HIV Reservoirs ‘Cure’?
An interview of Anthony Fauci, Director of the Institute of Allergy and Infectious Diseases, Bethesda, USA
Dr. Fauci was appointed Director of NIAID in 1984. He oversees an extensive research portfolio of basic and applied research to prevent, diagnose, and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. Dr. Fauci has made seminal contributions to the understanding of how the AIDS virus destroys the body's defenses leading to its susceptibility to deadly infections. He continues to devote much of his research time to identifying the nature of the immunopathogenic mechanisms of HIV infection and the scope of the body's immune responses to the AIDS retrovirus.
Alain Lafeuillade: at the 2010 CROI you used the terms ‘HIV sterilizing cure’ and ‘HIV functional cure’. What are your expectations for a ‘cure’?
Anthony Fauci: I believe that we will be able to achieve a functional cure in a subset of HIV-infected individuals, but not necessarily in the majority. I feel that the earlier one initiates anti-retroviral therapy (ART) following infection, the greater the chance we will be to achieve a functional cure. We know from studies in my own group that the size of the HIV reservoir is much smaller in individuals whose therapy was begun soon after infection (within a couple of months or earlier). Such patients have reasonable preservation of their immune function together with a small HIV reservoir. If an effective therapeutic vaccine or other immune enhancing approach is developed and administered to these individuals to contain this small reservoir, then I believe that a proportion of these individuals will be able to discontinue therapy without suffering from viral rebound, i.e. a “functional cure”. With regard to a sterilizing cure, I believe that this will be very difficult and may not ever be achievable, at least not in the majority of patients. However, I believe that we should continue to keep this as a goal. I believe that it can only be accomplished with a new generation of drugs or gene therapy approaches that could truly eliminate viral-infected cells.
AL: How are the NIH and the NIAID committed towards trying to find a cure?
AF: The NIH and NIAID is firmly committed to trying to find a cure for HIV infection. We already have a considerable amount of resources invested in grants and contracts for this purpose and NIAID has recently initiated the Martin Delaney Collaboratory: Towards an HIV-1 Cure Program with a commitment of an additional $8.5 million per year for 5 years with the possibility of even more. In addition, we have been attempting to stimulate interest on the part of young investigators to pursue this goal.
AL: What is, in your opinion, the knowledge we currently lack on the biology of HIV persistence and HIV reservoirs to go forward?
AF: There are many unanswered questions in the areas of the biology of HIV persistence and HIV reservoirs. Among these is our lack of precise knowledge as to the extent and diversity of the reservoir. Investigators have out of necessity studied the reservoir predominantly in peripheral blood CD4+ lymphocytes and to some extent in gut associated lymphoid tissue (GALT). However, there may be other unrecognized sites that exist. In addition, the precise molecular mechanisms involved in the formation and persistence of reservoirs are unclear.
AL: Is it realistic to invest in this quest (the cure) when millions of HIV-infected individuals on earth do not even have access to antiretroviral drugs?
AF: It will be difficult, but it is not unrealistic. With the proper global political will and commitment of resources, we can do both. The 2 goals are quite compatible with each other. Certainly, we need to treat people who are HIV-infected and are not yet receiving therapy that they require. However, therapy for HIV infection is currently a life-long commitment. It will be economically unfeasible to support the treatment of tens of millions of people with ART for life. The alternatives are to do a better job at preventing new infections and to develop a means of safely discontinuing therapy in individuals who have responded successfully to therapy, i.e. cure them.
AL: Although this is quite outside our scope, our readers would like to know where you stand about the use of pre-exposure prophylaxis, first in poor countries, then in developed countries?
AF: Pre-exposure prophylaxis (PrEP) has been shown to be effective in a recent study among men who have sex with men (MSM). The degree of efficacy was closely related to the adherence of the subjects in the study to the regimen of taking their pills as close to every day as possible. I am optimistic about the ultimate beneficial role that PrEP will play as part of a combination prevention regimen for HIV infection. However, I do not think that we can make any pronouncements about the use of PrEP in either developing or developed countries until we determine their efficacy among a range of risk categories. In addition, studies need to continue regarding safety, adherence, and development of drug resistance. Also, and importantly, the cost-benefit ratio must be determined, particularly in countries where there are not enough resources to treat people who are already HIV-infected.
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Key words: PreP, hiv cure, hiv persistence, hiv reservoirs cure