Contents

Beyond the Berlin, London and Düsseldorf patients

The results from patients in London and Düsseldorf reported in this issue of TreatmentUpdate, together with the well-known case of the Berlin patient, are very exciting. It is possible that in the course of the next several years, if no trace of HIV can be found in their blood and tissue samples, both patients could be declared cured. If that happens, then a total of three patients with HIV will be cured.

What about other HIV-positive people?

There have been other attempts to cure people with HIV using stem cell transplants with the rare delta-32 mutation. Immune systems that arise from these stem cells lack a co-receptor needed by HIV called CCR5 (R5) and are resistant to most strains of HIV. In the past, many of these attempts have failed, usually because people died from complications arising from cancer (HIV-positive people with cancer were enrolled in these attempts, as stem cell transplants can be dangerous). However, other experiments with delta-32 stem cell transplantation have been conducted and it is plausible that over the next five to 10 years a handful of people could be declared cured by scientists should no trace of HIV be found in their tissues and blood.

Stem cell transplants

Transplants of stem cells are dangerous as the recipient’s immune system must first be significantly weakened prior to and after transplantation. Such transplants are expensive, require extensive medical care and monitoring, and donors with the delta-32 mutation are rare. In research settings where HIV cure experiments are underway, stem cell transplants with the delta-32 mutation are generally reserved only for some cases where HIV-positive people have life-threatening cancers that do not respond to several courses of chemotherapy and/or radiation. So, what can scientists learn from the experiments with the patients from Berlin, London and now Düsseldorf that can be safely applied to more people with HIV in the future? Here are some areas that could see changes:

Conditioning regimens

Conditioning regimens are used prior to receiving a stem cell transplant so that a person’s immune system is greatly weakened. This is necessary so that the person’s immune system does not attack the stem cells. Conditioning regimens can also help destroy residual HIV-infected cells and cancerous cells.

The combination of life-threatening cancer, chemotherapy, conditioning regimen, stem cell transplants and immune suppressive therapies that the Berlin patient received was intense and left him weakened for several years afterwards. However, it is encouraging that the London patient was given what some researchers called a “milder conditioning regimen” than the Berlin patient. This could mean that in the future, more people may be able to survive and eventually thrive after the combination of a stem cell transplant, conditioning regimen and other immune suppressive therapy.

Some researchers have suggested that instead of the traditional chemotherapy used in conditioning regimens, more targeted and safer therapies might be considered. For instance, some scientists are proposing that highly specialized antibodies be used for conditioning regimens. These antibodies have been developed in the lab and used in experiments with mice and monkeys. The antibodies target and disable key cells of the immune system, and they target a protein on cells of the immune system called CD117. Preliminary clinical trials with these antibodies are underway in HIV-negative people with cancer. It is possible that if targeting CD117 in HIV-negative people is a safe and effective form of conditioning therapy, it will be tested in some HIV-positive people who are going to get stem cell transplants. However, there are still issues that need to be worked out with these antibodies in people, such as:

  • What is the full range of effects of inhibiting CD117 on cells of the bone marrow and immune system?
  • In addition to cells of the bone marrow, CD117 is found on a group of cells called mast cells, which are widely distributed in the body. Impairing their activity via the antibody that attacks CD117 may affect the tissues that such mast cells are in.
  • Also, CD117 is found on a wide range of tissues, such as some cells of the central nervous system and others in the intestine, kidneys and so on. Researchers are uncertain about the effects of the CD117 antibody on these cells and tissues.

Thus, detailed results from both pilot and large studies with this antibody in HIV-negative people are awaited.

Graft vs. Host Disease (GvHD)

After a transplant of cells, tissues or an organ, it is common for some degree of GvHD to occur. In such cases, the new immune system attacks parts of the body. If left unmanaged, GvHD can have life-threatening consequences. Transplant drugs that suppress the immune system can be used to help control GvHD.

Note that some researchers think that a degree of GvHD may be useful in cases of HIV-positive people who have received a stem cell transplant. GvHD may have played a role in helping the immune system rid the body of HIV-infected cells in the cases of the Berlin, London and Düsseldorf patients. Additional research and further experiments with stem cell transplants and GvHD in HIV-positive people are needed to clarify the role of GvHD in HIV cure studies.

The delta-32 mutation and other approaches

As mentioned earlier, the delta-32 mutation results in cells that lack the co-receptor CCR5 (R5). Cells without this co-receptor are resistant to most strains of HIV.

In other cases (apart from the Berlin, London and Düsseldorf patients) of cancer where HIV-positive people have received a stem cell transplant that was from a donor who did not have the rare delta-32 mutation, sometimes a temporary remission from HIV occurred. This outcome strongly suggests that the delta-32 mutation is a critical aspect of successful long-term remission and, hopefully, an HIV cure.

However, the mutation is rare and using stem cell transplants as a routine procedure with currently used techniques is not likely. What is more likely is that different approaches to an HIV cure will be tested over the coming decade. Some of these approaches will seek to do the following:

  • use gene therapies to make a person’s immune system resistant to most strains of HIV by causing them to stop expressing the CCR5 co-receptor
  • enhance the ability of the immune system to recognize and kill HIV-infected cells with techniques such as CAR-T cell therapy (chimeric antigen receptor) and toll-like receptor agonists
  • help the immune system with highly effective antibodies that target HIV or certain receptors on cells of the immune system, such as the alpha4beta7 receptors

What to expect from HIV cure research?

