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

The reasons for the failure of the immune system to control HIV-1 infection, and the resulting immunodeficiency, remain unclear. HIV-1 persists in its host despite vigorous immune responses, including a strong, and probably functional, HIV-specific cytotoxic T-lymphocyte response. Interestingly the immunological features of HIV-1-infected individuals show many similarities to those seen in elderly people without HIV infection. We propose that, through a process of continuous immune activation, HIV-1 infection leads to an acceleration of the adaptive immune system ageing process, resulting in premature exhaustion of immune resources, which participates in the onset of immunodeficiency. This hypothesis might shed new light on HIV-1 pathogenesis and could suggest the need to reconsider current immunotherapeutic strategies to fight the virus.
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PMID:Premature ageing of the immune system: the cause of AIDS? 1246 69

Virus-specific T-cell responses, important for the control of HIV-1 infection, are seen in HIV-1-infected subjects in the early stages of infection. A progressive variable decline in HIV-1-specific CD4 and CD8 T-cell responses during the course of the infection is not reversed by the administration of potent antiretroviral drugs. The mechanisms responsible for this HIV-1-inflicted loss are complex, involving processes ranging from T-cell ontogeny to the final stages of antigen presentation and T-cell differentiation. HIV-1-specific CD4 and CD8 T cells are present in most patients, but have been rendered anergic, either directly by HIV-1 or indirectly by clonal inactivation, exhaustion and/or suppression. The absence of functional HIV-1-specific T cells in chronic infection, even after the initiation of antiretroviral therapy, indicates that additional immunomodulatory therapy is required. To induce or maintain such cellular responses in an immunosuppressed environment of chronic infection is proving difficult to achieve. The induction of virus-specific CD4 T-cell and, subsequently, CD8 T-cell responses may require different novel approaches based on an appreciation of the complex mechanisms involved in the loss of these responses.
J HIV Ther 2002 May
PMID:Mechanisms of loss of HIV-1-specific T-cell responses. 1255 85

Deficiencies in potentially highly protective HIV-1-specific immune responses have led to interventions with immunotherapeutic strategies such as post-exposure vaccination. The application of exogenous antigen to the HIV-infected individual by therapeutic vaccination might be expected to induce renewed virus-specific effector T-cell and neutralising-antibody responses. However, the nature of HIV-1 immunopathogenicity precludes this approach: high levels of viral turnover, persistent expression and presentation of HIV-1 antigen to the immune system, T-cell hyperactivation and exhaustion and clonal T-cell anergy all successfully counter any effect of exogenous antigen. Even with the use of highly active antiretroviral therapy (HAART), when HIV-1 activity is profoundly restricted, the induction of immune responses remains problematic. Different vaccine strategies are currently being tested, including a whole killed virus preparation (Remune), a yeast virus-like particle (p24 VLP), whole antigen preparations (VaxSyn), canarypox immunogens (ALVAC) and DNA plasmids. Therapeutic vaccine strategies currently in the earliest stages of development include adenovirus vectors and a topical DNA preparation, DermaVir.
J HIV Ther 2002 May
PMID:Improving HIV-specific immune responses in HIV-infected patients. 1255 87

Telomere length is abnormally short in the CD8(+) T-cell compartment of human immunodeficiency virus type 1 (HIV-1)-infected persons, likely because of chronic cell turnover. Although clonal exhaustion of CD8(+) cytotoxic T lymphocytes (CTL) has been proposed as a mechanism for loss of antigen-specific responses, the functional consequences of exhaustion are poorly understood. Here we used telomerase transduction to evaluate the impact of senescence on CTL effector functions. Constitutive expression of telomerase in an HIV-1-specific CTL clone results in enhanced proliferative capacity, in agreement with prior studies of other human cell types. Whereas the CTL remain phenotypically normal in terms of antigenic specificity and requirements for proliferation, their cytolytic and antiviral capabilities are superior to those of control CTL. In contrast, their ability to produce gamma interferon and RANTES is essentially unchanged. The selective enhancement of cytolytic function in memory CTL by ectopic telomerase expression implies that loss of this function (but not cytokine production) is a specific consequence of replicative senescence. These data suggest a unifying mechanism for the in vivo observations that telomere lengths are shortened in the CD8(+) cells of HIV-1-infected persons and that HIV-1-specific CTL are deficient in perforin. Telomerase transduction could therefore be a tool with which to explore a potential therapeutic approach to an important pathophysiologic process of immune dysfunction in chronic viral infection.
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PMID:Differential impairment of lytic and cytokine functions in senescent human immunodeficiency virus type 1-specific cytotoxic T lymphocytes. 1258 33

