Our search criteria was to include a comprehensive list of references based upon each author's research and knowledge database and then to reduce the number of references cited to include either a seminal paper or a more recent published paper that best reflects our current understanding of the points discussed. We also opted for human clinical research data to support our hypotheses and selected key references from individual laboratories to balance contributions from many laboratories. We
ReviewBarriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs
Introduction
Antiretroviral therapy (ART) is one of the major medical successes of the late 20th century. Effective ART results in indefinite viral suppression, restored immune function, improved quality of life, the near normalisation of expected lifespan, and reduced viral transmission. Despite the inherent potency of ART to suppress virus replication, treatment approaches have limitations; ART does not eliminate viral reservoirs, and needs lifelong adherence to expensive regimens that have potential short-term and long-term toxic effects. In 2010, more than 34 million people were estimated to be living with HIV, an increase of 17% over the past 10 years, and the number is expected to increase. Will we have enough resources worldwide to provide treatment and monitoring to all who need them? Even for those with access to ART, individual adherence is a big drawback. Additionally, despite virus control, HIV-associated complications persist, including a higher than normal risk of cardiovascular disease, cancer, osteoporosis, and other end-organ diseases. This increased risk might be due to the toxic effects of treatment or the consequences of persistent inflammation and immune dysfunction associated with HIV. Therefore, novel treatment approaches that eliminate persistent virus and do not need lifelong adherence to expensive and potentially toxic antiretroviral drugs are needed.
Two broadly defined categories of a cure for HIV infection exist—a functional cure and a sterilising cure. A functional cure is defined as host-mediated control of HIV replication, in the absence of ART. A functional cure suppresses viral replication for a pre-defined period of time (eg, 5 years) in the absence of treatment, restores and stabilises effective immune function, and decreases both HIV-induced inflammation (which could increase the risk of AIDS or non-AIDS morbidity) and in those individuals that maintain stable low-level plasma viral loads, reduces the risk of virus transmission to others. A functional cure is achieved spontaneously by a rare group of individuals who naturally control HIV replication without treatment (so-called elite controllers). These patients are characterised by a favourable HLA profile and potent HIV-specific CD8 T-cell responses that are associated with a low viral DNA reservoir. In 2010, a second group of patients who initiated ART during acute infection, and controlled HIV for several years after interruption of ART was identified.1 These so-called post-treatment controllers are very rare, and unlike elite controllers, do not show strong HIV-specific CD8 T cell responses or have protective HLA alleles.2, 3
A sterilising cure needs the complete elimination of replication-competent virus. Complete elimination of virus was probably first achieved after myeloablative chemotherapy, whole-body irradiation, and successful transplantation of haemopoietic stem cells from a CCR5 delta32 homozygous donor into an HIV-infected individual with acute myelogenous leukaemia (the so-called Berlin patient).4, 5 In a recent report6 from Boston, USA, two patients with relapsed Hodgkin's lymphoma treated with ART who received a CCR5+/+ haemopoietic stem-cell transplant, had undetectable pro-viral DNA and replication-competent HIV 8–17 months after transplantation. These findings suggest that ablative conditioning, immunosuppressive treatment, and post-transplant graft-versus-host disease—all of which were common in the Berlin patient and the Boston cases—might cause substantial and perhaps curative reductions in the size of the reservoir.6 To establish whether the Boston individuals were truly cured, ART will need to be interrupted. Efforts to pursue both functional and sterilising cures are in progress. An effective cure might need a combination of approaches For example, attempts to eradicate the reservoir might not work unless the capacity of the immune system to clear and control the virus is enhanced.
Section snippets
Establishment and maintenance of HIV latency
The HIV reservoir is established during primary infection. Administration of ART in very early acute infection seems to result in a low post-treatment total, and integrated DNA and HIV RNA concentrations, suggesting that aggressive treatment can decrease the size of the viral reservoir.1, 7, 8, 9 Although early treatment can substantially reduce the size of the total reservoir, a stable population of latently infected CD4 cells transits into the long-lived latent reservoir, and is unaffected by
Treatment intensification of ART
If persistent low-level replication of HIV or de-novo infection of new target cells continues during treatment, the addition of potent agents (so-called intensification) to a stable regimen could help reduce reservoir size. In treatment-intensification studies up to now, new classes of drugs such as the HIV integrase inhibitor raltegravir or the CCR5 inhibitor maraviroc have not reduced residual viraemia.26 Some reports have shown that intensification with an integrase inhibitor leads to
Conclusions
To achieve a cure for HIV, the efforts of the global research community need to be coordinated and transparent in sharing both positive and negative clinical results (panel). The discovery of a cure is one of the major medical challenges of our time. This goal has rallied all sectors of the biomedical community—ie, public, private, academic, and community groups, and consultation has led to the elaboration of a document that describes a strategy leading to a cure.14 Many challenges are
Search strategy and selection criteria
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2022, eBioMedicineCitation Excerpt :Well-coordinated innate and adaptive immune responses are also pivotal during chronic viral infections.5 During treated chronic viral infections, such as antiretroviral therapy (ART)-treated HIV infection, the state of chronic low-level immune activation/inflammation accompanied by immune exhaustion can lead to the development of inflammation-associated diseases6 and can contribute to viral persistence.7 Such immunological imbalances during acute and chronic viral infections likely involve multiple mechanisms, not all of which are well characterized.
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