Is HIV eradication a realistic aim? Joep M.A. Lange Center for Poverty-related Communicable Diseases Academic Medical Center / University of Amsterdam & Amsterdam Institute for Global Health and Development
HIV eradication? • At the level of the individual • At the level of the population
Where does HIV “live”?: cellular level (1) • CD4+ T cells • Predominantly memory CD4+ T cells • Latent reservoir • Dendritic cells • Acute infection? • Macrophages • Role as long-term reservoir unclear Stebbing J, et al. N Engl J Med 2004;350:1872-80
Where does HIV “live”?: cellular level (2) • CD8+ T cells • Expression of CD4 by activiated CD8+ T cells • Effect on viral reservoir? • Natural killer T cells • Highly susceptible to CCR5-tropic strains; depletion during HIV infection • Natural killer cells • Viral DNA persists in NK cells after 1 or 2 years of effective HAART • May act as a viral reservoir Stebbing J, et al. N Engl J Med 2004;350:1872-80
Where does HIV “live”?: organ level • Lymphoid organs • In acute infection mucosa dominant site of infection • Lymph node FDCs may become a major reservoir of infectious HIV in later stages of infection (pre-HAART) • Central nervous system • Strong evidence for “compartment” • May act as a reservoir, even during HAART • Genitourinary tract • See CNS Stebbing J, et al. N Engl J Med 2004;350:1872-80
Obstacles to HIV eradication in the individual • Latent reservoir • Ongoing viral replication • Anatomical reservoirs
Figure 1 Extremely slow decay of the latent reservoir in patients on HAART. (a) Frequency of latently infected cells in 62 HIV-1 infected adults who maintained suppression of viremia on combination therapy without failure.Results are expressed in terms of IUPM resting CD4+ T cells. Colored lines, repeat measurements in individual patients; closed symbols, successful detection of resting CD4+ T cells harboring replication-competent HIV-1 at the indicated frequencies; open symbols, unsuccessful virus isolation (in this instance, the upper bound on the infected-cell frequency, estimated based on the number of input cells, is plotted.). Siliciano JD, et al. Nat Med 2003;9:727-8
Figure 1 Extremely slow decay of the latent reservoir in patients on HAART. (b) Decay of the latent reservoir in the subset of 18 patients who maintained suppression of viremia on HAART for 3-7 years without blips (colored lines and symbols). a and b: Heavy black line, mean decay rate; ligth black lines, 95% confidence interval around the mean decay rate. Siliciano JD, et al. Nat Med 2003;9:727-8
Half-life of the latent reservoir estimated to be 4.6 months (range 1.9-8.7 months). Projected time for complete elimination of HIV in this compartment 7.7 years.Chun TW, et al. J Infect Dis 2007;195:1762-4
Effect of treatment, during primary infection on establishment and clearance of cellular reservoirs of HIV-1Strain MC, et al. J Infect Dis 2005;191:1410-8 • Total cell-associated infectivity (CAI) after 1 year of treatment undetectable in: • 9/9 patients initiating treatment during primary infection • 6/8 initiating treatment < 6 months after seroconversion • In contrast, all 17 control patients who initiated HAART during chronic infection retained detectable CAI after 3-6 years of treatment
Using the SCA, 77% of samples had quantifiable viremia; all patients had at least one sample with quantifiable viremiaPalmer S, et al. Proc Natl Acad Sci USA 2008;105:3879-84
What does residual viral expression in patients who receive ART reflect? • Incomplete suppression of ongoing viral replication? • Intermittent production from stable reservoirs of chronically infected cells? • Viral expression from self-limited reactivation of latently infected cells? Yukl & Wong. J Infect Dis 2008;197:640-2.
Persistence of HIV in Gut-Associated Lymphoid Tissue despite Long-Term Antiretroviral Therapy Tae-Wook Chun,1.a David C. Nickle,6.a Jesse S. Justement,1 Jennifer H. Meyers,1 Gregg Roby,1 Claire W. Hallahan,2 Shyam Kottlilil,1 Susan Moir, JoAnn M. Mican,4 James I. Mullins,6 Douglas J. Ward,7 Joseph A. Kovacs,5 Peter J. Mannon,3 and Anthony S. Fauci1 1Laboratory of Immunoregulation, 2Biostatistical Research Branch, 3Laboratory of Host Defense, 4Division of Clinical Research, National Institute of Allergy and Infectious Diseases, 5Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; 6Department of Microbiology, University of Washington, Seattle; 7Dupont Circle Physicians Group, Washington, DC Chun TW, et al. J Infect Dis 2008;197:714-20
Evidence for HIV cross infection among all three cellular compartments • “Suggesting that CD4+ T cells in the blood are subjected to continuous infection while trafficking through the GALT • And that CD4+ T cells in the GALT may themselves be subjected to infection from infected CD4+ T cells trafficking through the gut.” Chun TW, et al. J Infect Dis 2008;197:714-20.
Additional “support” for ongoing viral replication • Further plasma viral load reduction in patients on stable therapy with < 50 HIV-1 RNA copies/mL, following treatment intensification. • Indirect evidence comes from the many patients who continue to have heightened levels of immune activation despite having received suppressive ART for years. Yukl & Wong. J Infect Dis 2008;197:640-2.
