HIV Cure Through Eradication of Viral Reservoirs PDF Download

Author: Maher M. Elsheikh
Publisher:
ISBN: 9780355967555
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Languages : en
Pages :

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Book Description
Persistence of the latent HIV reservoir is the main obstacle in preventing or curing HIV. Even though a combination of antiretroviral therapy (cART) is effective in controlling the virus by suppressing its replication and infectivity to below detection levels, cART cannot eliminate the latent reservoir, and must be taken for life. After encountering HIV, some infected CD4+ T cells revert to a resting state and persist as memory T cells that remain quiescent while containing the stable HIV proviral DNA (latent reservoir). With a stable and long-lived reservoir, HIV remains a global health problem because the proviral DNA is transcriptionally silent but is capable of producing infectious particles when cART is interrupted. According to WHO, more than 34 million people died due to AIDS over the past three decades, and about 37 million are currently living with it. In addition, there are approximately two million new cases each year. HIV-infected individuals do not achieve complete immunologic reconstitution because viral suppression is incomplete, and immune activation occurs chronically. The inability of cART to eradicate HIV from latent viral reservoirs necessitates the development of novel therapeutic approaches to eradicate the virus from infected individuals so that cART can be discontinued. The goal of this work was to investigate innovative experimental approaches to eradicate the latent HIV reservoir by targeting specific molecular mechanisms within the PKC/NF-kB and p-TEFb signaling pathways of HIV-infected resting memory CD4+ T cells involved in viral replication and silencing during the HIV life cycle. This goal was successfully achieved by implementing two independent experimental approaches: 1) Eliminating HIV infected cells by inducing reactivation of latent HIV and targeting the activated cells for apoptosis (sterilizing cure). 2) Inducing permanent silencing of HIV in the latent viral reservoir by shutting down the HIV replication machinery, which could permanently inhibit viral replication in the infected cells (functional cure). Subsequently, we were able to identify latency reactivating agents and apoptosis inducing agents that, when used in combination, dramatically reduced the latent HIV reservoir. We were also able to identify several viral silencing agents (VSA) that target essential cellular and viral proteins within the NF-[kappa]B and PKC signaling pathways in infected cells. These VSAs curtail HIV proviral transcription and elongation, which permanently silence latent HIV for multi-generations. They were also effective in reducing viral transcription. Although our data demonstrated that this combination treatment has great potential as an effective anti-HIV therapy, additional testing using larger sample sizes and multiple latency cell models that target various cell reservoirs is needed in order to demonstrate that this therapy is effective and fully functional against various viral sanctuaries in the human body, and is capable of completely eliminating the reservoir with minimal cytotoxicity. Nevertheless, this was an important initial step to prove that our proposed strategy can be successful and should be evaluated further. This novel treatment strategy has the possibility of eliminating the latent HIV reservoir to achieve a drug-free remission and to cure HIV in the future.