Tags
antiretroviral therapy (ART), Disulfiram, Latency-reversing Agents (LRA), Mississippi baby, Panobinostat, Romidepsin, The Berlin Patient, Timothy Ray Brown, Valproate, Vedolizumab, Virus latency, Vorinostat
Recent Documented Cases Of HIV Cure And Near Misses
- As of 2016, there is one confirmed case of HIV cure, that of Timothy Ray Brown – Wikipedia, one of two The Berlin Patient – Wikipedia. Diagnosed with HIV in 1995 while studying in Berlin, Germany, in 2007 he underwent Hematopoietic stem cell transplantation – Wikipedia from a donor with a rare CCR5 – Wikipedia homozygous delta32 mutation, homozygous meaning in both alleles (1, 2). The CCR5-delta 32 mutation renders a person resistant to HIV infection by disabling its entry into susceptible cells that express CCR5 on their cell surface. Timothy Ray Brown is considered completely cured, sterile cure as in no longer harboring HIV in his body. He is off of antiretroviral therapy (ART), Management of HIV/AIDS – Wikipedia.
- Two Boston patients were also treated using stem cell transplantation though not from CCR5-delta32 homozygous donors. However, they experienced relapse (3).
- The VISCONTI cohort is a group of 14 French patients who started ART within the first few weeks of getting HIV infected (4). In remission now for 12 years and counting, they’re considered ‘functionally’ cured of HIV, i.e., continuing to harbor HIV but no longer needing to take ART. The same group’s also reported similar outcome for a perinatally infected case treated from birth for at least the first 5 years. This patient remained in remission when re-examined at length at 18 years of age (5).
- The Mississippi baby – Wikipedia is a case diagnosed as HIV positive at birth and treated with powerful ART starting from the first hours of life. However, s/he suffered a relapse in 2014 (6), this after ART for the 1st 18 months followed by a full 27 months of remission.
Clearly, HIV’s ability to become latent, Virus latency – Wikipedia, is a challenge both for effective anti-HIV immunity and for accurate assessments of disease status. In such a situation a person may appear aviremic, i.e., no virus detected in circulation, and yet have sufficient virus within latently infected cells to trigger relapse.
Main Obstacle To HIV Cure: Virus latency – Wikipedia
CD4 T cells (T helper cell – Wikipedia) and other Myeloid – Wikipedia, i.e., bone-marrow-derived, cells are the main targets of HIV infection. Problem is replication-competent HIV provirus can persist in resting CD4 T cells and maybe in these other cells as well. In other words, virus latency.
Accurately assess latent virus load, reverse it and help sustain effective anti-HIV immunity to completely eradicate HIV, these are the key steps necessary to mediate ‘cure’ in HIV patients on ART.
To devise a cure in those on ART, an accurate measure of virus load is key. However, it’s technically difficult to do so.
- Methods that measure integrated HIV virus DNA tend to overestimate latency since they can’t discriminate replication-defective HIV DNA (7).
- Similar drawback attends methods that measure HIV RNA (8).
- While the quantitative viral outgrowth assay (QVOA) is far better at measuring frequency of truly latent, replication-competent provirus (9, 10), it tends to underestimate the size of the latent reservoir (8).
Latency-reversing Agents (LRA) such as Disulfiram – Wikipedia, Panobinostat – Wikipedia, Romidepsin – Wikipedia, Valproate – Wikipedia, and Vorinostat – Wikipedia interfere with latency process. However, several technical challenges in accurately assessing their capacity to inhibit and/or reverse latency include
- Data that suggests each one may reverse latency in only a subset of HIV-infected cells.
- How accurately do data from animal models or in vitro studies recapitulate the situation in human patients?
Such doubts suggest combinations of LRAs may be needed to fully reverse latency. Obviously, if latency’s successfully reversed, anti-HIV immunity needs to kick in to completely eliminate the virus.
- However, is that possible for HIV patients on ART?
