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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A dynamical system modeling the HIV infection, including a mutation occurrence process, is used, after simplifications, to show the impact of the viral diversity on the immune response and disease dynamics, by introducing an indicator of the immune system behavior, the immunological recognition efficacy (IRE) index. The existence, the expression and the stability of the endemically infected steady state of the IRE index-based model, as function of this index, are mathematically analyzed. The monotony of the steady state with respect to the IRE index is studied and an asymptotic analysis of the dynamical system performed. It is shown that the IRE index-based model provides a bound to the responses of the initial complex dynamical system. The biological interpretation of these mathematical results is the exhaustion of the immune system as a consequence of the continuous generation of viral mutants.
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PMID:A modeling approach to the impact of HIV mutations on the immune system. 1556 49

There is a generalized age-related decline in immune responses which leads to increased susceptibility of elderly to infection and, possibly, to autoimmune disease and cancer. This is associated with phenotypic changes of CD8+ T lymphocytes that include the loss of costimulatory molecules CD28 and CD27, which are important for proliferation and cell survival of CD8+ T cells. Loss of these molecules is associated with less ability to respond to recurrent infection. Functional changes within T cells during ageing include a reduction in the number of naive T cells and a progressively limited T cell repertoire. Furthermore, persistent life-long antigenic stress upon the memory pool leads to telomere erosion and concomittant loss of proliferative capacity, a phenomenon known as replicative senesence. In this review, we discuss that replicative senescence, or clonal exhaustion, may also occur in relatively young individuals, as evidenced from HIV-infected individuals and healthy Ethiopians. We discuss data suggesting that T cell defects may arise in individuals because of chronic antigen activation leading to rapid ageing of the memory CD8+ T cell pool.
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PMID:Significance of senescence for virus-specific memory T cell responses: rapid ageing during chronic stimulation of the immune system. 1562 72

Persistence is a hallmark of infection by viruses such as HIV, hepatitis B virus, hepatitis C virus and LCMV. In the case of LCMV, persistence may often be associated with exhaustion of CD8(+) T cells. We demonstrate here that persistent antigen suppressed IL-7Ralpha expression and this correlated with T cell exhaustion and reduced expression of the anti-apoptotic molecule B cell leukemia/lymphoma 2 (Bcl-2). In contrast, exposure to short-lived antigen only temporarily suppressed IL-7Ralpha expression, failed to induce T cell exhaustion, and primed T cells. Persistent antigen also suppressed IL-7Ralpha expression on primed T cells and this correlated with exhaustion of a previously stable primed T cell population. These findings suggest that antigen longevity regulates T cell fate.
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PMID:Inverse correlation between IL-7 receptor expression and CD8 T cell exhaustion during persistent antigen stimulation. 1572 49

Dehydroepiandrosterone (DHEA) therapy is controversial due to sensationalized reports of epidemiologic studies and the over-the-counter availability of DHEA. Human clinical trials have investigated the potential efficacy of DHEA therapy in multiple conditions with resultant inconsistencies in findings. DHEA is unique compared with other adrenal steroids because of the fluctuation in serum levels found from birth into advancing age. The lower endogenous levels of DHEA and DHEA sulfate found in advancing age have been correlated with a myriad of health conditions. Also, some studies suggest gender-specific actions of endogenous and exogenous DHEA. We reviewed only pharmacokinetic studies and human clinical trials investigating the efficacy of DHEA therapy that were placebo-controlled as these provided the most reliable scientific basis for the evaluation of DHEA therapy. Pharmacodynamic studies suggest that doses of 30-50mg of oral DHEA may produce physiologic androgen levels, especially in women. These studies report a dose-dependent effect and lack of accumulation of serum androgen levels. Pharmacologic studies also reveal a gender-specific response to DHEA therapy such that testosterone levels are increased in women but not in men. Clinical trials suggest that 50mg of oral DHEA, but not <30mg, can increase serum androgen levels to within the physiologic range for young adults with primary and secondary adrenal insufficiency, possibly improve sexual function, improve mood and self-esteem, and decrease fatigue/exhaustion. Whereas DHEA replacement therapy may be effective in treating patients with adrenal insufficiency, human clinical trials investigating its efficacy in conditions such as systemic lupus erythematosus, HIV, Alzheimer disease, advancing age, male sexual dysfunction, perimenopausal symptoms, depression, and cardiovascular disease have not provided consistent findings.
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PMID:The use of dehydroepiandrosterone therapy in clinical practice. 1578 47

