Monitoring HIV DNA and cellular activation markers in HIV-infected humanized mice under cART
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Monitoring HIV DNA and cellular activation markers in HIV-infected humanized mice under cART Mary-Aude Rochat, Erika Schlaepfer, Stefan P. Kuster, Duo Li, Annette Audige, Sandra Ivic, Audrey Fahrny and Roberto F. Speck*
Abstract Background: The major obstacle to cure of HIV type-1 infection is the presence of the HIV reservoir, hidden from the immune system and insensitive to combined antiretroviral therapy (cART). Eradication approaches have been hindered by the difficulty for accurately monitoring its size in vivo, especially in the lymphoid organs. Humanized mouse models are a valuable tool for systematically assess the efficacy of therapeutic interventions in reducing the HIV reservoir. Nonetheless, persistence of the HIV reservoir over time, in the presence of cART, has yet to be analyzed in this in vivo model. Findings: We found that the proviral DNA as well as the total DNA were very stable in the spleen and mesenteric lymph node irrespective of the length of cART. Notably, the amount of proviral DNA was very similar in the spleen and lymph node. Furthermore, we observed a correlation between the percentage of splenic human CD4+ T-cells with total HIV DNA, between the number of human CD38 + CD8+ T-cells in the spleen with the amount of integrated HIV DNA, and eventually between the hCD4/hCD8 ratio in the spleen with integrated as well as total HIV DNA implying that the CD8+ T cells influence the size of the HIV reservoir. Conclusions: Here, we demonstrated the stability of this reservoir in humanized mice irrespective of the length of cART, confirming the relevancy of this model for HIV latency eradication investigations. Notably, we also found correlates between the frequency of CD4+ T-cells, their activation status and viral parameters, which were analogous to the ones in HIV-infected patients. Thus, hu-mice represent a very valuable HIV latency model. Keywords: HIV-1, HIV reservoir size, Humanized mice, cART, Alu-PCR
Introduction The cure for HIV is impeded by the latent reservoir of HIV, which is established during acute HIV infection, is non-responsive to cART [1, 2] and has a very slow decay rate with a ̴ t½ of 44 months [3, 4]. Memory CD4+ T-cells with ̴ 1/10e5 latently infected [5] are the major cell subset making up this latent reservoir [6]. The persistence of this reservoir might be mediated by either cellular intrinsic longevity [7] and self-renewal capacity [8] or homeostatic proliferation through cytokines and cell-cell interactions [6, 9]. * Correspondence: [email protected] Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
Several humanized mouse (hu-mice) models recapitulate key features of HIV infection [10–13] and have been successfully used for studying various eradication approaches [14–17]. However, this model has yet to be validated for some key aspects of HIV latency such as for its stability over time. Furthermore, hu-mice are chimeric animals, w
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