is hiv eradication a realistic aim?

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


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


Obstacles to HIV eradication in the individual

Latent reservoir

Ongoing viral replication

Anatomical reservoirs

Siliciano JD, et al. Nat Med 2003;9:727-8

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.).


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.

Chun TW, et al. J Infect Dis 2007;195:1762-4

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.


Effect of treatment, during primary infection on establishment and clearance of cellular reservoirs of HIV-1

Strain 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

Strain MC, et al. J Infect Dis 2005;191:1410-8

Palmer S, et al. Proc Natl Acad Sci USA 2008;105:3879-84

Using the SCA, 77% of samples had quantifiable viremia; all patients had at least one sample with quantifiable viremia

Palmer 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


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.

Sharkey ME, et al. Nat Med 2006;6:76-81

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.

Van Praag R, et al. AIDS 2002;16:719-25

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.”


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

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.

N Engl J Med 2009;360:692-8.

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.


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

is hiv eradication a realistic aim?

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