Biomedical subjects

Angela R McLean

Publications and source records attributed to Angela R McLean.

8 recordsLinked to original sources

PubMed2006

Inefficient cytotoxic T lymphocyte-mediated killing of HIV-1-infected cells in vivo.

Understanding the role of cytotoxic T lymphocytes (CTLs) in controlling HIV-1 infection is vital for vaccine design. However, it is difficult to assess the importance of CTLs in natural infection. Different human leukocyte antigen (HLA) class I alleles are associated with different rates of progression to AIDS, indicating that CTLs play a protective role. Yet virus clearance rates following antiretroviral therapy are not impaired in individuals with advanced HIV disease, suggesting that weakening of the CTL response is not the major underlying cause of disease progression and that CTLs do not have an important protective role. Here we reconcile these apparently conflicting studies. We estimate the selection pressure exerted by CTL responses that drive the emergence of immune escape variants, thereby directly quantifying the efficiency of HIV-1-specific CTLs in vivo. We estimate that only 2% of productively infected CD4+ cell death is attributable to CTLs recognising a single epitope. We suggest that CTLs kill a large number of infected cells (about 10(7)) per day but are not responsible for the majority of infected cell death.

Cell Survival↗

PubMed2005

Quantification of the virus-host interaction in human T lymphotropic virus I infection.

BACKGROUND: HTLV-I causes the disabling inflammatory disease HAM/TSP: there is no vaccine, no satisfactory treatment and no means of assessing the risk of disease or prognosis in infected people. Like many immunopathological diseases with a viral etiology the outcome of infection is thought to depend on the virus-host immunology interaction. However the dynamic virus-host interaction is complex and current models of HAM/TSP pathogenesis are conflicting. The CD8+ cell response is thought to be a determinant of both HTLV-I proviral load and disease status but its effects can obscure other factors. RESULTS: We show here that in the absence of CD8+ cells, CD4+ lymphocytes from HAM/TSP patients expressed HTLV-I protein significantly more readily than lymphocytes from asymptomatic carriers of similar proviral load (P = 0.017). A high rate of viral protein expression was significantly associated with a large increase in the prevalence of HAM/TSP (P = 0.031, 89% of cases correctly classified). Additionally, a high rate of Tax expression and a low CD8+ cell efficiency were independently significantly associated with a high proviral load (P = 0.005, P = 0.003 respectively). CONCLUSION: These results disentangle the complex relationship between immune surveillance, proviral load, inflammatory disease and viral protein expression and indicate that increased protein expression may play an important role in HAM/TSP pathogenesis. This has important implications for therapy since it suggests that interventions should aim to reduce Tax expression rather than proviral load per se.

Adult↗

PubMed2004

Quantifiable cytotoxic T lymphocyte responses and HLA-related risk of progression to AIDS.

There are significant associations between possession of certain HLA class I alleles and rate of progression to AIDS. Immunological data provide an explanatory mechanism for this relationship. Patients with HLA types associated with rapid disease progression recognize a significantly smaller fraction of their known repertoire of viral epitopes than do patients with HLA types associated with slow progression. Population frequency of HLA types (or supertypes) and their capacity to elicit cytotoxic T lymphocyte responses are also negatively correlated. These data provide an immunological mechanism to explain HLA-related risk of progression to AIDS and emphasize the central role of viral evolution in the pathogenesis of HIV.

Acquired Immunodeficiency Syndrome↗

PubMed2004

What have we learnt from SARS?

With outbreaks of infectious disease emerging from animal sources, we have learnt to expect the unexpected. We were, and are, expecting a new influenza A pandemic, but no one predicted the emergence of an unknown coronavirus (CoV) as a deadly human pathogen. Thanks to the preparedness of the international network of influenza researchers and laboratories, the cause of severe acute respiratory syndrome (SARS) was rapidly identified, but there is no complacency over the global or local management of the epidemic in terms of public health logistics. The human population was lucky that only a small proportion of infected persons proved to be highly infectious to others, and that they did not become so before they felt ill. These were the features that helped to make the outbreak containable. The next outbreak of another kind of transmissible disease may well be quite different.

Disease Outbreaks↗

PubMed2003

Repeated challenge with prion disease: the risk of infection and impact on incubation period.

