International AIDS Society global scientific strategy: towards an HIV cure 2016

Steven G Deeks¹, Sharon R Lewin^{2

3}, Anna Laura Ross⁴, Jintanat Ananworanich^{5

6}, Monsef Benkirane⁷, Paula Cannon⁸, Nicolas Chomont⁹, Daniel Douek¹⁰, Jeffrey D Lifson¹¹, Ying-Ru Lo¹², Daniel Kuritzkes¹³, David Margolis¹⁴, John Mellors¹⁵, Deborah Persaud¹⁶, Joseph D Tucker¹⁷, Françoise Barre-Sinoussi¹⁸; International AIDS Society Towards a Cure Working Group; Galit Alter¹⁹, Judith Auerbach¹, Brigitte Autran^{20

21

22}, Dan H Barouch^{23

19}, Georg Behrens²⁴, Marina Cavazzana²⁵, Zhiwei Chen²⁶, Éric A Cohen²⁷, Giulio Maria Corbelli²⁸, Serge Eholié²⁹, Nir Eyal³⁰, Sarah Fidler³¹, Laurindo Garcia³², Cynthia Grossman³³, Gail Henderson¹⁴, Timothy J Henrich^{1

13}, Richard Jefferys³⁴, Hans-Peter Kiem³⁵, Joseph McCune¹, Keymanthri Moodley³⁶, Peter A Newman³⁷, Monique Nijhuis³⁸, Moses Supercharger Nsubuga³⁹, Melanie Ott⁴⁰, Sarah Palmer⁴¹, Douglas Richman⁴², Asier Saez-Cirion¹⁸, Matthew Sharp⁴³, Janet Siliciano⁴⁴, Guido Silvestri⁴⁵, Jerome Singh⁴⁶, Bruno Spire⁴⁷, Jeffrey Taylor⁴⁸, Martin Tolstrup⁴⁹, Susana Valente⁵⁰, Jan van Lunzen⁵¹, Rochelle Walensky⁵², Ira Wilson⁵³, Jerome Zack⁵⁴

Affiliations

¹ Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
² The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.
³ Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia.
⁴ International and Scientific Relations Office, ANRS, Paris, France.
⁵ US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
⁶ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
⁷ Molecular Virology Lab, Institute of Human Genetics, CNRS UPR 1142, Université de Montpellier, Montpellier, France.
⁸ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁹ CRCHUM and Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montréal, Quebec, Canada.
¹⁰ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
¹¹ AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
¹² World Health Organization Regional Office for the Western Pacific, Manila, Philippines.
¹³ Brigham &Women's Hospital, Boston, Massachusetts, USA.
¹⁴ University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
¹⁵ Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹⁶ Johns Hopkins University School of Medicine &Bloomberg School of Public Health, Baltimore, Maryland, USA.
¹⁷ University of North Carolina-Project China, Guangzhou, China.
¹⁸ Institut Pasteur, Paris, France.
¹⁹ Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
²⁰ Sorbonne Universités, UPMC Univ Paris 06, CIMI-Paris, France.
²¹ Inserm U1135, CIMI-Paris, Paris, France.
²² AP-HP, Hôpital Pitié-Salpêtrière, Département d'Immunologie, Paris, France.
²³ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
²⁴ Clinic for Immunology and Rhematology, Hannover Medical School, Hanover, Germany.
²⁵ Centre d'Investigation Clinique en biothérapie, Hôpital Necker-Enfants Malades, Paris, France.
²⁶ AIDS Institute, The University of Hong Kong, Pok Fu Lam, Hong Kong.
²⁷ Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, Quebec, Canada.
²⁸ European AIDS Treatment Group, Italy.
²⁹ Programme PAC-CI, Centre Hospitalier Universitaire de Treichville, Abidjan, Côte d'Ivoire.
³⁰ Harvard T. H. Chan School of Public Health, Department of Global Health and Population, Boston, Massachusetts, USA.
³¹ Department of Medicine, Imperial College London, London, United Kingdom.
³² The B-Change Group, Manila, Philippines.
³³ National Institute of Mental Health, NIH, Bethesda, Maryland, USA.
³⁴ Treatment Action Group, New York, New York, USA.
³⁵ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
³⁶ Centre for Medical Ethics and Law, Department of Medicine, Stellenbosch University, Western Cape, South Africa.
³⁷ Factor-Inwentash Faculty of Social Work, University of Toronto, Toronto, Ontario, Canada.
³⁸ Department of Medical Microbiology, Virology, University Medical Center Utrecht, Utrecht, Netherlands.
³⁹ Joint Clinical Research Centre, Kampala, Uganda.
⁴⁰ Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA.
⁴¹ Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, Australia.
⁴² Virginia San Diego Healthcare System and University of California, San Diego, San Diego, California, USA.
⁴³ Independent HIV Education and Advocacy Consultant, San Francisco, California, USA.
⁴⁴ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁴⁵ Yerkes National Primate Research Centre, Emory University, Atlanta, Georgia, USA.
⁴⁶ Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
⁴⁷ INSERM UMR_S912, Marseille, France.
⁴⁸ CARE Collaboratory Community Advisory Board, Palm Springs, California, USA.
⁴⁹ Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁵⁰ Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA.
⁵¹ ViiV Healthcare, London, United Kingdom.
⁵² Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁵³ Department of Health Services, Policy &Practice, Brown University School of Public Health, Providence, Rhode Island, USA.
⁵⁴ David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