Data from comparative trials involving more than 500 patients indicate that hydroxyurea is safe and augments suppression of HIV-1 replication when used in combination with didanosine or didanosine/stavudine as initial therapy or in patients without extensive antiretroviral experience. Additional studies will determine the optimum dosage and schedule for hydroxyurea and its effects when used with other agents and in patients with advanced disease or extensive pretreatment. Activities of hydroxyurea include inhibition of HIV-1 in active and resting CD4 lymphocytes and macrophages, potentiation of the activity of nucleoside reverse transcriptase inhibitors (NRTIs), compensation for resistance to adenosine analogue NRTIs, and potential increased phosphorylation of pyrimidine NRTIs. Recent attention, however, has focused on the potential immunomodulatory effects of hydroxyurea. The cytostatic effect of this agent on both CD4 and CD8 T cells may provide immunological benefits by reducing immune system overactivation, thus preventing both CD8 T cell exhaustion and CD4 T cell depletion. Accumulating evidence indicates that hydroxyurea-containing regimens may be associated with decreased levels of activated CD8 T cells, increased levels of naive CD4 and CD8 T cells, and preservation of the HIV-1-specific immune response. Further study of the potential for beneficial immunomodulation with hydroxyurea-containing regimens is needed to ascertain the clinical implications of these initial findings.
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PMID:Hydroxyurea: overview of clinical data and antiretroviral and immunomodulatory effects. 1602 81

The onset of AIDS is characterized by the collapse of the immune system after a prolonged asymptomatic period. The mechanistic basis of this disease progression has remained obscure, hindering the development of effective therapies. Here I present a mechanism that underlies the deterioration of the immune system during HIV infection. The elevated turnover of lymphocytes throughout the asymptomatic period is postulated to result in the accumulation of deleterious mutations, which impairs immunological function, replicative ability and viability of lymphocytes. This mutational meltdown is proposed to occur throughout the hierarchy of lymphocyte progenitors, resulting in the deterioration of lymphocyte regeneration and an ensuing rise in viral loads. A mathematical model is used to illustrate this mechanism of progressive immunological deterioration. Mutation accumulation may explain not only the decline in CD4+T cells, but also the functional deterioration of CD4+T cells, CD8+T cells and B cells, and the exhaustion of lymphocyte regeneration.
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PMID:The role of mutation accumulation in HIV progression. 1609 99

Switching from IgM to IgG and IgA is essential for antiviral immunity and requires engagement of CD40 on B cells by CD40L on CD4(+) T cells. HIV-1 is thought to impair CD40-dependent production of protective IgG and IgA by inducing progressive loss of CD4(+) T cells. Paradoxically, this humoral immunodeficiency is associated with B cell hyperactivation and increased production of nonprotective IgG and IgA that are either nonspecific or specific for HIV-1 envelope glycoproteins, including gp120. Nonspecific and gp120-specific IgG and IgA are sensitive to antiretroviral therapy and remain sustained in infected individuals with very few CD4(+) T cells. One interpretation is that some HIV-1 Ags elicit IgG and IgA class switch DNA recombination (CSR) in a CD40-independent fashion. We show that a subset of B cells binds gp120 through mannose C-type lectin receptors (MCLRs). In the presence of gp120, MCLR-expressing B cells up-regulate the CSR-inducing enzyme, activation-induced cytidine deaminase, and undergo CSR from IgM to IgG and IgA. CSR is further enhanced by IL-4 or IL-10, whereas Ab secretion requires a B cell-activating factor of the TNF family. This CD40L-related molecule is produced by monocytes upon CD4, CCR5, and CXCR4 engagement by gp120 and cooperates with IL-4 and IL-10 to up-regulate MCLRs on B cells. Thus, gp120 may elicit polyclonal IgG and IgA responses by linking the innate and adaptive immune systems through the B cell-activating factor of the TNF family. Chronic activation of B cells through this CD40-independent pathway could impair protective T cell-dependent Ab responses by inducing immune exhaustion.
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PMID:HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors. 1654 27