Natural exposure to prion disease is likely to occur throughout successive challenges, yet most experiments focus on single large doses of infectious material. We analyze the results from an experiment in which rodents were exposed to multiple doses of feed contaminated with the scrapie agent. We formally define hypotheses for how the doses combine in terms of statistical models. The competing hypotheses are that only the total dose of infectivity is important (cumulative model), doses act independently, or a general alternative that interaction between successive doses occurs (to raise or lower the risk of infection). We provide sample size calculations to distinguish these hypotheses. In the experiment, a fixed total dose has a significantly reduced probability of causing infection if the material is presented as multiple challenges, and as the time between challenges lengthens. Incubation periods are shorter and less variable if all material is consumed on one occasion. We show that the probability of infection is inconsistent with the hypothesis that each dose acts as a cumulative or independent challenge. The incubation periods are inconsistent with the independence hypothesis. Thus, although a trend exists for the risk of infection with prion disease to increase with repeated doses, it does so to a lesser degree than is expected if challenges combine independently or in a cumulative manner.

Animals↗

PubMed2002

Residual HIV-specific CD4 and CD8 T cell frequencies after prolonged antiretroviral therapy reflect pretreatment plasma virus load.

BACKGROUND: Virus-specific cellular immune responses mediated by CD4 and CD8 T lymphocytes are thought to be central to the effective control of HIV-1 replication in vivo. However, quantitative correlations between HIV-specific T lymphocyte frequencies and plasma virus load (pVL) have proved difficult to establish in infected human individuals. This most likely reflects the complex interactions between the virus and these immune effector cells in the absence of treatment. OBJECTIVE: To assess frequencies of HIV-specific T lymphocytes after prolonged suppression of viral replication, i.e., under conditions where the effects of virus on the immune response are standardized and minimized, thereby fixing an important variable in a dynamic multivariate system. METHODS: HIV-specific CD4 and CD8 T lymphocyte frequencies were measured in 122 individuals after prolonged periods of successful combination antiretroviral therapy (ART) administered during chronic HIV-1 infection. RESULTS: The residual frequency of both CD4 and CD8 T lymphocytes specific for HIV-1 was inversely related to the pretreatment pVL. This relationship appeared to be non-linear, indicating the presence of a threshold pretreatment pVL level above which HIV-specific CD4 and CD8 T lymphocyte responses could not be maintained when antigenic drive was suppressed. Substantial populations of functional HIV-specific CD4 and CD8 T lymphocytes were generally detectable after prolonged ART only in those individuals with a pretreatment plasma HIV-1 RNA < 100,000 copies/ml. CONCLUSION: These findings identify a quantitative immune associate of host-virus interactions in established HIV-1 infection.

Adult↗

PubMed2002

BSE - a wolf in sheep's clothing?

The entire sheep flock in the UK has been threatened with slaughter if BSE is found in farmed sheep, largely on the grounds that an epidemic of BSE in sheep could be harder to contain than was the case for cattle, and that lamb could present a greater risk to consumers than beef. However, identifying BSE in a sheep is not straightforward, because of its similarities to the related disease, scrapie. Here, we review the likelihood that any UK sheep have BSE, how they might have got it, how a case could be identified and what the Government is doing in terms of surveillance and possible control methods.

Alleles↗

PubMed2002

Human immunodeficiency virus-specific CD8(+) T-cell responses do not predict viral growth and clearance rates during structured intermittent antiretroviral therapy.

There is a continuing search for better ways to use existing drugs against human immunodeficiency virus (HIV). One idea is to use short therapy interruptions to "autovaccinate" HIV-infected patients. A group of 13 chronically HIV-infected patients enrolled in a trial of such so-called structured treatment interruptions (STIs) were intensively studied with respect to their viral load (VL) and HIV-specific CD8+ T-cell (cytotoxic T-lymphocyte [CTL]) responses. We found that 10 of the 13 patients had plateau VLs after STIs that were lower than their pretreatment VLs. While viral rebound rates became lower over STIs, there were no changes in clearance rates. Although numbers of CTLs did increase over the same time that viral rebounds decreased, there was no correlation between CTL count and either viral rebound rates or clearance rates. Finally, we asked whether absolute numbers of or changes in numbers of CTLs predict plateau VLs after STIs. No measure of CTLs was able to predict plateau VLs. Thus, there was no signature in these data of an important contribution to virological control from HIV-specific CD8+ T lymphocytes.

Adult↗