A cure for AIDS: a matter of timing?
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REVIEW
Open Access
A cure for AIDS: a matter of timing? Iart Luca Shytaj and Andrea Savarino*
Abstract Despite the huge clinical success of antiretroviral therapy, several factors such as side effects, requirement of life-long adherence, high cost, incomplete access to therapies and development of drug resistance make the quest for an ultimate cure of HIV/AIDS a worldwide priority of biomedical research. In this respect, several sterilizing or functional cures have been reported in the last years in both non-human primates and humans. This review provides a summary of the main results achieved so far, outlining their strengths as well as their limitations. A synthetic interpretation of these results could be pivotal in order to develop an effective and widely available cure. Keywords: Eradication, Functional cure, Reservoirs, Acute HIV infection, Stem cell transplantation, Vorinostat, Therapeutic vaccine, Auranofin, BSO
Review Introduction
The quest of a cure for AIDS has been defined a “herculean task” [1], given the enormous complexities behind it and the numerous setbacks that have curbed early enthusiasms along the years. The ultimate goal of research for a cure is the complete eradication of the virus from the organism (i.e. a “sterilizing cure”), but a more feasible goal may be the achievement of spontaneous drugfree control of the infection without disease progression (i.e. a functional cure) [2]. The enormous difficulties that have been encountered in the quest of a cure for AIDS reside in the complex virus/host interplay that is a hallmark of this disease. Infection with HIV is initially characterized by a primary (acute) phase in which the virus is partially controlled by a robust immune response of the host [3]. Unfortunately, this immune response is not sufficient to eradicate the virus from the body, opening the way to the asymptomatic (chronic) phase. The chronic phase is characterized by an initial “steady state” between the virus and the immune system that is then slowly tilted in favor of the former, eventually leading to AIDS in the majority of the patients [4]. Treatment with antiretroviral drugs (ART) can reproducibly decrease viremia to levels below the limit of detection of the routine clinical assays and delays immune deterioration, but is not sufficient to tackle the viral reservoirs or to induce a strong immune response against the virus [5-7]. The
viral reservoirs are formed early during acute infection [8] and are exceptionally stable sources of viral persistence [6,9], harboring latent copies of integrated virus that are “invisible” to the immune system and unharmed by ART (5,6,9, for a review on the latency mechanisms, see: [10]). Viral reservoirs can be of both myeloid and lymphoid lineage, allowing a widespread distribution to different compartments such as the central nervous system, the gut-associated lymphoid tissue and the reproductive tract [11]. At a cellular level, central and transitional memory T-cells (TCM and TTM) were recently identified as a crucial source of viral
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