Data from basic science and clinical studies suggest that hydroxyurea (hydroxycarbamide)-based regimens are effective treatment options for patients with HIV at various stages of disease. In vitro studies of HIV-infected lymphocytes have shown that hydroxyurea: (i) inhibits viral DNA synthesis; (ii) synergistically interacts with nucleoside reverse transcriptase inhibitors (NRTI); and (iii) increases the antiviral activity of didanosine. Clinical studies have confirmed that hydroxyurea in combination with didanosine produces potent and sustained viral suppression in patients with HIV infection. However, some concerns have been recently raised on the use of hydroxyurea in association with NRTI. Hydroxyurea can cause myelosuppression, skin toxicities, mild gastrointestinal toxicity, and abnormalities of renal and liver functions. In addition, hydroxyurea may accentuate the toxic effects of nucleoside analogues. In fact, some clinical data seem to indicate an increased risk of pancreatitis and neuropathy when hydroxyurea is combined with didanosine and stavudine. Since hydroxyurea-related toxicity is dose dependent, a systematic study of hydroxyurea optimal dosage and schedule was initiated to monitor patients for possible nucleoside toxicity. In the Research Institute for Genetic and Human Therapy (RIGHT) 702 study it was shown that a low, well-tolerated hydroxyurea dose (600 mg daily) achieved better antiretroviral activity than higher doses, together with better CD4+ cell count increase and fewer adverse effects. In this paper the effects of hydroxyurea as salvage therapy for heavily pretreated patients with advanced HIV disease are presented. These studies have shown that some patients with extensive pretreatment experience and advanced disease can respond substantially to the addition of hydroxyurea. The addition of hydroxyurea to didanosine does not prevent the emergence of resistance to didanosine; nonetheless, the efficacy of this therapeutic regimen may not be attenuated by the presence of didanosine-resistant HIV mutants. Since CD4 T lymphocyte activation is essential for virus replication and CD8 T lymphocyte activation may contribute to pathogenesis, the combination of hydroxyurea with other drugs may lead to the inhibition of HIV, by blocking the 'cell activation-virus production-pathogenesis' cycle. Clinical data indicate that hydroxyurea may play a role in attenuation of viral rebound and immune reconstitution by decreasing CD4 T cell proliferation, as well as preventing the exhaustion of CD8 T cell populations that may result from excessive activation during HIV infection. While the combination of hydroxyurea with didanosine has provided hope, future studies including those that evaluate optimal dosing and long-term toxicity are needed to define the role for this agent in the treatment of HIV infection.
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PMID:Hydroxyurea in the treatment of HIV infection: clinical efficacy and safety concerns. 1281 30

In animal models, lymphocytic choriomeningitis virus (LCMV) may be controlled after acute infection or may establish various levels of persistence. Cytotoxic responses mediated by CD8(+) T cells are responsible for both initial control of LCMV and for immunopathology. As discussed in this article, there is emerging evidence that the levels of antigen to which the immune system is exposed over time are important in controlling CD8(+) T cell activation, memory responses and exhaustion, and that these levels are affected by the efficiency of T cell help and the presence of antibody. To enable lasting control of LCMV infection, CD8(+) T cells, CD4(+) T cell help and B cells are all required. These findings have important implications for the prevention and treatment of infection by viruses such as hepatitis B and C viruses, cytomegalovirus and HIV. See accompanying article http://dx.doi.org/10.1002/eji.200324717
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PMID:Commentary: T cells get by with a little help from their friends. 1476 36

CD8 CTLs are a major effector for protection against cancer as well as many infectious diseases, including HIV/AIDS. CD8 CTL recognize antigenic peptides in the context of class I MHC. CTL functional avidity has been shown to be an important determinant of in vivo efficacy. CTL that can recognize peptide/MHC only at high antigen density are termed low avidity CTL, while those that can recognize their cognate antigen at low densities are termed high avidity CTL. Recent studies have demonstrated that high avidity CTLs are essential for the effective clearance of viral infections and for the elimination of tumor cells. At this time, approaches that can target high avidity cells for expansion in vivo are not well defined; however, new insights are beginning to emerge. A recent study has shown that prime-boost immunization may be an effective method to generate high avidity CTLs that recognize HIV antigens. In addition, we recently found that high levels of costimulation (signal 2) can skew the CTL response toward higher avidity cells. Thus, vectors expressing a triad of costimulatory molecules (TRICOM) or dendritic cells expressing higher levels of costimulatory molecules, can be used to induce high avidity CTL. Finally a critical role for CD4+ T cell help in the generation of high avidity cells has recently been identified (Palmer, manuscript submitted). While high avidity CTLs are superior for viral and tumor clearance, they also have a greater sensitivity to antigen induced cell death. In some types of chronic infections, such as HIV and HCV, as well as in cancer, the host may lose, by clonal exhaustion or other apoptotic mechanisms, the effector cells that are most critical to viral or tumor clearance. In this review, we examine the current knowledge concerning CTL avidity. We discuss the factors that may distinguish high avidity CTLs from low avidity CTLs and describe some of the mechanisms these cells use to clear viral infections. In addition, we study possible immunization strategies that may be used to elicit higher avidity CTLs and describe what is known about the factors that render these cells more susceptible to apoptosis than low avidity CTLs. Finally, we will incorporate these various elements into a general discussion of possible approaches for induction and maintenance of an effective immune response that can result in clearance of tumors or chronic viral infections and the relevance to vaccine development.
Curr HIV Res 2003 Jul
PMID:Molecular mechanisms and biological significance of CTL avidity. 1504 53

