Abstract
This manuscript describes a novel strategy to improve HIV DNA vaccine design. Employing a new information theory based bioinformatic algorithm, we identify a set of nucleotide motifs which are common in the coding region of HIV, but are under-represented in genes that are highly expressed in the human genome. We hypothesize that these motifs contribute to the poor protein expression of gag, pol, and env genes from the c-DNAs of HIV clinical isolates. Using this approach and beginning with a codon optimized consensus gag gene, we recode the nucleotide sequence so as to remove these motifs without modifying the amino acid sequence. Transfecting the recoded DNA sequence into a human kidney cell line results in doubling the gag protein expression level compared to the codon optimized version. We then turn both sequences into DNA vaccines and compare induced antibody response in a murine model. Our sequence, which has the motifs removed, induces a five-fold increase in gag antibody response compared to the codon optimized vaccine.
Highlights
In the effort to create a vaccine for human immunodeficiency virus type 1 (HIV-1), poor immune response to the HIV proteins is a fundamental problem
We identify multiple nucleotide motifs from a systematic comparison of the HIV-1 genome and the human genome, which we conjecture to play a causative role in poor synthesis and nuclear confinement
We predict that the motif with the largest ratio of densities is responsible for nuclear isolation of HIV mRNAs
Summary
In the effort to create a vaccine for human immunodeficiency virus type 1 (HIV-1), poor immune response to the HIV proteins is a fundamental problem. For a DNA vaccine, the immune response is correlated with protein expression levels, so an increase in expression of these proteins could alleviate a significant road block to the construction of a viable DNA vaccine.[1,2] Transcription of the HIV DNA copy is an inefficient process that is aided by the addition of an HIV protein (TAT). In addition the large mRNAs from HIV have inherent RNA processing problems and are not efficiently exported from the nucleus in the absence of a helper protein (REV) These m-RNA synthesis and transport problems are presumably due to a set of RNA sequences or structures encoded in HIV DNA and RNAs.[3,4] We hypothesize that identifying and removing these signals, which cause the poor synthesis and nuclear confinement of HIV RNA, should significantly increase expression levels of these proteins and improve the immune response
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