Abstract
The underlying molecular mechanism and their general effect on the replication capacity of HIV 1 drug-resistance-associated mutations is often poorly understood. To elucidate the effect of two such mutations located in a region with a high density of spicing regulatory elements on the HIV-1-splicing outcome, bioinformatic predictions were combined with transfection and infection experiments. Results show that the previously described R263K drug-resistance-associated integrase mutation has additionally a severe effect on the ESE2b splicing regulatory element (SRE) in exon 2b, which causes loss of SD2b recognition. This was confirmed by an R263R silent mutation with a similar predicted effect on the exon 2b SRE. In contrast, a V260I mutation and its silent counterpart with a lower effect on ESS2b did not exhibit any differences in the splicing pattern. Since HIV-1 highly relies on a balanced splicing reaction, changes in the splicing outcome can contribute to changes in viral replication and might add to the effect of escape mutations toward antiviral drugs. Thus, a classification of mutations purely addressing proteins is insufficient.
Highlights
Human immunodeficiency virus 1 (HIV-1) infection is still not sterile curable to this day, several promising results have at least demonstrated viral clearance from infected hosts in cell cultures and small animal models using genome-editing approaches [1]
The tool evaluates sequence stretches in a sliding window according to the probability of sequence areas to act as splicing regulatory element (SRE) by posing as binding sites for splicing regulatory proteins, mainly of the SR or hnRNP family [28,29]
By infection and transfection experiments, and the employment of splicing reporters, this work demonstrates that resistance-associated HIV-1 integrase mutations can highly influence the viral splicing pattern
Summary
Human immunodeficiency virus 1 (HIV-1) infection is still not sterile curable to this day, several promising results have at least demonstrated viral clearance from infected hosts in cell cultures and small animal models using genome-editing approaches [1]. The development and current availability of antiviral treatment are already making significant contributions to improving quality of life and increasing life expectancy [2,3]. Country-specific studies and data from the World Health Organization and UNAIDS, respectively, suggest that overall, both the number of HIV-1 patients receiving highly active antiretroviral therapy (HAART) and the duration of treatment increased over the past years [4,5,6]. HIV-1 highly relies on host factors for replication, in particular the cellular splicing machinery [9].
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