284,841 research outputs found
HIV Escape from antiretrovirals and CTL responses: Parallels and differences
No full textDr. Mallal describes mechanisms by which HIV viruses escape from cytotoxic T lymphocytes (CTL) responses and anti-retroviral drugs. In the presentation, Dr. Mallal particularly focuses on HIV escape from CTL responses and hypothesizes on the selective pressure involved in generating these escape mutations.
It is well known that the molecular interaction of HIV epitopes with the major histocompatibility complex (MHC) molecule is delicate and depends on the amino acid sequences within the binding groove. Certain escape mutations aim to disrupt this interaction which allows the viral epitopes to circulate freely and thus remaining undetectable by CTLs.
Subsequent to HIV transmission from one host to the next, it is hypothesized that the virus begins to shed its escape mutations. Shortly after, the virus adapts to the human leukocyte antigen (HLA) profile of the host by generating alternative escape mutations. It is important to recognize that these escape mutation can, and most often do, come at a replicative cost.
Dr. Mallal presents the results of HIV reverse transcriptase sequencing in 2 cohort studies and their association with the HLA type, in turn supporting the hypothesis that escape mutations can in fact be HLA class 1 allele specific
Co-evolution of HLA and viruses
No full textSimon Mallal, MB, BS, is Director of the Institute for Immunology and Infectious Diseases at Murdoch University and a Clinical Immunologist and Immunopathologist at Royal Perth Hospital. His research examines genetic influences on clinical outcomes in HIV and other diseases. More recently he has focused on viral adaptation to HLA-restricted immune responses and the implications of this for HIV vaccine immunogen design
Clinical applications of pharmacogenetics in HIV
No full textGiven on behalf of Dr. Elizabeth Phillips, Dr. Mallal presents pharmacogenetics and pharmacogenomics in clinical practice. Polymorphisms in both hosts and pathogens constitute a large challenge in therapy. Pathogenic adaptability, as seen in HIV, will shape the response to particular drug interventions. Similarly, the host genetic makeup will also affect the response to treatment. Drugs therefore help us elucidate these polymorphic backgrounds.
Pharmacogenetics refers to a clinical entity (phenotype) that is further characterized by genetics (genotype). Conversely, pharmacogenomics attempts to identify the genotype in order to predict the risk of developing a particular phenotype.
Pharmacogenetic and pharmacogenomic approaches in choosing an optimal antiretroviral regimen are exemplified in abacavir hypersensitivity reactions. Clinical diagnosis of abacavir hypersensitivity has been shown to yield false positives (CNA3005, CNA30024). This over diagnosis subsequently leads to prompt discontinuation of abacavir which incurs significant healthcare costs. A study by Dr. Phillips and colleagues (2005) demonstrated that disrupting treatment too early resulted in increased consultations with emergency physicians and/or specialists with higher costs for services. Furthermore, it took longer for these patients to achieve undetectable viral loads.
