Paul Volberding, MD
Ann Intern Med. Published online 14 January 2014 doi:10.7326/M13-2893
The world desperately needs an HIV cure, but recent news is not promising. Of the millions of persons chronically infected since the epidemic’s emergence, only 1 is alive and free of the virus, and we now know that HIV has reemerged in 2 more persons previously believed to have been cured. Where do we stand now, and where is there room for optimism?
Compared with most infectious agents, HIV seems uniquely designed to persist in its host and be transmitted. The natural immune response does not control HIV as it establishes a chronic infection, which helps explain the frustration in developing a truly effective vaccine. Furthermore, the virus hides within the genomes of certain cells, where it is protected from elimination by otherwise potent antiretroviral drugs (1). These cells form a functional reservoir of HIV in the body that is ready to be reactivated later when, for example, therapy is discontinued (2). Despite these substantial challenges, a vigorous and collaborative worldwide search for an HIV cure is under way.
HIV cure research is propelled by intriguing clinical observations, increasingly powerful antiviral medications, and the fruits of an unprecedented basic scientific investment that has exposed new targets for attacking the viral reservoir. Cure research began with the knowledge that some infected persons maintain normal immune health despite productive infection (3) and that others are naturally able to suppress viral growth to levels undetectable with common laboratory tests (4). The rebound of HIV levels after treatment is also not uniform. Although HIV levels surge shortly after treatment cessation in most cases, this can take a considerable amount of time in others. In 1 recently reported French cohort, the virus remained suppressed in 14 patients many months after treatment was stopped, even though they had not been cured (5). These observations underscore the wide range in an individual’s innate ability to control HIV infection and the hope that durable viral control might be induced in others with antiretrovirals and other drug therapy.
Optimism in discovering an HIV cure soared with the first reported case. Tim Brown was chronically infected with HIV when he developed acute leukemia. He received standard treatment with aggressive chemotherapy and a repeated course of bone marrow transplantation from an unrelated donor. As is common, he had severe adverse effects, notably including graft-versus-host disease. In a rare twist, however, Mr. Brown’s donor was chosen on the basis of carrying an uncommon mutation that confers resistance to HIV infection. After surviving his leukemia treatment, Mr. Brown showed no remaining HIV infection even after discontinuing antiretroviral therapy and despite many efforts to find the virus in his blood and various areas of the body (6). Because this patient’s constellation of diseases, treatments, and complications is unique, it remains unknown whether his outcome can be replicated in others.
One possible cause of Tim Brown’s cured infection was the conditioning chemotherapy regimen coupled with bone marrow transplantation, a background similar to that of the 2 HIV-infected patients who were recently believed to have been cured. These patients developed Hodgkin lymphoma and were treated with bone marrow transplantation. Their conditioning regimens were less aggressive than Mr. Brown’s but appropriate for their diagnoses. Also, their marrow donors did not carry the HIV-resistant mutation. Still, these patients provided an opportunity to explore whether their chemotherapy regimen could reduce or even eliminate the HIV reservoir by replacing those cells with those of their donors. We therefore watched closely when, with full informed consent, their antiretroviral medication was intentionally discontinued after successful transplantation. Early optimism in these 2 cases was unfortunately not sustained. In both patients, HIV was not detected while they received antiretroviral therapy (7) but has reemerged in the peripheral blood—early in 1 patient and later in the second—and both have resumed HIV treatment (8).
Scientific progress is rarely linear. HIV is a formidable opponent, and the biology of the virus–host interaction is complex. From the 2 recent cases, we have learned of the highly variable time for HIV to reemerge, possibly suggesting differential reservoir depletion. These cases might also imply a crucial role for the HIV-resistant mutation in selected donors. Although such donors are rare, a similar end may be achieved with the use of an existing medication that uses the same cell surface receptor to block HIV infection. That approach could be easily explored, but another more difficult question centers on the graft-versus-host disease seen in the only well-documented cured patient. Although that disease could not be ethically induced, immune-based therapies that reproduce aspects of it might be feasible. The 2 recent cases are disappointing, but they may open new and productive research directions.
Bone marrow transplantation will never become relevant for the millions of HIV-infected patients worldwide, but insights gained, combined with parallel approaches, may move us toward a simple, inexpensive, and much-needed cure while we await a vaccine. In a remarkable and global effort, researchers aimed at discovering a cure are collaborating and sharing new data in an unprecedented manner. Some are seeking to better identify and measure the cells harboring the HIV reservoir. Others are testing drugs designed to selectively activate the latent HIV genome in the reservoir, thus making it susceptible to antiretroviral attack. Still others are learning how the immune system might be better directed to control HIV replication by repairing the fundamental weakness in our natural defense mechanism.
Our HIV drugs are good, but they will never be enough to end the global epidemic. As inexpensive, potent, and convenient as current antiretroviral drugs have become, their costs and the cost of new medical care infrastructure will remain formidable barriers. Lifelong medication adherence will be impossible for some patients, and others will have access to care limited by the stubborn stigma of HIV as a sexually transmitted infection. The epidemic will be stopped when a truly effective preventive vaccine is developed, but in the meantime, an inexpensive, nontoxic curative medication or regimen may be possible, offering hope to millions. HIV drug discovery led directly to the antiviral cure of another chronic infection, hepatitis C virus (9). Armed with the optimism of that breakthrough, we must also continue our search for an HIV cure. Given the longer perspective and our accelerating research investment and momentum, the 2 cases of HIV reemergence after marrow transplantation can truly be seen as steps forward rather than the start of a retreat.
1 Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278:1295-300. [PMID: 9360927]
2 Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000;407:523-6. [PMID: 11029005]
3 Lifson AR, Buchbinder SP, Sheppard HW, Mawle AC, Wilber JC, Stanley M, et al. Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics. J Infect Dis. 1991;163:959-65. [PMID: 1673465]
4 Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008;197:126-33. [PMID: 18171295]
5 Hocqueloux L, Prazuck T, Avettand-Fenoel V, Lafeuillade A, Cardon B, Viard JP, et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS. 2010;24:1598-601. [PMID: 20549847]
6 Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360:692-8. [PMID: 19213682]
7 Henrich TJ, Hu Z, Li JZ, Sciaranghella G, Busch MP, Keating SM, et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis. 2013;207:1694-702. [PMID: 23460751]
8 Henrich TJ. Challenges and strategies towards functional cure: how low do you need to go? Presented at the Sixth International Workshop on HIV Persistence during Therapy, Miami, Florida, 3–6 December 2013.