Scientists in Japan have used CRISPR-Cas9 technology to stop human immunodeficiency virus type 1 (HIV-1) replication in latently infected T cells that can’t be controlled using existing drug treatments. The gene-editing approach effectively disrupts two regulatory HIV-1 genes, tat and rev, which are essential for viral replication. Describing their in vitro studies in Scientific Reports, the researchers at Kobe University Graduate School of Medicine and Kobe University Graduate School of Health Sciences say initial results indicate that using CRISPR-Cas9 to target HIV-1 regulatory genes may offer a new approach to achieving “functional cures.”
“These results show that the CRISPR-Cas9 system, by targeting the regulatory genes of HIV-1, tat and rev, is a promising method for treating HIV infection,” comments co-author Masanori Kameoka, Ph.D., an associate professor at Kobe University Graduate School of Health Sciences. “We now need to investigate how we can selectively introduce a CRISPR-Cas9 system that targets HIV-1 genes into the infected cells of patients.”
HIV-1 infects about 35 million people worldwide, and while lifelong antiretroviral therapy (ART) can help convert what is otherwise a deadly infection into a more “manageable chronic disease,” current treatments are not a cure because they can’t completely eradicate the virus, which inserts its genes into the host cells’ DNA, the authors explain. Despite treatment using ART, HIV-1 continues to replicate at a very low level in some latently infected immune system cell types, such as CD4+ cells, macrophages, and follicular dendritic cells. “Current antiviral compounds are incapable of targeting the integrated proviral genome inside these cellular reservoirs and rapid viral rebound ensues after ART cessation,” they explain. The virus can also hide out in tissues such as the central nervous system.
In conclusion, the results of the present study showed that the CRISPR/Cas9 system is robust and efficient for targeting the HIV-1 proviral genome to suppress replication in latency models. CRISPR efficiency mainly depends on how well the gRNA sequence matches the target DNA, and targeting of the highly conserved regulatory genes tat and rev is beneficial for this effect. Moreover, the importance of these genes to the transcription ability of HIV-1 may lessen the emergence of CRISPR escape mutants. The combination of multiple gRNAs may also maximize efficiency and minimize the risk of resistance. Recent studies may have proven efficacy in cell cultures and ex vivo; however, when in vivo safety and efficacy profiles have been established, CRISPR-bearing lentiviral vectors may be delivered into HIV-1-infected individuals to clear latent viral reservoirs. Based on the rapid advances being achieved in CRISPR/Cas9 research, a HIV-1 functional cure may soon be within reach.
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