Both increased lymphocyte renewal with subsequent exhaustion of the immune system and impaired T cell renewal have been put into view to account for CD4+ T cell depletion and development of AIDS in HIV-1- infected humans. Telomerase is an enzyme that is involved in mechanisms that control cell life span and replicative potential. The effect of HIV-1 on telomerase activity, certain regulators, and telomeric terminal restriction fragment length on lymphoid Jurkat cells was used in measuring the proliferative activity of T lymphoid cells before and after being infected. At the cellular level, the enzymatic activity remains almost stable but further analyses of fractionated cells revealed that telomerase activity in the nuclear compartment was diminished whereas in the cytoplasmic compartment it was relatively increased on HIV-1 infection. Two key components of telomerase regulation were further considered at the transcriptional level, that is, the mRNA levels of both human telomerase reverse transcriptase (hTERT)--including the relative amount of its alternative splicing variants--and hTR. They were unaffected on HIV-1 infection. Telomeric length was also conserved in infected cells. Overall, these findings demonstrate that HIV-1 infection of Jurkat cells down modulate telomerase activity in the nuclear compartment by affecting its cellular localization.
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PMID:HIV-1 infection downregulates nuclear telomerase activity on lymphoblastoic cells without affecting the enzymatic components at the transcriptional level. 1670 19

HAART in HIV-1-infected individuals has a broad spectrum of clinical outcomes. In the majority of patients, plasma viral load becomes undetectable and CD4+ T-cells increase over time. However, in a number of subjects a discrepancy between plasma viral load and the CD4+ T-cell recovery is observed. CD4+ T-cell count can rise despite persistently detectable plasma viral load (virologic nonresponders), or conversely does not increase despite full plasma viral load suppression (immunologic nonresponder). Defective immune reconstitution may depend on several factors including previous therapeutic failure, duration of antiretroviral therapy, low CD4+ T-cell count at the initiation of HAART, advanced stage of disease, low adherence to HAART, and previous treatment interruption. There is no definitive evidence that age, viral strain/clade, or host genetic factors play a role in these different responses to HAART. The roles of T-cell subsets, thymic function, and cytokines have been investigated. The increased T-cell activation/apoptosis has been associated with a lack of effective immunologic response. Unabated virologic replication in lymphoid tissues, despite undetectable plasma viral load, has been proposed as the underlying mechanism of cellular activation. However, this "paradoxical response" probably can be associated with other events. Insufficient CD4+ T-cell repopulation of lymphoid tissues may be due to a thymus failure or a defect in bone marrow function. Lifelong infection, the toxic effect of antiviral drugs on T- and B-cell precursors, the stage of disease, and the low number of CD4+ T-cells before HAART may also account for thymus exhaustion and insufficient T-cell renewal. Finally, an imbalance in the production of cytokines such as TNF, IL-2 and IL-7 may also be a crucial event for the induction of immune system failure. In patients in which CD4+ T-cells are not increased by HAART, therapeutic strategies aimed at increasing these cells and reducing the risk of infections are needed. IL-2 and/or other cytokines may be of benefit in this setting. Some antiviral drugs may be better than others in immunologic reconstitution. Protease inhibitors may have additional, independent positive effects on the immune system. On the other hand, there may be little rationale for using immunosuppressive agents such as cyclosporine or hydroxyurea in this subgroup of immunologic nonresponder patients, as these molecules may increase T-cell decline and/or favor susceptibility to infections.
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PMID:Failure to reconstitute CD4+ T-cells despite suppression of HIV replication under HAART. 1684 76

Currently 15,000 to 16,000 people with HIV/AIDS are living in Switzerland. Many of these patients suffer from diverse signs and symptoms. One of the most common symptoms reported in the literature is fatigue with a rate ranging from 20 to 74%. It is well known that fatigue impacts negatively on people's activities of daily living, on their sense of physical and mental health as well as on their quality of life. Likewise many patients of the ambulatory HIV centre at the University Hospital Basel in Switzerland, report severe exhaustion and signs that indicated fatigue. In order to provide evidence-based care to these patients, a clinical practice program was developed basing on a comprehensive literature review. The program has been implemented and assists nurses to effectively assess and provide an intervention to those patients with HIV/AIDS who suffer from fatigue. The program includes the elements: screening, systematic assessment and intervention. For the systematic assessment, the Global Fatigue Index and a visual analogue scale are utilized. In this article, relevant literature has been reviewed for the development of an evidence-based program of care for patients living with HIV. Such an approach is perceived to positively affect the outcomes of patients living with HIV.
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PMID:[An evidence based program to support HIV-infected patients suffering from fatigue]. 1694 86


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