HIV eradication: what does it take? “We must …continue to develop therapeutic agents that will suppress viral replication while they deplete the reservoir of archived viruses in HIV-infected cells in all the organs where these cells may reside.” Stebbing J, et al. N Engl J Med 2004;350:1872-80
Approaches to HIV eradication • Treatment intensification / novel antiretrovirals • “Purging the reservoirs” • Both • Gene therapy
Immuno-activation with anti-CD3 and recombinanthuman IL-2 in HIV-1-infected patients on potentantiretroviral therapy Jan M. Prinsa*, Suzanne Jurriaansc*, Rieneke M.E. van Praaga, Hetty Blaake, Ronald van Rije, Peter Th.A. Schellekensb, Ineke J.M. ten Bergeb, Si-La Yongb, Cecil H. Foxf, Marijke T.L. Roose, Frank de Wolf c, Jaap Goudsmitc, Hanneke Schuitemakere and Joep M.A. Langead From the aDepartment of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, and bDivision of Clinical Immunology and Rheumatology, cDepartment of Human Retrovirology, dNational AIDS Therapy Evaluation Centre (NATEC), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; eDepartment of Clinical Viro-Immunology, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam , the Netherlands; and fMolecular Histology Labs Inc., Gaithersburg, MD, USA. *The first two authors contributed equally to this study. Prins JM, et al. AIDS 1999;13:2405-10
OKT3 and IL-2 Treatment for Purging of the Latent HIV-1Reservoir in Vivo Results in Selective Long-Lasting CD4+T Cell Depletion R.M.E. van Praag1, J.M. Prins1, M.T.L. Roos2, P.Th. Schellekens3, I.J.M. ten Berge3, S-L. Yong3, H. Schuitemaker2, A.J.M. Eerenberg2, S. Jurriaans4, F. de Wolf4, C.H. Fox5, J. Goudsmit4, F. Miedema2, J.M.A. Lange1 1National Aids Therapy Evaluation Center (NATEC), Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, The Netherlands. 2Department of Clinical Viro-Immunology, CLB, and Laboratory for Experimental and Clinical Immunology, Academic Medical Center, Amsterdam, The Netherlands. 3Division of Clinical Immunology and Reumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.4Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 5Molecular Histology Lab Inc., Gaithersburg, Maryland. Van Praag R, et al. J Clin Immunol 2001;21:218-26
IL-7 is a potent and proviral strain–specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART Feng-Xiang Wang,1 Yan Xu,1 Julie Sullivan,1 Emily Souder,1 Elias G. Argyris,1 Edward A. Acheampong,1 Jaime Fisher,1 Maria Sierra,2 Michael M. Thomson,2 Rafael Najera,2 Ian Frank,3 Joseph Kulkosky,1 Roger J. Pomerantz,1 and Giuseppe Nunnari1 1Center for Human Virology and Biodefense, Division of Infectious Diseases and Environmental Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. 2Area de Patogenia Viral, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain. 3University of Pennsylvania, Division of Infectious Diseases, Philadelphia, Pennsylvania, USA. Wang FX, et al. J Clin Invest 2005;115:128-37
Depletion of latent HIV-1 infection in vivo: a proof-of-concept study Ginger Lehrman, Ian B Hogue, Sarah Palmer, Cheryl Jennings, Celsa A Spina, Ann Wiegand, Alan L Landay, Robert W Coombs, Douglas D Richman, John W Mellors, John M Coffin, Ronald J Bosch, David M Margolis Intensifying HAART with an HDAC inhibitor (valproic acid) and enfuvirtide for 3 months led to a decline in the frequency of resting cell infection (in 4 volunteers). Lehrman G, et al. Lancet 2005;366:549-55
Approaches to HIV eradication • Treatment intensification / novel drugs • “Purging the reservoirs” • Both • Gene therapy • How to reach all pockets where HIV is hiding?
Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation Gero Hütter, M.D., Daniel Nowak, M.D., Maximilian Mossner, B.S., Susanne Ganepola, M.D., Arne Müßig, M.D., Kristina Allers, Ph.D., Thomas Schneider, M.D., Ph.D., Jörg Hofmann, Ph.D., Claudia Kücherer, M.D., Olga Blau, M.D., Igor W. Blau, M.D., Wolf K. Hofmann, M.D., and Eckhard Thiel, M.D. Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell TransplantationGero Hütter, M.D., Daniel Nowak, M.D., Maximilian Mossner, B.S., Susanne Ganepola, M.D., Arne Müßig, M.D., Kristina Allers, Ph.D., Thomas Schneider, M.D., Ph.D., Jörg Hofmann, Ph.D., Claudia Kücherer, M.D., Olga Blau, M.D., Igor W. Blau, M.D., Wolf K. Hofmann, M.D., and Eckhard Thiel, M.D. N Engl J Med 2009;360:692-8. SUMMARY Infection with the human immunodeficiency virus type 1 (HIV-1)requires the presence of a CD4 receptor and a chemokine receptor,principally chemokine receptor 5 (CCR5). Homozygosity for a32-bp deletion in the CCR5 allele provides resistance againstHIV-1 acquisition. We transplanted stem cells from a donor whowas homozygous for CCR5 delta32 in a patient with acute myeloidleukemia and HIV-1 infection. The patient remained without viralrebound 20 months after transplantation and discontinuationof antiretroviral therapy. This outcome demonstrates the criticalrole CCR5 plays in maintaining HIV-1 infection.
Is HIV eradication at the individual level a worthy goal? Although the eradication of HIV is a daunting task, the goal of long-term containment of viral replication and prevention of immune dysfunction is eminently achievable. Stebbing J, et al. N Engl J Med 2004;350:1872-80
Is HIV eradication at the individual level a worthy goal? The question is whether, with advances in HIV therapy, striving for HIV eradication in more than a few specific cases, is worth the drastic interventions likely to be required to acccomplish this.
HIV eradication? • At the level of the individual • At the level of the population