Who would have thought?

Lederman, Michael M.a; Barre-Sinoussi, Francoiseb

Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e32835f94ed
STATE OF HIV CURE: Edited by Francoise Barre-Sinoussi and Michael M. Lederman
Author Information

aCase Western Reserve University School of Medicine and University Hospitals/Case Medical Center, Cleveland, Ohio, USA

bINSERM and Institut Pasteur, Paris, France and President of the International AIDS Society (IAS), Switzerland

Correspondence to Michael M. Lederman, Case Western Reserve University, 2061 Cornell Road, Cleveland, OH 44106, USA. Tel: +1 216 844 8786; e-mail: MXL6@case.edu

Article Outline

Until very recently, when AIDS clinicians and researchers were asked whether HIV-infected persons could ever be cured of infection, most of them were pessimistic, noting that reservoirs of infection could be found as latently infected viral genomes in quiescent cells [1], that years of suppressive antiretroviral therapies had minimal effect on the decay of this reservoir [2,3], that treatment interruptions characteristically allowed high level virus replication to resume [4,5] and that efforts to coax virus from latency by raiding their T-cell homes in lymphoid tissues were not only ineffective but reportedly life threatening [6]. Other likely sources of persistent infection in protected sites such as the central nervous system [7] or in mucosal tissues [8] only added to this pessimism.

But the tenor of these conversations changed with a single patient report that generated modest notice when presented as a poster at an international conference but hit the newsstands around the time of its publication in the New England Journal of Medicine. An HIV-infected man with refractory acute myelogenous leukemia was treated with aggressive chemotherapy, radiotherapy, immunotherapy and transplantation of hematopoietic stem cells from a donor who was homozygous for a 32 base pair deletion in the open reading frame for CCR5 a critical coreceptor for HIV cellular entry. The leukemia responded to treatment and amazingly, although antiviral therapies were not restarted, HIV could not be detected in the patient's blood or tissues years after the transplant [9,10]. What remains to be shown now is which of these interventions was responsible for the striking cure of this patient. It should be noted that there had been two earlier instances of apparent HIV eradication in persons undergoing bone marrow transplantation although in neither instance did the patient survive the procedure [11,12]. These less favorable outcomes underscore the risks attendant to ablative therapies and hematopoietic transplantation and remind us that reproducing this outcome will require careful attention to safety and to patient selection. Although this precise strategy is not broadly applicable to the HIV-infected population, there are undoubtedly lessons to be learned from trying to reproduce the success of this experiment that may help in the development of strategies to eradicate HIV. In this regard, a recent meeting detailed the cases of two patients who underwent allogeneic bone marrow transplantation for lymphomas followed by antiretroviral therapy and in whom viral DNA could not be detected in their peripheral blood cells for 2–3.5 years after treatment [13].

And while these early efforts will surely help inform the search for the cure, an ultimate goal of providing scalable and well tolerated approaches to eradicate infection from the millions of infected persons will undoubtedly be challenging. We will need to learn more about viral sanctuaries and sites of persistence where antiviral agents and immune mechanisms may be less effective. We need to identify well tolerated agents that can reactivate HIV from latency in a treated environment such that progeny viruses cannot find a new home. In addition, it may be necessary to induce a sufficiently active host immune response (whether adaptive or innate) such that induced viral expression marks the infected cell for destruction by endogenous defenses [14]. Stepping back we may be able to find markers that identify latently infected cells or other cells that serve as reservoirs for persistent infection. If so perhaps these markers could be used to target these cells for destruction with tolerable toxicities to uninfected cells?

Other strategies that are under investigation include efforts to repopulate the infected host with CD4+ cells rendered resistant to HIV. Making room for these manipulated cells might be achieved by low doses of cytotoxic chemotherapy, by introduction of selection constructs together with the resistance elements [15] or by allowing HIV replication to serve as the selection for resistant cells. In the latter instance, we need to learn how to balance the risks of sustained or intermittent HIV replication [16] with the need to select for the expansion of virus-resistant cells.

Finally, in the event that curative strategies can be applied safely, will this help to resolve the persistent inflammatory state that exists in many HIV-infected patients who are treated with combination antiretroviral therapies? And will cure of HIV infection permit complete restoration of immune competence in those otherwise effectively treated patients who have failed to restore immune function to normal levels? At this point, these questions are unanswered but strategies targeting inflammation and incomplete immune restoration are in development. Irrespective, the marshaling of the scientific skills and resources needed to define the road or roads to the cure of HIV infection will undoubtedly also pay dividends in understanding pathogenesis.

Back to Top | Article Outline


Several of the authors were asked to contribute as part of the IAS “Toward an HIV Cure” Initiative.

Françoise Barré-Sinoussi wishes to thank Asier-Saez Cirion, Daniel Scott-Algara and Olivier Rescaniere for their helpful contributions.

Back to Top | Article Outline
Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline


1. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278:1295–1300.
2. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999; 5:512–517.
3. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003; 9:727–728.
4. Hatano H, Vogel S, Yoder C, et al. Pre-HAART HIV burden approximates post-HAART viral levels following interruption of therapy in patients with sustained viral suppression. AIDS 2000; 14:1357–1363.
5. Oxenius A, Price DA, Gunthard HF, et al. Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Proc Natl Acad Sci U S A 2002; 99:13747–13752.
6. Prins JM, Jurriaans S, van Praag RM, et al. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS 1999; 13:2405–2410.
7. Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol 2005; 5:69–81.
8. Yukl SA, Gianella S, Sinclair E, et al. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis 2010; 202:1553–1561.
9. Allers K, Hutter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood 2011; 117:2791–2799.
10. Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009; 360:692–698.
11. Contu L, La Nasa G, Arras M, et al. Allogeneic bone marrow transplantation combined with multiple anti-HIV-1 treatment in a case of AIDS. Bone Marrow Transplant 1993; 12:669–671.
12. Holland HK, Saral R, Rossi JJ, et al. Allogeneic bone marrow transplantation, zidovudine, and human immunodeficiency virus type 1 (HIV-1) infection. Studies in a patient with non-Hodgkin lymphoma. Ann Intern Med 1989; 111:973–981.
13. Henrich TJ, Sciaranghella G, Li JZ, et al. Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning. In: 19th International AIDS Conference; 2012: Abstract no. THAA0101
14. Shan L, Deng K, Shroff NS, et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 2012; 36:491–501.
15. Vollweiler JL, Zielske SP, Reese JS, Gerson SL. Hematopoietic stem cell gene therapy: progress toward therapeutic targets. Bone Marrow Transplant 2003; 32:1–7.
16. El-Sadr WM, Lundgren J, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283–2296.
© 2013 Lippincott Williams & Wilkins, Inc.