Gene therapy or immunotherapy: which approach is more likely to deliver a cure for HIV?

Image: Sharon Lewin and John Frater in the online AIDS 2020 cure pre-conference debate.

Amidst speculation that a five-drug antiretroviral regimen and nicotinamide might have cured HIV in one man, researchers debated whether gene therapy or immunotherapy is more likely to lead to an HIV cure that can be delivered to millions during the AIDS 2020 Cure pre-conference last week.

A cure for HIV could take two forms, either a treatment or procedure that can eradicate the virus from the body or one which can keep the virus under control without the need for antiretroviral drugs – remission, in the parlance of the field.

Eradication of HIV is challenging because the virus inserts its DNA into long-lived cells in the body where it may lie dormant for decades – the so-called HIV reservoir. All this virus needs to be found, activated and purged, but presentations at AIDS 2020 show that the reservoir is more complex than previously assumed.

Glossary

gene

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

gene therapy

A type of experimental treatment in which foreign genetic material (DNA or RNA) is inserted into a person's cells to prevent or fight disease.

immunotherapy

Use of immunologic agents such as antibodies, growth factors, and vaccines to modify (activate, enhance, or suppress) the immune system in order to treat disease. It is applied in the cancer field and in HIV research (attempts to eliminate the virus). Immunotherapy is also used to diminish adverse effects caused by some cancer treatments or to prevent rejection of a transplanted organ or tissue.

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

reservoir

The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped. 

HIV is distributed across numerous tissues in the body, not just cells in the blood or lymph nodes, an autopsy study by the US National Institutes for Allergy and Infectious Disease shows. Predicting which tissues are the most important reservoirs is difficult, as the small study showed big variation between individuals.

Furthermore, the normal work of CD4 memory cells – activation and proliferation in response to pathogens – inevitably leads to cloning of cells containing HIV DNA and an increase in intact HIV DNA capable of producing new virus over time, Bethany Horsburgh of Australia’s Centre for Virus Research at Westmead Institute for Medical Research reported.

Even very early antiretroviral treatment appears unable to halt the development of a reservoir that can sustain SIV infection in the body, Dr Henintsoa Rabazantahary of Canada’s Université Laval told the conference. Her macaque study began treating some animals four days after infection, underscoring how quickly an intractable reservoir is established.

These findings emphasise the importance of approaches to curing HIV that go beyond the `shock and kill` regimens designed to activate HIV-infected cells, which have shown disappointing results in clearing the reservoir.

Gene therapy to eradicate HIV or immunotherapy to contain HIV are being explored as potential approaches but which is more likely to be successful? Two leading cure researchers debated the merits of the approaches at a pre-conference HIV cure workshop last week.

Professor Sharon Lewin, Director of the Doherty Institute of Infection and Immunity at the University of Melbourne argues that gene therapy is more likely to deliver an HIV cure than immunotherapeutic approaches aimed at long-term remission of HIV. Proof of concept for a gene therapy approach already exists, she said, in the form of the Berlin and London patients, Timothy Brown and Adam Castellijo, who were cured of HIV after stem cell transplants from donors with the CCR5 delta 32 mutation that confers resistance to HIV infection of cells.

Gene therapy can be used against multiple targets to engineer protection against HIV infection of cells, to purge the virus from infected cells and enhance immune defences that attack HIV.

But the big challenge for gene therapy is to develop an approach that doesn’t require cells to be taken out of the body for gene editing in the laboratory. Almost all gene therapy studies underway are using this 'ex vivo' approach, which harvests cells, edits them in the laboratory and then returns them to the patient’s body. Although the ex vivo approach has already been proved to work, both for HIV and cancer immunotherapy using CAR T-cells, it’s expensive and requires state of the art laboratory equipment.

The alternative, in vivo gene therapy, would require nanoparticles or a vector such as adenovirus to deliver the edited gene to cells. One study has already shown that it’s possible to achieve sustained production of a broadly neutralising antibody against HIV, VRC07, using an adenovirus vector to deliver an antibody gene.

Elimination of host stem cells, achieved in the cases of the Berlin and London patients through gruelling chemotherapy prior to bone marrow transplants, might soon be achievable through antibodies-drug conjugates that would target stem cells, Lewin suggested.

Professor John Frater of the University of Oxford sees immunotherapy as more likely to deliver long-term remission. He argued that gene therapy is still largely unproven in any field and the long-term safety of gene therapy is still unclear. In contrast, immunotherapies are already being used to treat cancers such as melanoma and lymphoma, as well as rheumatoid arthritis. Elite controllers of HIV, or long-term non-progressors, also offer evidence that the immune system can control HIV in some circumstances.

“Immunity is the best machine you could imagine – it’s had millions of years of R & D so we should use it and make the most of it,” he said. “Do not confuse the failure of vaccines so far as a red flag for immunotherapy”. A vaccine needs to target a rapidly mutating, fast-replicating virus, whereas an immunotherapy targets a stable antigen that is less prone to mutate – the cells in the HIV reservoir. “We need to think of it more like a strategy for cancer than infection,” he said.

Broadly neutralising antibodies represent one promising avenue of immunological research, along with therapeutic vaccination or anti-PD1 to activate exhausted host defences, Professor Miles Davenport of the Kirby Institute of Immunity & Infection, Australia, told a symposium on emerging cure strategies.

But he warned that we still don’t understand how immune control relates to viral rebound and how much the HIV reservoir might need to be reduced to make immunological control of HIV viable. What might overcome this challenge, he suggested, would be gene therapy approaches that could render 90% of cells resistant to infection. Modelling by his research group suggests that this level of transduction of cells would dramatically limit viral rebound, permitting immunological control of HIV.

In summary, it may not be a question of choosing between gene therapy or immunotherapy, but using both approaches to achieve HIV remission.

References

Rabezanahary  H et al. Contribution of monocytes and CD4 T cell subsets in maintaining viral reservoirs in SIV-infected macaques treated early after infection with antiretroviral drugs. 23rd International AIDS Conference, abstract OA004, 2020.

Horsburgh H et al. Cell proliferation contributes to the increase of genetically intact HIV over time. 23rd International AIDS Conference, abstract OA005, 2020.

Imamichi H et al. Multiple sanctuary sites for intact and “defective” HIV-1 in post-mortem tissues in individuals with suppressed HIV-1 replication: Implications for HIV-1 cure strategies. 23rd International AIDS Conference, abstract 0A006, 2020.

S Lewin & J Frater. Gene therapy vs. immunotherapy: which is more likely to work? – Debate. AIDS 2020: Virtual, HIV Cure pre-conference.

Davenport M. The promise of immunotherapy in HIV infection. AIDS 2020: Virtual symposium presentation, 'Pushing the boundaries: new approaches to a cure'.

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