PMID: 27400264
PMCID: PMC5322797
DOI: 10.1038/nm.4108

International AIDS Society global scientific strategy: towards an HIV cure 2016

Steven G Deeks et al. Nat Med. 2016 Aug.

. 2016 Aug;22(8):839-50.

doi: 10.1038/nm.4108. Epub 2016 Jul 11.

Authors

Affiliations

¹ Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
² The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.
³ Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia.
⁴ International and Scientific Relations Office, ANRS, Paris, France.
⁵ US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
⁶ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
⁷ Molecular Virology Lab, Institute of Human Genetics, CNRS UPR 1142, Université de Montpellier, Montpellier, France.
⁸ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁹ CRCHUM and Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montréal, Quebec, Canada.
¹⁰ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
¹¹ AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
¹² World Health Organization Regional Office for the Western Pacific, Manila, Philippines.
¹³ Brigham &Women's Hospital, Boston, Massachusetts, USA.
¹⁴ University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
¹⁵ Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹⁶ Johns Hopkins University School of Medicine &Bloomberg School of Public Health, Baltimore, Maryland, USA.
¹⁷ University of North Carolina-Project China, Guangzhou, China.
¹⁸ Institut Pasteur, Paris, France.
¹⁹ Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
²⁰ Sorbonne Universités, UPMC Univ Paris 06, CIMI-Paris, France.
²¹ Inserm U1135, CIMI-Paris, Paris, France.
²² AP-HP, Hôpital Pitié-Salpêtrière, Département d'Immunologie, Paris, France.
²³ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
²⁴ Clinic for Immunology and Rhematology, Hannover Medical School, Hanover, Germany.
²⁵ Centre d'Investigation Clinique en biothérapie, Hôpital Necker-Enfants Malades, Paris, France.
²⁶ AIDS Institute, The University of Hong Kong, Pok Fu Lam, Hong Kong.
²⁷ Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, Quebec, Canada.
²⁸ European AIDS Treatment Group, Italy.
²⁹ Programme PAC-CI, Centre Hospitalier Universitaire de Treichville, Abidjan, Côte d'Ivoire.
³⁰ Harvard T. H. Chan School of Public Health, Department of Global Health and Population, Boston, Massachusetts, USA.
³¹ Department of Medicine, Imperial College London, London, United Kingdom.
³² The B-Change Group, Manila, Philippines.
³³ National Institute of Mental Health, NIH, Bethesda, Maryland, USA.
³⁴ Treatment Action Group, New York, New York, USA.
³⁵ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
³⁶ Centre for Medical Ethics and Law, Department of Medicine, Stellenbosch University, Western Cape, South Africa.
³⁷ Factor-Inwentash Faculty of Social Work, University of Toronto, Toronto, Ontario, Canada.
³⁸ Department of Medical Microbiology, Virology, University Medical Center Utrecht, Utrecht, Netherlands.
³⁹ Joint Clinical Research Centre, Kampala, Uganda.
⁴⁰ Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA.
⁴¹ Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, Australia.
⁴² Virginia San Diego Healthcare System and University of California, San Diego, San Diego, California, USA.
⁴³ Independent HIV Education and Advocacy Consultant, San Francisco, California, USA.
⁴⁴ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁴⁵ Yerkes National Primate Research Centre, Emory University, Atlanta, Georgia, USA.
⁴⁶ Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
⁴⁷ INSERM UMR_S912, Marseille, France.
⁴⁸ CARE Collaboratory Community Advisory Board, Palm Springs, California, USA.
⁴⁹ Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁵⁰ Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA.
⁵¹ ViiV Healthcare, London, United Kingdom.
⁵² Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁵³ Department of Health Services, Policy &Practice, Brown University School of Public Health, Providence, Rhode Island, USA.
⁵⁴ David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

