Abstract
Reducing the pool of HIV-1 reservoirs in patients is a must to achieve functional cure. The most prominent HIV-1 cell reservoirs are resting CD4 + T cells and brain derived microglial cells. Infected microglial cells are believed to be the source of peripheral tissues reseedings and the emergence of drug resistance. Clearing infected cells from the brain is therefore crucial. However, many characteristics of microglial cells and the central nervous system make extremely difficult their eradication from brain reservoirs. Current methods, such as the “shock and kill”, the “block and lock” and gene editing strategies cannot override these difficulties. Therefore, new strategies have to be designed when considering the elimination of brain reservoirs. We set up an original gene suicide strategy using latently infected microglial cells as model cells. In this paper we provide proof of concept of this strategy.
Highlights
Since the introduction of the combination antiretroviral therapy in 1996 the lethal Human immunodeficiency virus 1 (HIV-1) infection has evolved to become a chronic disease
We show in this paper that a model of latently infected microglial cell when reactivated by Romidepsin and transduced by a recombinant Adeno associated virus (AAV) becomes apoptotic
The Recombinant AAV based vector (rAAV) contained the gene coding for the herpes simplex (HS) thymidine kinase and transcription of the vector was driven by the 5 ‘Long Terminal Repeat (LTR) HIV-1 promoter
Summary
Since the introduction of the combination antiretroviral therapy (cART) in 1996 the lethal HIV-1 infection has evolved to become a chronic disease. Resting CD4 + T cells are known to be the principal reservoir of HIV but we have abundant proofs that many other cell reservoirs such as hematopoietic stem cells, dendritic cells, microglial cells and cells from the monocyte-macrophage lineage (reviewed in [1,2,3]) exist. A prerequisite to successfully purge reservoirs is to understand the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency Understanding these mechanisms could help to identify new target proteins in the viral cycle, which are not affected by cART [4]. CTIP2 is involved in the control of the elongation process of gene transcription by inhibiting P-TEFb functions. [11, 12]
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