- Virus may persist as latent provirus in rare cells widely distributed within the body. How often does virus replicate under these conditions and does such replication engender sufficient antigen expression and presentation to trigger an effective immune response?
- Were such reactivation even to occur, wouldn’t anti-HIV immunity have waned in the meantime?
- Couldn’t such immunity also be depleted and/or dysfunctional as a result of HIV infection anyway? For e.g., latent virus sequestered within resting CD4 T cells does contain some CD8 T cell escape mutations (11), an important escape mechanism since CD8 T cells (Cytotoxic T cell – Wikipedia) are among the most effective in killing virus-infected cells.
- Those on ART tend to have low frequencies of HIV-specific CD8 T cells (12). This means there’s a need to support efficient anti-HIV immunity in such patients through the use of therapeutic vaccines. However, none are as yet available. Two major obstacles they face
- To work even in the presence of ART. After all, to stop ART would be too risky.
- Identify epitopes relevant during latency reversal.
A recent surprising study was a monkey study that showed ‘cure’ using Vedolizumab – Wikipedia, a monoclonal antibody (mAb) against a gut-specific cell-surface receptor, a4b7 (13, 14). However, at this stage, this is really preliminary data. Has to be replicated by other groups then tested in humans. Another caveat as well, namely, it used not HIV but rather SIV, Simian immunodeficiency virus – Wikipedia.
Thus, current path to HIV cure is far from straightforward. However, cases such as the Berlin patient and the VISCONTI cohort have at least cure put on the map, something that wasn’t even a consideration until fairly recently.
Bibliography
1. Hütter, Gero, et al. “Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation.” New England Journal of Medicine 360.7 (2009): 692-698. http://www.nejm.org/doi/pdf/10.1…
2. Yukl, Steven A., et al. “Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient.” PLoS Pathog 9.5 (2013): e1003347. http://journals.plos.org/plospat…
3. Henrich, Timothy J., et al. “Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases.” Annals of internal medicine 161.5 (2014): 319-327. https://www.researchgate.net/pro…
4. Sáez-Cirión, Asier, et al. “Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.” PLoS Pathog 9.3 (2013): e1003211. http://journals.plos.org/plospat…
5. Frange, Pierre, et al. “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.” The Lancet HIV 3.1 (2016): e49-e54. http://www.natap.org/2015/HIV/PI…
6. Luzuriaga, Katherine, et al. “Viremic relapse after HIV-1 remission in a perinatally infected child.” New England Journal of Medicine 372.8 (2015): 786-788. http://www.nejm.org/doi/pdf/10.1…
7. Eriksson, Susanne, et al. “Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies.” PLoS Pathog 9.2 (2013): e1003174. http://journals.plos.org/plospat…
8. Ho, Ya-Chi, et al. “Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure.” Cell 155.3 (2013): 540-551. http://www.cell.com/cell/pdf/S00…
9. Siliciano, Janet D., et al. “Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells.” Nature medicine 9.6 (2003): 727-728.
10. Crooks, Amanda M., et al. “Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies.” Journal of Infectious Diseases 212.9 (2015): 1361-1365. Implications for Eradication Strategies
11. Deng, Kai, et al. “Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations.” Nature 517.7534 (2015): 381-385. https://www.researchgate.net/pro…
12. Shan, Liang, et al. “Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation.” Immunity 36.3 (2012): 491-501. http://www.cell.com/immunity/pdf…
13. Byrareddy, Siddappa N., et al. “Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy.” Science 354.6309 (2016): 197-202.
14. Cohen, Jon. “Surprising treatment ‘cures’ monkey HIV infection.” (2016): 157-158.
Further reading
Margolis, David M., et al. “Latency reversal and viral clearance to cure HIV-1.” Science 353.6297 (2016): aaf6517.
https://www.quora.com/What-is-the-current-state-of-the-HIV-cure/answer/Tirumalai-Kamala
