Challenges to Finding an HIV Cure
An interview of Douglas Richman, Director, Center for AIDS Research, University of California San Diego, La Jolla, CA, USA
Dr. Richman trained in infectious diseases and medical virology with research on influenza virus, herpesviruses and hemorrhagic fever viruses before focusing on HIV in the 1980s. HIV drug resistance was originally recognized in his laboratory in 1988. In addition to his continuing interest in HIV treatment and drug resistance, his research interests have focused on HIV pathogenesis including the issues of viral latency and evolution. He is a Fellow of the American Association for the Advancement of Science, the American Association of Physicians and the Infectious Disease Society of America. He is a member of the NIH AIDS Vaccine Research Committee.
Alain Lafeuillade: In 2009 you took the lead by calling in the journal Science the set up of a coordinated initiative on HIV latency. Where are you two years later in terms of building this consortium?
Douglas Richman: Quite a few funding agencies and advocacy groups have supported this call to put more effort into this challenging but important initiative. The NIAID has explicitly expressed interest in this initiative and has announced several program announcements and requests for applications for funding in this research area.
AL: In a recent editorial in Current Opinion in HIV and AIDS, you looked less optimistic about the possibility to find an HIV cure one day. What are, in your view, the main holes in our knowledge explaining that eradication attempts hit a snag?
DR: No pessimism at all, just realism. What I tried to convey is that no magical eureka solution is just around the corner. As with the development of a vaccine for HIV, I believe we have a critically important goal which is a major scientific challenge and which if achieved will require substantial new basic scientific insights. I don’t believe in false promises. Neither goal will be achieved quickly or easily. I am concerned that we have fundamental ignorance abut the mechanisms for the establishment and maintenance of latency and the extent of the reservoirs. We also have inadequate assays for the latent reservoir which will permit adequate monitoring of intervention strategies. There is a lot of work to do.
AL: Do you think that everything has been said in terms of ongoing viral replication on effective HAART, and the debate is closed?
DR: Not all patients with undetectable HIV RNA in the plasma are completely suppressed in all compartments including the genital tract and CNS; nevertheless, I believe that the data are compelling that with current potent and tolerable regimens, the viremia seen below the limits of detection with standard assays does not represent ongoing cell to cell replication in most patients.
AL: Let us imagine that we have characterized all cell types involved in HIV persistence. Do you think that an eradication strategy should act against the very last cell, or is there a threshold of a few cells below which the infection would not reinitiate?
DR: One could either speculate or do the experiments and my preference is to pursue the latter. I am open-minded, but operate on the assumption of the worst case scenario which is eliminating the reservoir will be required. If things turn out to be easier, so much the better.
AL: Trials are ready to start with the objective to purge the reservoir with IL-7 or SAHA. Do you think that they are too early?
DR: I am confident that they will not solve the problem. The question is whether the studies will provide information that will move the field forward. Will they tell us how to better monitor the reservoir or to design studies?
AL: What is your feeling about stem cell therapy with Zinc Finger Nucleases?
DR: I look forward to seeing the data. Yet another step 1 in a multistep process.
AL: What should be in your view the top three priorities for a breakthrough?
1. Ascertain the mechanisms of establishment and maintenance of latency.
2. Characterize the reservoirs.
3. Develop assays to monitor these reservoirs to quantify the efficacy of perturbations of the reservoir.
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Key words: hiv cure, hiv persistence, hiv reservoirs