g. p53, DLG). Moreover, Tax silences cellular checkpoints, which guard against DNA structural damage and chromosomal missegregation, thereby favoring the manifestation of a mutator phenotype in cells.
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            Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression.

            The prognostic value of several immunologic markers were compared in Los Angeles Multicenter AIDS Cohort Study (MACS) participants, most of whom had been infected with HIV for >8 years. Markers studied included CD4+ cell number, flow cytometric measurements of CD8+ cell expression of CD38 and HLA-DR antigens, and serum markers of immune activation including neopterin, beta2-microglobulin, soluble interleukin-2 receptor, soluble CD8, and soluble tumor necrosis factor receptor-alpha (TNF-alpha) type II. Cox proportional hazards models indicated that elevated CD38 on CD8, a flow cytometric measurement of CD8+ T-lymphocyte activation, was the most predictive marker of those studied for development of a clinical AIDS diagnosis and death. As compared with the reference group, who had CD38 on CD8 7250 had relative risks (and numbers developing AIDS within 3 years) of 5.0 (15 of 81), 12.3 (24 of 60), and 41.4 (36 of 49), respectively. The strong prognostic value of CD38 on CD8 measurements and the fundamental importance of chronic immune activation in the pathogenesis of HIV disease suggests that this marker might have utility in the clinical management of HIV-infected persons.
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              Persistent immune activation in HIV-1 infection is associated with progression to AIDS.

              HIV-1 infection is characterized by chronic generalized CD8 and CD4 T cell hyperactivation, the biological effect of which is not understood. To study the relation between chronic immune activation and CD4 T cell depletion in HIV-1 infection. Prospective cohort study among participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS who have a known seroconversion date (n = 102). CD4 and CD8 T cell activation marker expression was analysed by FACScan before and after seroconversion (1 and 5 years after seroconversion); T cell proliferation and T cell numbers were also measured. Cox proportional hazard analyses were used to study the predictive value of these parameters for progression to AIDS. Preseroconversion low CD4 T cell numbers or elevated levels of CD4 T cell activation were associated with increased risk for development of AIDS after HIV-1 seroconversion. Progression to AIDS was associated with loss of both CD4 and CD8 naive T cells. The predictive value of CD8 T cell activation was confirmed and, in addition, in the course of infection low CD4 T cell counts and increasing proportions of dividing CD4 T cells, dividing CD8 T cells or elevated CD4 T cell activation marker expression became independent predictors of progression to AIDS. Increased T cell activation has predictive value for HIV-1 disease progression even before seroconversion. These data support the hypothesis that persistent hyperactivation of the immune system may lead to erosion of the naive T cell pool and CD4 T cell depletion.
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                Author and article information

                Journal
                BMC Infect Dis
                BMC Infectious Diseases
                BioMed Central
                1471-2334
                2009
                22 December 2009
                : 9
                : 211
                Affiliations
                [1 ]Department of Immunology, National Institute of Health, Maputo, Mozambique
                [2 ]Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
                [3 ]Departament of Genetics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
                [4 ]Center for Bone Marrow Transplantation, National Cancer Institute, Rio de Janeiro, Brazil
                Article
                1471-2334-9-211
                10.1186/1471-2334-9-211
                2813852
                20028500
                8a0e316b-748d-4791-b5a9-d2d92a84b01c
                Copyright ©2009 Gudo et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 May 2009
                : 22 December 2009
                Categories
                Research Article

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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