What Issues Are We Still Facing with Curing HIV?
Having infected more than 70 million individuals since the beginning of its epidemic,1 HIV has affected human lives and society in a number of ways. Although the availability of combination antiretroviral therapy (ART) has helped control HIV disease progression and made it possible for individuals with the disease to live longer lives, it is not curative. Individuals infected with HIV still face the challenge of lifelong adherence to ART.
The cost associated with the provision of ART and medical care is considerable,2 and the stigma of being infected with HIV remains a major source of psychological stress for those infected. As such, finding a cure for HIV is a goal that has been shared by all individuals living with HIV and their families, researchers, and clinicians.
The story of Timothy Brown, also known as the “Berlin patient,” cannot be omitted when discussing a cure for HIV.3 To date, Timothy remains the only HIV-infected individual with no detectable virus in his blood or tissue after being off of ART for years. He has had HIV for more than 10 years and received a hematopoietic stem cell transplant (HSCT) for acute myeloid leukemia from a donor who was homozygous for the chemokine receptor type 5 (CCR5) delta32 deletion. The inactive CCR5 gene product resulting from this mutation confers resistance against HIV by halting the viral entry into host cells. This means that Mr. Brown acquired the HIV-resistant cells that the donor naturally had. His transplant can be considered a form of gene therapy with HIV-resistant cells.
There have been other HIV-infected individuals who were at one point thought to have been “cured” of their HIV, although the virus became detectable again in all of these cases. One such case was observed at the University of Mississippi Medical Center in Jackson, Mississippi, and now is known as the “Mississippi baby,” as reported in 2013.4 This patient, who was born to a woman with untreated HIV, was placed on triple-drug ART within 30 hours after birth. When the child was 18 months of age, ART was discontinued by the caregiver; HIV was undetectable on subsequent measurements. Furthermore, ultrasensitive assay for detecting the virus showed no or extremely low virus in her system. Unfortunately, HIV viremia rebounded 28 months after ART cessation.5
Two other cases of “apparent cure” were also reported in 2013, and now are known as “Boston patients.” These patients underwent HSCT for lymphoma.6 A few years after the HSCT, ART was stopped because there was no evidence of ongoing HIV infection. Unfortunately, the patients experienced viral rebound after 3 and 8 months off of ART.7 While these individuals were treated with transplant, their donors did not happen to possess the protective mutation, unlike in the case of Timothy Brown. The phenomenon of long-term undetectable viremia in the absence of ART for a duration longer than expected (typically within 2 months), as observed in these cases, has been termed “viral remission.”
A plausible explanation for the apparent cure and subsequent rebound of HIV viremia is that the virus was “hiding” somewhere in the body. Indeed, HIV’s ability to cause latent infection is a major barrier to cure. After HIV infects the host cell, its genome can be integrated into that cell, where it is then called a “provirus” or “proviral DNA” and can remain replication-competent but transcriptionally-silent, mainly in long-lived memory CD4+ T cells.8 These latently infected cells can serve as the “reservoir” for HIV. In this context, the Mississippi baby can be viewed as a case in which very early initiation of ART likely prevented widespread establishment of a viral reservoir in the host.5 Similarly, it would be plausible to consider that bone marrow-ablative conditioning chemotherapy required for HSCT would reduce the size of the HIV reservoir in the body enough to delay viral rebound7 and that in certain situations where donor cells possess property that confers resistance to HIV, cure may be possible.3
The concept that early initiation of ART and the resulting smaller viral reservoir can be beneficial, as seen in the case of the Mississippi baby, is further supported by the observation of posttreatment controllers in the VISCONTI (Viro-Immunological Sustained CONtrol after Treatment Interruption) study.9 These individuals were generally started on ART during the acute phase of infection and sustained undetectable or very low viral load in the blood after cessation of ART, despite the evidence of remaining HIV infection in the host cells. Also in this group, a perinatally infected patient who was started on ART at 3 months of age has had very low level viremia (less than 50 copies per ml) without evidence of disease progression for 12 years after cessation of ART.10 However, posttreatment controllers have not been reliably reproducible. The window of opportunity to initiate ART during the acute phase of infection is not open to everyone as most HIV-infected patients seek clinical care after HIV has established infection, when it is too late to attempt to restrict viral reservoir size.
Perhaps the most studied approach, to date, for addressing HIV latency and reservoir is the so-called “shock-and-kill” strategy. With this, researchers attempt to reverse the latency by using “latencyreversing agents,” such as histone deacetylase inhibitors (HDIs),11,12 disulfiram,13 protein kinase C agonists,14 and Toll-like receptor 7 agonist among others,15 and have immunotherapy or an activated host’s immunity eliminate the latent HIV-infected cells. So far, there has been no published data available for the success of this approach in humans, although there are animal studies that seem promising for future application to humans.16,17 However, The Sunday Times reported in October 2016 that a British individual who was enrolled in the RIVER (Research in Viral Eradication of HIV Reservoirs) study, which utilizes the shock-and-kill approach, may have been cured of HIV.18
According to clinicaltrials.gov, as of November 2016, the RIVER study was sponsored by the Imperial College London and conducted in collaboration with other institutions, such as the University of Oxford and the University of Cambridge. Participants were randomly assigned to either a standard therapy group for combination ART or an experimental group, in which administration of two anti-HIV vaccines separated by 8 weeks was followed by vorinostat (a type of latencyreversal agent in the HDI class). Full details on the study may not be available in print any time soon as it is still in its early phase; however, the initial report seems to be compelling, and it is hoped that more information will be discussed at upcoming scientific conferences.