Direct cytopathic effects cannot explain the massive CD4+ T cell depletion in acquired immunodeficiency syndrome (AIDS) patients and several indirect mechanisms may be involved. A role has been proposed for apoptosis of uninfected lymphocytes, since lymphocytes from human immunodeficiency virus-1+ (HIV-1) individuals display increased levels of spontaneous apoptosis. This process may be ascribed in part to cell exhaustion by the chronic uncontrolled infection, but can also be directly induced by viral components, such as gp120, tat or nef. A key role is played by the death receptor Fas, but a role can also be played by other death receptors, such as the TNF and TRAIL receptors. By contrast, death of HIV-infected cells seems to be Fas-independent and driven by other viral components such as vpr and HIV proteases. A further role may be played by depletion of CD4+ T cell itself and hence the withdrawal of survival factors such as cytokines. Different ability of HIV strains to induce death of infected and uninfected cells might play a role in the clinical and biological differences displayed by HIV strains. A further variability may be ascribed to the intrinsic resistance of cells to apoptosis, which may depend on the individual genetic background or the use of drugs inhibiting apoptosis. The observation that when progression of HIV infection is slow due to "apoptosis-resistant" genetic backgrounds of the patients, or defective HIV-1 strains, or successful highly active antiretroviral therapy (HAART), generally also T cell apoptosis is low, suggests that HIV-infected subjects may benefit from therapies aimed to inhibit Fas function and/or spontaneous apoptosis.
Curr HIV Res 2003 Oct
PMID:Role of FAS in HIV infection. 1504 27

HIV establishes a chronic and latent infection that is not eliminated by the host immune defences. The virus induces extensive damage to the immune system, through virus-related and indirect pathogenic mechanisms. Both the cellular and the humoral arms of the immune system are unable to control the infection, which ultimately results in severe exhaustion of several lymphocyte functions and increased susceptibility to secondary and opportunistic infections. A striking pathological feature induced by the persistent viral replication is the aberrant activation of cells of the immune system. Among these cells, B lymphocytes are severely damaged and show signs of phenotypic and functional alterations. In parallel to the polyclonal B cell activation and hypergammaglobulinemia, B cells from patients show impaired reactivity to immunisation and in vitro activation signals. In addition, B lymphocytes from HIV-infected subjects are primed for apoptosis. The role of protective humoral immunity in the control and clinical progression of HIV infection is still much debated and controversial. The aim of the present review is to discuss the mechanisms involved in the loss of B cell functions during HIV infection. In particular, we discuss the role that T and B cell immune activation plays for B cell polyclonal activation and loss of memory B lymphocytes. The current knowledge on B cell damage is also discussed in the context of anti-HIV therapeutic treatment.
Curr HIV Res 2004 Jan
PMID:B lymphocyte dysfunctions in HIV infection. 1505 37

Within-patient HIV populations evolve rapidly because of a high mutation rate, short generation time, and strong positive selection pressures. Previous studies have identified "consistent patterns" of viral sequence evolution. Just before HIV infection progresses to AIDS, evolution seems to slow markedly, and the genetic diversity of the viral population drops. This evolutionary slowdown could be caused either by a reduction in the average viral replication rate or because selection pressures weaken with the collapse of the immune system. The former hypothesis (which we denote "cellular exhaustion") predicts a simultaneous reduction in both synonymous and nonsynonymous evolution, whereas the latter hypothesis (denoted "immune relaxation") predicts that only nonsynonymous evolution will slow. In this paper, we present a set of statistical procedures for distinguishing between these alternative hypotheses using DNA sequences sampled over the course of infection. The first component is a new method for estimating evolutionary rates that takes advantage of the temporal information in longitudinal DNA sequence samples. Second, we develop a set of probability models for the analysis of evolutionary rates in HIV populations in vivo. Application of these models to both synonymous and nonsynonymous evolution affords a comparison of the cellular-exhaustion and immune-relaxation hypotheses. We apply the procedures to longitudinal data sets in which sequences of the env gene were sampled over the entire course of infection. Our analyses (1) statistically confirm that an evolutionary slowdown occurs late in infection, (2) strongly support the immune-relaxation hypothesis, and (3) indicate that the cessation of nonsynonymous evolution is associated with disease progression.
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PMID:A statistical characterization of consistent patterns of human immunodeficiency virus evolution within infected patients. 1550 26


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