Abstract
Frameshifting during translation of viral or in rare cases cellular mRNA results in the synthesis of proteins from two overlapping reading frames within the same mRNA. In HIV-1 the protease, reverse transcriptase, and integrase enzymes are in a second reading frame relative to the structural group-specific antigen (gag), and their synthesis is dependent upon frameshifting. This ensures that a strictly regulated ratio of structural proteins and enzymes, which is critical for HIV-1 replication and viral infectivity, is maintained during protein synthesis. The frameshift element in HIV-1 RNA is an attractive target for the development of a new class of anti HIV-1 drugs. However, a number of examples are now emerging of human genes using −1 frameshifting, such as PEG10 and CCR5. In this study we have compared the HIV-1 and PEG10 frameshift elements and shown they have distinct functional characteristics. Frameshifting occurs at several points within each element. Moreover, frameshift modulators that were isolated by high-throughput screening of a library of 114,000 lead-like compounds behaved differently with the PEG10 frameshift element. The most effective compounds affecting the HIV-1 element enhanced frameshifting by 2.5-fold at 10 μM in two different frameshift reporter assay systems. HIV-1 protease:gag protein ratio was affected by a similar amount in a specific assay of virally-infected cultured cell, but the modulation of frameshifting of the first-iteration compounds was not sufficient to show significant effects on viral infectivity. Importantly, two compounds did not affect frameshifting with the human PEG10 element, while one modestly inhibited rather than enhanced frameshifting at the human element. These studies indicate that frameshift elements have unique characteristics that may allow targeting of HIV-1 and of other viruses specifically for development of antiviral therapeutic molecules without effect on human genes like PEG10 that use the same generic mechanism.
Highlights
33 million people are estimated to be infected with HIV-1 globally, with an annual death rate estimated to be 1.8 million [1]
This enabled the cloning of the HIV-1 frameshift element, and expression of the downstream reporter indicated a frameshift rate within the expected range of 5−10% with slight variation depending on the reporters used [27,36]
Modulators of the HIV-1 frameshift efficiency have the potential to be specific for the HIV-1 frameshift element because of structurally unique features that distinguish it from the well doi:10.1371/journal.pone.0139036.g005
Summary
33 million people are estimated to be infected with HIV-1 globally, with an annual death rate estimated to be 1.8 million [1]. Regarded as a chronic disease in developed countries, in part due to the availability of combination therapies that contain a cocktail of different drug classses, HIV-1 infection still remains a significant ongoing health problem with an increasing occurrence of drug resistance in patients to one or more of the drugs in current use [2]. In developing countries it remains a persistent threat to populations not able to access expensive drugs and, in particular, the virus continues to cause devastation in sub-Saharan Africa, Asia and Eastern Europe. Patients harboring drug resistant strains of virus are a growing subgroup that highlights the need for new treatment options. One strategy to keep the therapeutic options ahead of the ability of the virus to develop resistance to available drugs is to develop new combination therapies focusing on a broader target spectrum [3]
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