Abstract
HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery.
Highlights
The genome of the human immunodeficiency virus-1 (HIV-1) is composed of nine viral genes that are required for all processes in the viral replicative cycle, including viral assembly, viral entry and receptor binding, membrane fusion, reverse transcription, integration, and proteolytic protein processing (Fig. 1)
A cocktail of three antiretroviral drugs is used as a combinatorial antiretroviral therapy that can effectively suppress viral replication, reduce rates of transmission, and improve patients’ life expectancy by prolonging the onset of acquired immunodeficiency syndrome (AIDS) [2]
Owing to improvements in the efficacy and availability of antiretroviral drugs and efforts in HIV/ AIDS prevention, recent years have seen a decrease in the incidence of HIV-1 infection
Summary
The genome of the human immunodeficiency virus-1 (HIV-1) is composed of nine viral genes (gag, pol, vif, vpr, tat, rev, vpu, env, and nef) that are required for all processes in the viral replicative cycle, including viral assembly, viral entry and receptor binding, membrane fusion, reverse transcription, integration, and proteolytic protein processing (Fig. 1). Because of the limitations and adverse effects associated with current cART regimens, it is necessary to develop alternative therapeutic strategies that are safer, more efficacious, and more resistant to viral escape Such emerging therapeutic strategies include gene-based and nucleic-acid-. Like cART, gene-therapy strategies against HIV-1 are often designed to target multiple viral mechanisms, which reduces the possibility of viral-escape-induced drug resistance and improves therapeutic efficacy. This is true for RNAi therapeutics, as small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) can be designed to target conserved 21-nucleotide sequences within the 9.2-kb HIV-1 genomic RNA, thereby expanding the possible targets far beyond those of current drugs. Multiplexing siRNAs or shRNAs as a single therapy can increase the overall potency and reduce the dosage of each component required to minimize off-target toxicity
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