To date, HIV treatment regimens have primarily targeted virus enzymes or the process of virus-cell fusion, but not the integrated proviral DNA. Current highly antiretroviral therapy (HAART) targets the viral reverse transcriptase, protease and fusion proteins and this regime has transformed HIV-1 infection into a chronic disease and curtailed the mobidity of infected individuals(1)…that is, if you have access to antiretroviral drugs.
Since traditional vaccine aproaches have, up to date, failed miserably(2), new therapeutic interventions must be brought to the clinic.
A new attractive alternative has just been published(3) which is the specific erradication of the integrated HIV-1 provirus(4) in the host’s DNA.
In brief, the authors evolved a CRE recombinase(5)(6) which specifically recognizes sequences present in HIV-1 Long Terminal Repeats (LTRs)(7) and “splices out” the proviral DNA in cells infected with HIV-1.
This piece of work is quite interesting as proof-of-principle but it’s unlikely to be of immediate therapeutic use, although other authors have been able to engineer Cre recombinases which are cell membrane permeable and can even cross the blood-brain barrier(8).
Stay tuned…
References:
1) Lalezari JP et al. “Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America .” N Engl J Med. 2003 May 29;348(22):2175-85. Epub 2003 Mar 13
2) http://www.nature.com/news/2007/071114/pdf/450325a.pdf
3) Sarkar, Indrani et al. “HIV-1 proviral DNA excision using an evolved recombinase” Science. 2007 Jun 29;316(5833):1912-5
4) For a small review on the life cycle of a retrovirus: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.1437
5) For more on CRE recombinase:
http://en.wikipedia.org/wiki/Cre_recombinase
(6) Glaser S, et al “Current issues in mouse genome engineering.” Nat Genet. 2005 Nov;37(11):1187-93.
(7) For more on LTR’s please visit:
http://www.stanford.edu/group/nolan/tutorials/retcl_3_ltrs.html
(8) Jo, Dawoong et al. “Epigenetic regulation of gene structure and function with a cell-permeable Cre reombinase” Nat Biotechnol. 2001 Oct;19(10):929-33
2 comments:
I found this post (and anything relating to the molecular events involved in HIV infection) very interesting! The events that occur in an HIV infection that we learned about in class are FASCINATING to me. The HIV virus is very clever (unfortunately)! I had some questions about your post: what exactly does CRE refer to? Also, I thought that the HIV virus mutates itself very rapidly. How would this therapeutic approach involving excision of viral specific DNA be useful with a virus that constantly mutates?? Any thoughts??
I tried to find some more information on LTR of HIV to see if they are conserved. There is a ppaer published that examined the LTR of long term HIV survivors that found that nearly all of the LTR were highly comnserved among the different individuals. I wonder if this is the case for all those infected with HIV- which would make this type of theapry promising.J Virol. 1997 July; 71(7): 5608–5613.
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