News From HIV Persistence Workshop Day 4 PDF Print E-mail
Written by Alain Lafeuillade   
Friday, 09 December 2011 00:00

HIV Persistence, Reservoirs and Eradication Strategies Workshop: Day 4

HIV_persistence-d4

The fourth day of the workshop, on December 9, 2011, was completely devoted to new strategies for targeting HIV reservoirs. This included the use of anti-latency agents as well as gene therapy or other revolutionary approaches. It was the opportunity to describe what is currently going on in the world for a cure and what is planned to be tested soon.


Daniel Kuritzkes addressed the design of clinical trials for eradication. The endpoints in these trials are not straightforward. What are the biological tools to measure the reservoir? Is absence of viremia during analytic treatment interruption the ultimate test? It is also important to clearly define who are the patients we first have to study: acutely infecetd patients? Patients with advanced disease or those with well preserved immune functions? Perhaps elite controllers might also be a population to include? How long is long enough for HIV in terms of remission without ART? It is also challenging to define an acceptable level of risk in the context of generally effective ART. A true cure will need to prove the absence of transmission of the virus. It will also be necessary to distinguish relapse from reinfection.

David Margolis presented data from his vorinostat trial. Four patients are already enrolled after a long process of several years for approval. This study uses a single 400 mg dose of vorinostat and looks at HIV expression in resting cells. Initially, the 4 patients were selected because in vitro their resting CD4 cells showed increased viral RNA expression following the presence of vorinostat. From oncologic studies, we know that the peak of vorinostat in plasma occurs between 4 and 8 hours after a single administration. A mean increase in vivo of 4.4 fold of resting CD4 T cell associated RNA was found after administration of 400 mg of vorinostat and sampling patients at around +6 hours post administration. This induction concerned full-length RNA.

Several presentations then addressed the gene therapy approach. This strategy is designed to modify the expression of HIV coreceptors and render cells resistant to viral infection. HIV uses a main receptor, CD4, to enter cells together with a coreceptor, either CXCR4 or CCR5. The "Berlin patient" who was reported last year as cured from HIV received 2 bone marrow transplants from a donor with a genetic deletion on CCR5.
Carl June is conducting a trial in 12 patients where their CD4+ lymphocytes are treated with a drug, the zinc finger nuclease, to knock out CCR5 expression. Once reinfused, these modified cells are able to survive in the patient body and colonize gut-associated lymphoid tissue. During a period of ART interruption these cells were not selected but showed an antiviral effect with a drop in viremia. One patient even reached undetectable levels.

Finally, Keith Jerome showed another type of gene therapy approch which consists in engineering endonucleases able to specifically target integrated HIV sequences. 




Key words: HDAC inhibitors, HIV cure, HIV eradication., HIV gene therapy, HIV persistence, HIV reservoirs
Last Updated on Friday, 09 December 2011 19:13
 

Smileys

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