In the short-term, results from HIV cure experiments currently in progress will be available over the next five years. Some of these experiments involve stem cell transplants from donors who have the delta-32 mutation. Other experiments seek to try and effect the same result as the delta-32 mutation via gene therapy or a combination of approaches that were previously mentioned.

Hopefully all of these experiments will prove to be safe and show at least a degree of efficacy. Researchers will learn from these experiments, refine their approaches to a cure and then move ahead with clinical trials. Thus, some progress should be made over the coming decade.

In the meantime, it is important for HIV-positive people to stay healthy so that they are in the best possible condition should they choose to enroll in some of these clinical trials. Unless people volunteer for HIV cure clinical trials, the field will not be able to move forward.

Resources

The Canadian HIV Cure Enterprise (CanCURE)

—Sean R. Hosein

REFERENCES:

  1. Peterson CW, Kiem HP. Lessons from London and Berlin: Designing a scalable gene therapy approach for HIV cure. Cell Stem Cell. 2019 May 2;24(5):685-687.
  2. Colonna L, Peterson CW, Schell JB, et al. Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation. Nature Communications. 2018 Oct 25;9(1):4438.
  3. Kuhlmann AS, Peterson CW, Kiem HP. Chimeric antigen receptor T-cell approaches to HIV cure. Current Opinion in HIV/AIDS. 2018 Sep;13(5):446-453.
  4. Saez-Cirion A, Müller-Trutwin M. The yellow brick road towards HIV eradication. Trends in Immunology. 2019; in press.
  5. Calenda G, Frank I, Arrode-Brusés G, et al. Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques. PLoS Pathogens. 2019 May 13;15(5):e1007776.
  6. Pardons M, Baxter AE, Massanella M, et al. Single-cell characterization and quantification of translation-competent viral reservoirs in treated and untreated HIV infection. PLoS Pathogens. 2019 Feb 27;15(2):e1007619.
  7. Chan P, Ananworanich J. Perspective on potential impact of HIV CNS latency on eradication. AIDS. 2019; in press.
  8. Pang WW, Czechowicz A, Logan AC, et al. Anti-CD117 antibody depletes normal and myelodysplastic syndrome human hematopoietic stem cells in xenografted mice. Blood. 2019 May 9;133(19):2069-2078.
  9. Manz MG, Russkamp NF. Selective CD117± HSC exchange therapy. Blood. 2019 May 9;133(19):2007-2009.
  10. Zerbato JM, Purves HV, Lewin SR, et al. Between a shock and a hard place: challenges and developments in HIV latency reversal. Current Opinion in Virology. 2019 Apr 29;38:1-9.
  11. Christensen-Quick A, Massanella M, Frick A, et al. Subclinical cytomegalovirus DNA is associated with CD4 T cell activation and impaired CD8 T cell CD107a expression in people living with HIV despite early antiretroviral therapy. Journal of Virology. 2019; in press.
  12. Gupta RK, Abduljawad S, McCoy L, et al. Sustained HIV-1 remission following homozygous CCR5 delta-32 allogenic HSCT. In: Program and abstracts of the Conference on Retroviruses and Opportunistic Infections, 4–7, March 2019, Seattle, Washington. Abstract 29.
  13. Gupta RK, Abdul-Jawad S, McCoy LE, et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature. 2019 Apr;568(7751):244-248.
  14. Arslan S, Litzow MR, Cummins NW, et al. Risks and outcomes of allogeneic hematopoietic stem cell transplantation for hematologic malignancies in patients with HIV infection. Biology of Blood and Bone Marrow Transplantation. 2019; in press.
  15. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014 Jul 17;124(3):344-53.
  16. Baker KS, Leisenring WM, Goodman PJ, et al. Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood. 2019; in press.
  17. Paim AC, Rizza SA, Badley AD, et al. Transient loss of HIV-1 DNA in an HIV-1 positive patient after kidney transplantation: A case report. American Journal of Medicine. Am J Med. 2018 Oct;131(10):e423-e424.
  18. Julg B, Barouch DH. Neutralizing antibodies for HIV-1 prevention. Current Opinion in HIV/AIDS. 2019; in press.
  19. Hütter G. More on shift of HIV tropism in stem-cell transplantation with CCR5 delta32/delta32 mutation. New England Journal of Medicine. 2014 Dec 18;371(25):2437-8.
  20. Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. New England Journal of Medicine. 2009 Feb 12;360(7):692-8.
  21. Delville M, Touzot F, Couzin C, et al. Safety of CD34+ Hematopoietic stem cells and CD4+ T lymphocytes transduced with LVsh5/C46 in HIV-1 infected patients with high-risk lymphoma. Molecular therapy. Methods & clinical development. 2019 Feb 26;13:303-309.
  22. Vibholm LK, Konrad CV, Schleimann MH, et al. Effects of 24 week toll-like receptor 9 agonist treatment in HIV-1+ individuals: a single-arm, phase 1B/2A trial. AIDS. 2019; in press.