This advance in research has undoubtedly led us closer to a cure for HIV, and if the UK study above has produced a first case of intentionally induced cure, that would be a tremendous step toward achieving a reproducible cure strategy. Today, it is estimated that there are more than 35 million individuals living with HIV in the world, and the yearly mortality is estimated to be more than 1 million.1 Although the first case of intentional cure in HIV has long been awaited, the ultimate goal at present is to provide all HIV-infected individuals with safe, effective, and affordable HIV curative therapy so that the virus can be eliminated from the planet. To accomplish this, continuous research from various scientific approaches, including molecular virology, immunology, and cell and gene therapy, is crucial.
Kengo Inagaki, MD, FAAP, is an assistant professor in the Division of Pediatric Infectious Disease and the director of the Pediatric HIV program at the University of Mississippi Medical Center, Batson Children’s Hospital. He received his medical degree from Tokyo Medical and Dental University in Tokyo, Japan, and completed a pediatric infectious disease fellowship and physician scientist training program at St. Jude Children’s Research Hospital in Memphis, TN.
REFERENCES:
1. World Health Organization. Global Health Observatory (GHO) data. WHO website. www.who.int/gho/hiv/en/. Accessed November 28, 2016.
2. The Joint United Nations Programme on HIV/AIDS (UNAIDS). The gap report. UNAIDS website. http://files.unaids.org/en/media/ unaids/contentassets/documents/unaidspublication/2014/ UNAIDS_Gap_report_en.pdf. Updated September 2014. Accessed November 28, 2016.
3. Hütter 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(7):692-698. doi:10.1056/NEJMoa0802905.
4. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV- 1 viremia after treatment cessation in an infant. N Engl J Med. 2013;369(19):1828-1835. doi:10.1056/NEJMoa1302976.
5. Luzuriaga K, Gay H, Ziemniak C, et al. Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med. 2015;372(8):786- 788. doi:10.1056/NEJMc1413931.
6. Henrich TJ, Hu Z, Li JZ, 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(11):1694- 1702. doi:10.1093/infdis/jit086.
7. Henrich TJ, Hanhauser E, Marty FM, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014;161(5):319-327. doi:10.7326/ M14-1027.
8. Buzon MJ, Sun H, Li C, et al. HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat Med. 2014;20(2):139-142. doi:10.1038/nm.3445.
9. Sáez-Cirión A, Bacchus C, Hocquelox L, et al; ANRS VISCONTI Study Group. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9(3):e1003211. doi:10.1371/journal.ppat.1003211.
10. Frange P, Faye A, Avettand-Fenoël V, et al; ANRS EPF-CO10 Pediatric Cohort; ANRS EP47 VISCONTI Study Group. HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report. Lancet HIV. 2016;3(1):e49-54. doi:10.1016/s2352-3018(15)00232-5.
11. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482-485. doi:10.1038/nature11286.
12. Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10(10):e1004473. doi:10.1371/journal.ppat.1004473.
13. Elliott JH, McMahon JH, Chang CC, et al. Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 doseescalation study. Lancet HIV. 2015;2(12):e520-529. doi:10.1016/s2352- 3018(15)00226-x.
14. Darcis G, Kula A, Bouchat S, et al. An in-depth comparison of latency-reversing agent combinations in various in vitro and ex vivo HIV-1 latency models identified bryostatin-1+JQ1 and ingenol- B+JQ1 to potently reactivate viral gene expression. PLoS Pathog. 2015;11(7):e1005063. doi:10.1371/journal.ppat.1005063.
15. Novis CL, Archin NM, Buzon MJ, et al. Reactivation of latent HIV-1 in central memory CD4+ T cells through TLR-1/2 stimulation. Retrovirology. 2013;10:119. doi:10.1186/1742-4690-10-119.
16. Halper-Stromberg A, Lu CL, Klein F, et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell. 2014;158(5):989-999. doi:10.1016/j. cell.2014.07.043.
17. Borducchi EN, Cabral C, Stephenson KE, et al. Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys. Nature. 2016. doi:10.1038/nature20583. [Epub ahead of print]
18. Leake J. British scientists hopeful for HIV cure. The Times website. www.thetimes.co.uk/article/british-scientists-on-brink-of-hiv-curew7zb86zw0. Published October 2, 2016. Accessed November 28, 2016.
