Identification of liver-specific enhancer-promoter activity in the 3′ untranslated region of the wild-type AAV2 genome ..!!!

Adeno-associated virus-2 (AAV2) is a small virus known to infect a majority of humans (causing sore throat, upper respiratory diseases), and at least some of the other primate species. AAVs have not been believed to cause disease –– which is a major reason why we are sharing this provocative publication [attached] with all of GEITP..!! Sero­logical evidence suggests lifetime infection rates of 35% to 70%, depending on geographic location. The view that AAVs are harmless is supported by observations of a “weak induction of innate immunity” (which likely reflects the absence of a host–virus arms race throughout evolutionary time). In fact, there is even some evidence that AAVs provide protective effects against viral infection and the formation of cancerous tumors.

In the course of evaluating AAV vector constructs for the treatment of metabolic liver disease, the lab of these authors unexpectedly observed transgene expression from a “negative control” construct (AAV-ΔLSP1-eGFP) –– which lacks a heterologous liver-specific enhancer–promoter element composed of the apolipoprotein E (APOE) enhancer and the human α1-antitrypsin (hAAT; encoded by SERPINA1) promoter. This construct showed transgene expres­sion in a human liver (hepatoma) cell line, but not in human embryonic-kidney-derived cells. Authors found that this same (putatively pro­moterless) construct also was expressed in mouse liver.

For many years, AAV2-based vectors have also been powerful tools for gene transfer and genome-editing applications; the level of interest in AAV2-based vectors has recently surged in response to reports of therapeutic efficacy in human clinical trials, most notably for those in hemophilia patients. It therefore comes as no surprise that this recent reported association between AAV2 integration events and human hepatocellular carcinoma (HCC) has generated controversy about the causal, or incidental, nature of this association –– and the implications for AAV vector safety. In the attached article, authors describe and characterize a previously unknown liver-specific enhancer–promoter element in the (naturally-occurring) wild-type AAV2 genome that is found between the stop codon of the cap gene (which encodes proteins that form the capsid), and the “right-hand” inverted terminal repeat. This 124-nucleotide sequence is within the 163-nucleotide common insertion region of the AAV2 genome –– which has been implicated in dysregulation of known HCC driver genes and thus offers added insight into the possible association between AAV integration events and the multifactorial pathogenesis of HCC.

This topic is reminiscent of Simian virus 40 (SV40), a DNA polyomavirus found in both monkeys and humans. Between 1955 and 1963, SV40 was discovered to be present [Am J Epidemiol 1976; 103: 1–12, PMID 174424] in about 90% of children and 60% of adults in the U.S. –– due to having received SV40-contaminated polio vaccines. Similar to other polyomaviruses, SV40 is a DNA virus that has the potential to cause tumors in animals, but most often it simply persists as a latent infection.

Nature Genetics Aug 2o17; 49: 1267–1273

This entry was posted in Center for Environmental Genetics. Bookmark the permalink.