PMID: 27400264
PMCID: PMC5322797
DOI: 10.1038/nm.4108

Abstract

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy.

PubMed Disclaimer

Figures

**Figure 1. Cases of post-treatment control and resission**
Viral rebound following cessation of ART usually occurs within 2–3 weeks. In some circumstances viral rebound has been significantly delayed in the setting of stem cell transplantation (Boston patients) or very early ART in an infant (Mississippi child). In some individuals, long term post treatment control (PTC) off ART has been achieved. In these PTC, ART was nearly always initiated in acute infection and virus is usually detected at low levels in plasma. Timothy Brown remains the only HIV-infected individual off ART with no virus detected in blood or tissue. He received a stem cell transplant from a donor who was CCR5D32 negative and remains off ART for over 7 years.

**Figure 2. Mechanisms that maintain HIV latency in resting CD4+ T-cells**
There are multiple blocks to viral production in latently infected resting CD4+ T-cells including the site of integration (1), epigenetic silencing (2), lack of cellular transcription factors (3), incomplete elongation of transcripts (4), nuclear retention of transcripts (5) and micro RNAs limiting translation of viral proteins (6). TCR = T cell receptor; TF = transcription factors; co-Act = co-activators; MS = multiply spliced; US = unspliced; miRNA = microRNA.

**Figure 3. Using targeted nucleases against HIV**
Targeted nucleases, such as zinc finger nucleases and CRISPR/Cas9, provide more precise methods of gene therapy. They create site-specific DNA breaks, whose subsequent repair by the non-homologous end joining (NHEJ) pathway can be exploited to disrupt a gene, such as CCR5, or even an integrated HIV genome. Alternatively, repair can occur through homologous recombination, and a co-introduced DNA homology template can be designed to create small mutations in host genes, or direct the site-specific insertion of an anti-HIV gene.

**Figure 4. Assays used to quantify HIV persistence on ART**
The frequency of cells that produce infectious virus is only a subset of cells that are infected with intact (highlighted in a red line) and defective genomes (total pool of infected cells). US = unspliced; MS = multiply spliced; QVOA = quantitative viral outgrowth assay; MVOA = murine viral outgrowth assay

See this image and copyright information in PMC

References

1. UN Joint Programme on HIV/AIDS (UNAIDS) The Gap Report, 2014. [accessed 23 April 2015]; available at: http://www.refworld.org/docid/53f1e1604.html.
1. Barre-Sinoussi F, Ross AL, Delfraissy JF. Past, present and future: 30 years of HIV research. Nature reviews. Microbiology. 2013;11:877–883. - PubMed
1. Deeks SG, et al. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol. 2012 - PMC - PubMed
1. Van Lint C, Emiliani S, Ott M, Verdin E. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. Embo J. 1996;15:1112–1120. - PMC - PubMed
1. Coull JJ, et al. The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J Virol. 2000;74:6790–6799. - PMC - PubMed

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International AIDS Society global scientific strategy: towards an HIV cure 2016

Affiliations

International AIDS Society global scientific strategy: towards an HIV cure 2016

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical