Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection.
Nancie M. Archin,Naveen K. Vaidya,Naveen K. Vaidya,Jo Ann D. Kuruc,Abigail L. Liberty,Ann Wiegand,Mary F. Kearney,Myron S. Cohen,John M. Coffin,Ronald J. Bosch,Joseph J. Eron,David M. Margolis,Alan S. Perelson +12 more
TLDR
In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, it is found that early ART reduced the generation of latently infected cells, reinforcing and extending the concept that new approaches will be needed to eradicate HIV infection.Abstract:
HIV type 1 (HIV-1) persists within resting CD4+ T cells despite antiretroviral therapy (ART). To better understand the kinetics by which resting cell infection (RCI) is established, we developed a mathematical model that accurately predicts (r = 0.65, P = 2.5 × 10−4) the initial frequency of RCI measured about 1 year postinfection, based on the time of ART initiation and the dynamic changes in viremia and CD4+ T cells. In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, we found that early ART reduced the generation of latently infected cells. Although RCI declined after the first year of ART in most acutely infected patients, there was a striking absence of decline when initial RCI frequency was less than 0.5 per million. Notably, low-level viremia was observed more frequently as RCI increased. Together these observations suggest that (i) the degree of RCI is directly related to the availability of CD4+ T cells susceptible to HIV, whether viremia is controlled by the immune response and/or ART; and (ii) that two pools of infected resting CD4+ T cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART. These findings reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir.read more
Citations
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Defective proviruses rapidly accumulate during acute HIV-1 infection.
Katherine M. Bruner,Alexandra J. Murray,Ross A. Pollack,Mary Soliman,Sarah B. Laskey,Adam A. Capoferri,Adam A. Capoferri,Jun Lai,Matthew C. Strain,Steven M. Lada,Rebecca Hoh,Ya Chi Ho,Douglas D. Richman,Douglas D. Richman,Steven G. Deeks,Janet D. Siliciano,Robert F. Siliciano,Robert F. Siliciano +17 more
TL;DR: It is demonstrated that early initiation of ART limits the size of the reservoir but does not profoundly affect the proviral landscape, and hurdles that must be overcome are revealed to successfully analyze future HIV-1 cure strategies.
Journal ArticleDOI
Towards an HIV cure: a global scientific strategy
Steven G. Deeks,Brigitte Autran,Ben Berkhout,Monsef Benkirane,Scott Cairns,Nicolas Chomont,Tae Wook Chun,Melissa J Churchill,Michele Di Mascio,Christine Katlama,Alain Lafeuillade,Alan L. Landay,Michael M. Lederman,Sharon R Lewin,Frank Maldarelli,David M. Margolis,Martin Markowitz,Javier Martinez-Picado,James I. Mullins,John W. Mellors,Santiago Moreno,Una O'Doherty,Sarah Palmer,Marie Capucine Penicaud,Matija Peterlin,Guido Poli,Jean-Pierre Routy,Christine Rouzioux,Guido Silvestri,Mario Stevenson,Amalio Telenti,Carine Van Lint,Eric Verdin,Anne Woolfrey,John A. Zaia,Françoise Barré-Sinoussi +35 more
TL;DR: The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure and several priorities for basic, translational and clinical research were identified.
Journal ArticleDOI
Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys
James B. Whitney,Alison L. Hill,Srisowmya Sanisetty,Pablo Penaloza-MacMaster,Jinyan Liu,Mayuri Shetty,Lily Parenteau,Crystal Cabral,Jennifer L. Shields,Stephen Blackmore,Jeffrey Y. Smith,Amanda L. Brinkman,Lauren Peter,Sheeba I. Mathew,Kaitlin M. Smith,Erica N. Borducchi,Daniel I. S. Rosenbloom,Mark G. Lewis,Jillian Hattersley,Bei Li,Joseph Hesselgesser,Romas Geleziunas,Merlin L. Robb,Jerome H. Kim,Nelson L. Michael,Dan H. Barouch +25 more
TL;DR: It is demonstrated that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the ‘eclipse’ phase, and before detectable viraemia, which raises important new challenges for HIV-1 eradication strategies.
Journal ArticleDOI
International AIDS Society global scientific strategy: towards an HIV cure 2016
Steven G. Deeks,Sharon R Lewin,Anna Laura Ross,Jintanat Ananworanich,Monsef Benkirane,Paula M. Cannon,Nicolas Chomont,Daniel C. Douek,Jeffrey D. Lifson,Ying-Ru Lo,Daniel R. Kuritzkes,David M. Margolis,John W. Mellors,Deborah Persaud,Joseph D. Tucker,Françoise Barré-Sinoussi,Galit Alter,Judith D. Auerbach,Brigitte Autran,Dan H. Barouch,Georg M. N. Behrens,Marina Cavazzana,Zhiwei Chen,Éric A. Cohen,Giulio Maria Corbelli,Serge Eholié,Nir Eyal,Sarah Fidler,Laurindo Garcia,Cynthia I. Grossman,Gail E. Henderson,Timothy J. Henrich,Richard Jefferys,Hans-Peter Kiem,Joseph M. McCune,Keymanthri Moodley,Peter A. Newman,Monique Nijhuis,Moses Supercharger Nsubuga,Melanie Ott,Sarah Palmer,Douglas D. Richman,Asier Sáez-Cirión,Matthew G.F. Sharp,Janet M. Siliciano,Guido Silvestri,Jerome Amir Singh,Bruno Spire,Jeff Taylor,Martin Tolstrup,Susana T. Valente,Jan van Lunzen,Rochelle P. Walensky,Ira B. Wilson,Jerome A. Zack +54 more
TL;DR: A group of international experts to develop a scientific strategy for research towards an HIV cure summarized the group's strategy in this Perspective.
Journal ArticleDOI
Immune activation and HIV persistence: implications for curative approaches to HIV infection
TL;DR: A vicious cycle might exist in which HIV persistence causes inflammation that in turn contributes to HIV persistence, suggesting novel interventions aimed at curing the infection or preventing the development of inflammation‐associated end‐organ disease.
References
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HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time
TL;DR: A new mathematical model was used to analyze a detailed set of human immunodeficiency virus-type 1 (HIV-1) viral load data collected from five infected individuals after the administration of a potent inhibitor of HIV-1 protease, providing not only a kinetic picture ofAIDS pathogenesis, but also theoretical principles to guide the development of treatment strategies.
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Latent infection of CD4 + T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy
Diana Finzi,Joel N. Blankson,Janet M. Siliciano,Joseph B. Margolick,Karen Chadwick,Theodore C. Pierson,Kendall A. Smith,Julianna Lisziewicz,Franco Lori,Charles Flexner,Thomas C. Quinn,Richard E. Chaisson,Eric S. Rosenberg,Bruce D. Walker,Stephen J. Gange,Joel E. Gallant,Robert F. Siliciano +16 more
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Journal ArticleDOI
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Alan S. Perelson,Paulina Essunger,Yunzhen Cao,Mika Vesanen,Arlene Hurley,Kalle Saksela,Martin Markowitz,David D. Ho +7 more
TL;DR: It is estimated that 2.3–3.1 years of a completely inhibitory treatment would be required to eliminate HIV-1 from these compartments, and even longer treatment may be needed because of the possible existence of undetected viral compartments or sanctuary sites.
Journal ArticleDOI
Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells.
Janet D. Siliciano,Joleen Kajdas,Diana Finzi,Thomas C. Quinn,Thomas C. Quinn,Karen Chadwick,Joseph B. Margolick,Colin Kovacs,Stephen J. Gange,Robert F. Siliciano +9 more
TL;DR: It is shown that even in treated patients who have had no detectable viremia for as long as 7 years, the reservoir decays so slowly that eradication is unlikely.
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