Studies show that abacavir hypersensitivity can be more accurately diagnosed with the patch test. Dr. Mallal reiterates the differences between pharmacogenetics and pharmacogenomics by pointing out that patch testing should be employed in abacavir sensitized individuals, therefore serving as a diagnostic test and not a predictive test
Prospective genetic screening decreases the incidence of Abacavir hypersensitivity reactions in the Western Australian HIV cohort study
No full textAbacavir therapy is associated with significant drug hypersensitivity in ∼8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allelle. In this prospective study, involving 260 abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of abacavir hypersensitivity among 148 HLA-B*5701–negative recipients
Abacavir and the altered peptide repertoire model: Clinical implications
No full textStructural and biochemical studies showing that abacavir binds non-covalently to the floor of the peptide binding groove of HLAB* 5701 with exquisite specificity to alter the self-peptides that load on the molecule to be presented to the immune system have recently been published [14]. This precise mechanistic explanation of why abacavir binds to HLA-B*5701 and no other allele accounts for the 100% negative predictive value of HLA-B*5701 testing for hypersensitivity which underpins its utility as a screening test. The specificity of the interaction between abacavir, peptide and HLA-B*5701 provides strong evidence that abacavir will not cause any off-target, HLA restricted immune-mediated side effects in HLA-B*5701 negative individuals. The rapid and direct non-covalent binding of abacavir to HLA-B*5701 without the requirement for metabolism of the drug explain the clinical symptoms of hypersensitivity including dose-related escalation of symptoms and rapid offset of symptoms following drug cessation. Importantly, if abacavir were being developed today its propensity to bind HLA-B*5701, alter the peptide repertoire presented, and the functional consequences of this interaction between HLA-B*5701 and abacavir could be determined in vitro and before use in man. This provides an important pre-clinical screening strategy to identify compounds in development that bind HLA and alter peptide presentation which could then be structurally modified to abrogate this property to avert hypersensitivity while retaining on-target effects
Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level
No full textSelection of HIV-1 variants resistant to antiretroviral therapy is well documented. However, the selection in vivo of HIV-1 mutant species that can escape host immune system HLA class I restricted cytotoxic T-lymphocyte responses has, to date, only been documented in a few individuals and its clinical importance is not well understood. This thesis analyses the observed diversity of the HIV-1 reverse transcriptase protein in a well characterised, stable, HLA-diverse cohort of HIV-1 infected patients with over two thousand patient-years of observation. The results show that HIV-1 polymorphism is selected within functional constraints and is associated with specific HLA class I alleles. Furthermore, these associations significantly cluster along the sequence and tend to occur within known corresponding HLA-restricted epitopes. Absence of polymorphism is also HLA-specific and more often seen with common HLA alleles. Knowledge of HLA specific viral polymorphisms can be used to model an individual’s viral load from their HLA type and viral sequence. These results suggest that cytotoxic T-lymphocyte escape mutation in HIV-1 is critical to the host at an individual and population level as well as to short and long term viral evolution. This work provides new insights into viral-host interactions and has clinical implications for individualisation of HIV-1 therapy and vaccine design
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Diffusive author(s), cohesive author: Analysis of S/N (1994)
No full textThis study indicates the ways in which various aspects of the author(s) are brought forth in Dumb type’s performance art, the S/N production. Previous research has suggested a non-hierarchical organization of Dumb type and the absence of a “privileged author” in Dumb type’s collaborative work, S/N. However, the results that I have investigated from member’s interviews on the creative process of S/N along with my analysis of the recorded images of S/N, indicate a different aspect of the author(s). First, S/N was created through, so to speak, the collective ideas of the members of Dumb type. Further, S/N has at least nine quotations from previous performances, installations, and printed writings, besides the work-in-progress technique. Explicating one of the “author functions” as given by Michel Foucault, each text has plural subjects of the author. However, it has been revealed from members’ interviews that Teiji Furuhashi had a decision-making role in selecting the members’ ideas within the performance. Since then, S/N has had plural subjects of creation; however, Furuhashi is one of the subjects of creation along with the “privileged author.” S/N has plural authors (diffusive authors) yet at the same time, it has a “privileged author,” Teiji Furuhashi (cohesive author)
HIV/AIDS: HIV: Experiencing the pressures of modern life
No full textHIV/AIDS HIV, the wily virus that causes AIDS, is able to outwit any number of host immune defenses that it encounters during infection. However, as Nolan, James and Mallal discuss in their Perspective, there is increasing evidence that small pockets of individuals are relatively protected against HIV infection, and also experience less aggressive HIV disease progression, due to a fortuitous genetic barrier. The Perspective authors discuss the finding that a low copy number of the gene encoding CCL3L1, a ligand for CCR5 (the coreceptor that HIV must bind to for invasion of human T cells to proceed), can markedly alter HIV disease outcomes. The authors discuss the need to take into account genetic barriers like the CCR5-CCL3L1 network when developing vaccines against HIV
- …
