de Sousa Marques, R.L.; (2009) A mouse model for the pathogenesis of immunodeficiency virus infection. Doctoral thesis , UCL (University College London).

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Abstract

T lymphocyte numbers in the human body are kept constant by homeostatic mechanisms balancing cell gain and loss. These mechanisms eventually fail in HIV infection, which is characterized by progressive immune deficiency attributable to a slow but relentless depletion of CD4+ T cells, the main viral targets. HIV infection is also associated with increased T cell turnover and a state of generalized immune activation. One of the fundamental questions in the field of HIV research is the relation between CD4+ T cell depletion and immune activation. It has been suggested that the virus has a direct effect by killing CD4+ T cells and increased T cell turnover reflects a homeostatic response to CD4+ T cell depletion. Alternatively, chronic immune activation may lead to enhanced turnover of T cells by ongoing proliferation-differentiation and cell death. In both cases, AIDS is the result of an exhaustion of the regenerative capacity of the immune system. To address these questions we examined the consequences of activated CD4+ T cell killing in a virus-free mouse model. Immunodeficiency viruses are highly selective for activated/memory and regulatory CD4+ T cells due to restricted expression of CCR5, the co-receptor for HIV and SIV, or CD134 (OX40, TNFRSF4), the cellular receptor for FIV. Activated CD4+ T cells were depleted by conditional reactivation of diphtheria toxin gene mediated by Tnfrsf4-driven Cre recombinase expression. Conditional ablation of activated CD4+ T cells resulted in accelerated turnover, with only a minimal apparent effect on their numbers, and was associated with a reduction in CD4:CD8 ratio and development of CD4+ T cell immune deficiency, resembling HIV infection. Importantly, activated CD4+ T cell killing also resulted in generalized immune activation, including lymph node enlargement, B cell expansion, elevated serum levels of proinflammatory cytokines and increased turnover and activation of CD8+ T cells, characteristic of HIV infection. CD8+ T cell activation correlated with lack of regulatory CD4+ T cell function and was prevented upon regulatory CD4+ T cell reconstitution. We therefore propose a causal link between memory and regulatory T cell depletion and immune deficiency and immune activation, respectively.

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