An overview of HIV cure research

The desire for a cure for HIV has existed since the start of the epidemic. In the 1980s, many people were optimistic that science would find a cure within a few years. However, as more was learned about the complexity of this retrovirus, hope of a cure gave way to the goal to develop effective treatments that would delay disease progression. This breakthrough came in 1996 with combinations of anti-retroviral drugs being used to suppress HIV replication, halt HIV disease progression and improve immune health, saving the lives of millions. Despite the extraordinary success of this approach, which may result in a near normal life span, virologically suppressed HIV positive individuals still have an increased risk of non-AIDS illnesses and are required to take antiretroviral medication for the rest of their lives. Antiretroviral therapy is expensive, requires high levels of adherence, can have serious side effects and HIV quickly rebounds as soon as it is ceased.

HIV is not eradicated by antiretroviral treatment

HIV is a retrovirus, which means it insinuates itself into the genome of human cells. In the case of HIV it infects important cells of the immune system known as CD4 T-cells. Most of the CD4+ T cells infected by HIV die soon after being infected, but it is now understood that HIV remains hidden and dormant within a small proportion of CD4+ ‘memory T-cells’.  CD4+ memory T cells are produced in response to previous infections, or cancer cells, and provide long-term specific protection against rechallenge with the same pathogen.  These cells are relatively inactive unless they are being rechallenged and hence provide an excellent milieu for HIV to remain dormant. This pool or reservoir of virus in memory CD4+ cells is called latent HIV. It is highly likely that HIV also remains latent in long lived immune cells within tissues.

Recent real world approaches to a cure

The only person to have been cured of HIV is Timothy Ray Brown, otherwise known as the Berlin patient. In 2006 Brown was diagnosed with leukaemia and his treatment included intensive chemotherapy, a bone marrow transplant and whole body radiation therapy. This involved the complete destruction of his immune system and the introduction of donor bone marrow as the basis for building a new immune system. The process is both expensive and very risky with very high mortality rates. Prior to the transplant Brown’s doctor had the idea of sourcing bone marrow from a donor who had a genetic mutation to CCR5, which is the primary entry point for HIV into CD4+ cells. The genetic mutation meant that no CCR5 is produced on CD4+ cells thus making infection with HIV almost impossible. After two attempts, Brown’s procedure worked and to this day he remains free of HIV.

Subsequent attempts to reproduce Brown’s results in other HIV positive people with haematological malignancies using bone marrow transplants have not been successful.  These have shown that bone marrow transplants without the kind of genetic mutation that Brown received, or where the individuals don’t first completely destroy the patient’s own immune system, are not able to cure HIV. However individuals were able to remain in HIV remission, off antiretroviral treatment for up to 32 weeks.

Another approach investigated in recent years has involved the commencement of antiretroviral medication within days of becoming infected with HIV. It was believed that early antiretroviral therapy may prevent the establishment of viral reservoirs and therefore prevent HIV from re-emerging after a period of effective antiretroviral treatment. A baby in Mississippi was started on anti-retroviral treatment 30 hours after birth and continued on treatment for 18 months. The baby then ceased treatment and for two years her blood tests showed no evidence of active HIV infection. The virus then re-emerged after 27 months, showing that an HIV viral reservoir must have been established very early in infection. This study also demonstrated that HIV can be put into ‘remission’ for quite long periods of time without requiring antiretroviral therapy.  Similar cases of adults who received treatment within weeks or months of HIV infection and subsequently enjoyed remission off treatment for periods of 3-5 years are well documented, but relatively rare.

The meaning of a “cure” for HIV

Until 2014 cure researchers distinguished between a “functional cure” and a “sterilizing cure”. A functional cure was envisaged as the effective suppression of HIV without the need for daily treatment. Included in this idea are approaches such as therapeutic vaccines that might help the immune system supress HIV but without entirely getting rid of it. A “sterilizing cure” was envisaged as the complete eradication of HIV from the body.

Currently, cure researchers prefer the terms “HIV remission” or “antiretroviral-free viral suppression” as a more accurate and realistic descriptions of what they aim to achieve. (Persaud & Lewin, 2015)

Current approaches to cure research

Contemporary cure research might be characterised as belonging to one of the following four approaches (Katlama et.al, 2013).

1. Purging the reservoir (sometimes also called “shock and kill”). This approach seeks to find drugs that will force latent HIV out of the viral reservoir and thus expose it to antiretroviral treatment and possibly other elements to kill off the virus. Some of the agents currently under investigation are Histone deacetylase inhibitors (HDACi) and PD-1 inhibitors.
2. Gene therapy aims to identify genetic characteristics that help to naturally control the virus in some people called “elite controllers” or “long term non-progressors” and develop mechanisms for transferring these characteristics into others. One of the main targets for research in this field is the CCR5 receptor – a crucial entry point for HIV into healthy CD4 cells. A missing CCR5 receptor was preferred in the donor bone marrow that led to Timothy Ray Brown’s cure. Scientists are exploring ways to manipulate genes in order to turn off this receptor.
3. Stem cell transplantation is the process that Timothy Ray Brown undertook and it has thus far provided the only in vivo cure of HIV. However, transplantation is an expensive and risky process and with current technology could not be scaled up.
4. Therapeutic vaccines aim to stimulate certain immune responses in people with HIV leading better and more durable suppression of HIV by the immune system. Such approaches are challenged by the rapid mutation of HIV and the difficulty of finding antibodies that can work broadly and for long enough to be effective.

While these are currently distinct areas of work there is speculation that achieving remission may require a combination of approaches, mirroring the combination approach to antiretroviral treatment.

The timeline for an HIV cure

Major breakthroughs in medical science that quickly lead to scalable solutions for patients are extremely rare. HIV cure researchers have learned much over several decades and recent efforts to invigorate the field through the establishment of the Martin Delaney Collaboratories at the US National Institutes of Health have provided welcome stimulus and focus. Nonetheless it is likely to be many years if not decades before an effective cure can be brought to market. Scientific research proceeds cautiously by building knowledge based on what has gone before. This is necessarily slow and painstaking. Researchers must also carefully balance the risks and potential benefits of their research in order to design studies that will produce the best quality data and are least likely to do harm. The importance of achieving equitable access to any HIV remission or cure technologies across high and low-income settings is being addressed by community organisations and researchers and is integral to any future success in curing HIV at a global level. Notwithstanding the need for a measured scientific approach, there is currently a high sense of optimism in relation to HIV remission and cure research.

References

Katlama, C., Deeks, S., Autran, B. et.al., (2013) Barriers to a cure for HIV: new ways to target and readicate HIV-1 reservoirs. Lancet. 2013 Jun 15;381(9883):2109-17

Persaud, D., & Lewin, S. (2015). Viral reservoirs, development of viral latency and approaches to curing HIV infection. In UNAIDS, Biomedical AIDS Research: recent and upcoming advances. Geneva: UNAIDS.

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