Increasingly, researchers are investigating genetic fixes for otherwise intractable conditions. For example, see the recent blog entry A genetic fix for obesity? Now, a possible genetic fix is suggested that addresses HIV, a fix that undoes an ancient mutation present in humans.
The work is reported in a recent online publication Reawakening Retrocyclins: Ancestral Human Defensins Active Against HIV-1. The good news is that primates including us humans have a gene that produces retrocyclin, antiviral peptide proteins in the defensin family of proteins. Retrocyclin is a powerful anti-viral substance and “was recently shown to strongly inhibit HIV entry into human cells by blocking the interaction of viral proteins with their cellular receptors(ref).” The bad news is that way back in evolutionary history our branch of primates, including gorillas and chimps, experienced a “nonsense mutation” in the retrocyclin gene, so it fails to do its job and produce the retrocyclin proteins. A nonsense mutation is one where a codon encoding an amino acid is changed into a premature stop codon. This means the protein-making machinery in the cell ribosomes reading mRNA instructions as if they were on a tape stops before it should resulting in an incomplete protein being made or no protein at all.
The research challenge was to see if repairing the 7 million-year old nonsense mutation in the human retrocyclin gene could restore retrocyclin production and block entry of HIV into human cells like it does in Old World monkeys. “To determine whether human cells have retained the capacity to make retrocyclin protein, Venkataraman et al. corrected the premature stop codon mutation in a copy of the human retrocyclin gene. Next, they inserted the corrected gene into human promyelocytic cells, and looked to see if protein was produced from the gene. They found that cells harboring the corrected gene could make a protein similar to the monkey version of retrocyclin. But could human retrocyclin block HIV infection? Indeed, extracts made from cells containing the corrected gene could reduce HIV growth, and so could the retrocyclin protein purified from these extracts. Collectively, these results suggest that human cells have a potentially important—but latent—mechanism to protect against HIV(ref).”
So, there is a possibility that a genetic fix could be created to mobilize retrocyclin to protect against HIV. But the researchers identified an alternative and much easier approach, and that is to use aminoglycosides instead to override the erroneous stop signals in human retrocyclin protein production. “An aminoglycoside is a molecule composed of a sugar group and an amino group. Several aminoglycosides function as antibiotics that are effective against certain types of bacteria. They include amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin, and apramycin(ref).” Aminoglycosides “– don’t block protein creation in human cells but cause ribosomes to make occasional errors—like missing stop codons. The authors found that treating human cells with aminoglycosides allowed the cells to make retrocyclin at sufficiently high levels to inhibit infection by HIV(ref).”
Hmm. What this seems to say is that taking one or several of those antibiotics might help protect against HIV infection. The research says “– we exploited the ability of aminoglycoside antibiotics to read-through the premature termination codon within retrocyclin transcripts to produce functional peptides that are active against HIV-1(ref).” One possibility would be to make topical creams containing such antibiotics to inhibit sexual transmission of HIV. Of course there are likely to be other disease risks associated with ignoring protein-making stop instructions and taking these antibiotics. In any event, human activation of retrocyclin seems to be a promising avenue of research for prevention of HIV infections and AIDS. If it can be done safely and economically, tens of millions of lives and billions or trillions of dollars could be saved.
