No abstract

Seroepidemiology shows that infections with adeno-associated virus (AAV) are widespread, but diverse AAV serotypes isolated from humans or nonhuman primates have so far not been proven to be causes of human disease. In view of the increasing success of AAV-derived vectors in human gene therapy, definition of the in vivo sites of wild-type AAV persistence and the clinical consequences of its reactivation is becoming increasingly urgent. Here, we identify the presumed cell type for AAV persistence in the human host by highly sensitive AAV PCRs developed for the full spectrum of human AAV serotypes. In genomic-DNA samples from leukocytes of 243 healthy blood donors, 34% were found to be AAV positive, predominantly AAV type 2 (AAV2) (77%), AAV5 (19%), and additional serotypes. Roughly 11% of the blood donors had mixed AAV infections. AAV prevalence was dramatically increased in immunosuppressed patients, 76% of whom were AAV positive. Of these, at least 45% displayed mixed infections. Follow-up of single blood donors over 2 years allowed repeated detection of the initial and/or additional AAV serotypes, suggestive of fluctuating, persistent infection. Leukocyte separation revealed that AAV resided in CD3 ϩ T lymphocytes, perceived as the putative in vivo site of AAV persistence. Moreover, infectious AAVs of various serotypes could be rescued and propagated from numerous samples. The high prevalence and broad spectrum of human AAVs in leukocytes closely follow AAV seroepidemiology. Immunosuppression obviously enhances AAV replication in parallel with activation of human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6), reminiscent of herpesvirus-induced AAV activation.IMPORTANCE Adeno-associated virus is viewed as apathogenic and replication defective, requiring coinfection with adenovirus or herpesvirus for productive infection. In vivo persistence of a defective virus requires latency in specialized cell types to escape the host immune response until viral spread becomes possible. Reactivation from latency can be induced by diverse stimuli, including infections, typically induced upon host immunosuppression. We show for the first time that infectious AAV is highly prevalent in human leukocytes, specifically T lymphocytes, and that AAV is strongly amplified upon immunosuppression, along with reactivation of latent human herpesviruses. In the absence of an animal model to study the AAV life cycle, our findings in the human host will advance the understanding of AAV latency, reactivation, and in vivo pathogenesis.

Regular blood donation is associated with pronounced decreases of BP in hypertensives. This beneficial effect of blood donation may open a new door regarding community health care and cost reduction in the treatment of hypertension.

SummaryDer Aderlass zählt zu den wichtigsten traditionellen Behandlungsverfahren der traditionellen Medizin in den unterschiedlichsten Kulturen. Das zwischenzeitlich durch missbräuchliche Anwendung in Ungnade gefallene Verfahren hat sich heute z.B. zur Behandlung von Patienten mit Hämochromatose und Polycythaemiaverawieder etabliert.In den letzten Jahren konnten positive Ergebnisse bei therapierefraktärem Hypertonus gezeigt werden. So konnte im Rahmen von Studien bei Patienten nach Nierentransplantation und bei Patienten mit metabolischem Syndrom der Blutdruck durch Aderlass erfolgreich gesenkt werden. Weitere Forschungsarbeit zu den vielversprechenden Ergebnissen ist allerdings notwendig, um die Ergebnisse zu untermauern.Perspektiven ergeben sich zudem in Anbetracht der zunehmenden Blutknappheit. Allerdings steht die Klärung ethischer Fragestellungen noch aus.