Abstract
Globally, human immunodeficiency virus type 1 (HIV-1) infection is a major health burden for which successful therapeutic options are still being investigated. Challenges facing current drugs that are part of the established life-long antiretroviral therapy (ART) include toxicity, development of drug resistant HIV-1 strains, the cost of treatment, and the inability to eradicate the provirus from infected cells. For these reasons, novel anti-HIV-1 therapeutics that can prevent or eliminate disease progression including the onset of the acquired immunodeficiency syndrome (AIDS) are needed. While development of HIV-1 vaccination has also been challenging, recent advancements demonstrate that infection of HIV-1-susceptible cells can be prevented in individuals living with HIV-1, by targeting C-C chemokine receptor type 5 (CCR5). CCR5 serves many functions in the human immune response and is a co-receptor utilized by HIV-1 for entry into immune cells. Therapeutics targeting CCR5 generally involve gene editing techniques including CRISPR, CCR5 blockade using antibodies or antagonists, or combinations of both. Here we review the efficacy of these approaches and discuss the potential of their use in the clinic as novel ART-independent therapies for HIV-1 infection.
Highlights
Human immunodeficiency virus type 1 (HIV-1) infection has been a global health problem for over 30 years, affecting more than 37 million people worldwide today [1]
Holt et al demonstrated that 11% of hematopoietic stem and progenitor cells (HSPCs) engrafted into a mouse model contained the chemokine receptor type 5 (CCR5) disruption, which is a much higher frequency of edited cells found to engraft into mice compared to the insertion experiments by Manotham et al which were not engrafted into mice, demonstrating how much more efficient simple cleavage is compared to introduction of a gene
This modification of CD4+ T cells allowed inhibition of human immunodeficiency virus type 1 (HIV-1) infection and resulted in a significant reduction in viral load, as measured by p24 ELISA and qRT-PCR. This led to less reduction in CD4+ T cell counts [137]. These successful in vitro and in vivo studies led to clinical trials, where ZF nucleases (ZFN) CCR5 modified CD4+ T cells were transplanted into HIV-1-infected patients that had predominant CCR5utilizing virus and initially 13.9% of peripheral CD4+ T cells contained the CCR5 knockdown but at 42 months the concentration of peripheral CD4+ T cells with this modification had reduced to 1.7%
Summary
Human immunodeficiency virus type 1 (HIV-1) infection has been a global health problem for over 30 years, affecting more than 37 million people worldwide today [1]. The transplant caused his HIV-1 viral load to decrease to undetectable limits [8, 9] The reason for this was found to be that the stem cell donor was homozygous for C-C chemokine receptor type 5 (CCR5) D32. This 32-base pair deletion in the CCR5 allele provides a mutation for the CCR5 gene, which encodes the CCR5 that is used as a co-receptor by HIV-1 for attachment and entry into the host cell [8, 9] Another HIV-1 individual, Adam Castillejo, underwent a similar but less toxic version of allogeneic hematopoietic stem cell transplant from a homozygous CCR5D32 donor. Thirty months after analytical treatment interruption, the London patient, as he has been designated, has no detectable viral load in any of the examined regions including the peripheral blood, intestinal tissue, CSF, and lymph nodes This led the authors to conclude that this patient represents a model for HIV-1 cure [10, 11]. We highlight the biological functions of CCR5, summarize methods investigated for ablation of CCR5 in these studies, and evaluate the potential of their approaches to serve as a therapeutic for an HIV-1 cure
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