By Sam Keane | Apr 19 2019

In modern history, few diseases have captured the public’s imagination more than HIV/AIDS. Emerging in the West in 1981 and reaching epidemic levels not long after, it was widely regarded as incurable, despite the investment of millions of dollars into AIDS research every year. In recent months however, two developments have inspired hope among the medical community that a cure for the disease is on the way.

HIV (Human Immunodeficiency Virus) is a virus that attacks the body’s immune system. The virus targets specific immunological cells known as “Helper T-Cells” or CD4 cells, using them to reproduce and eventually destroying them. The destruction of these cells results in severe damage to the body’s immune system, making it more susceptible to common infections such as tuberculosis and pneumonia. HIV is transmitted primarily by unprotected sex (including anal and oral sex). The virus can also be contracted from contaminated blood transfusions, hypodermic needles and from mother to child during pregnancy or breastfeeding. HIV cannot be contracted from non-sexual contact with an affected individual or from other bodily fluids such as urine, saliva or sweat.

In the immediate aftermath of contracting the virus, a person infected with HIV will not display any obvious symptoms. They may experience a brief flu-like illness, following which, the virus enters a prolonged latent period which lasts, on average, about 8 years. Towards the end of this asymptomatic period, the patient may experience fever, weight loss, gastrointestinal problems and muscle pains. As the infection progresses, the patient’s immune system becomes more and more compromised. The risk of developing common infections such as pneumocystis pneumonia and other respiratory illnesses increases greatly. Tumours that rarely affect people who have an uncompromised immune systems may also appear. These late symptoms of infection are referred to as Acquired Immunodeficiency Syndrome (AIDS). Patients suffering from AIDS frequently experience severe fever, diarrhoea, intense sweating, swollen lymph nodes and dramatic weight loss. After an AIDS diagnosis, without treatment, survival times averages from 6 to 19 months.

HIV is thought to have originated from what is now the Democratic Republic of Congo in the early part of the 20^th century, when the virus crossed the species barrier from chimpanzees to humans. Recent genetic analysis of stored blood samples has found that HIV was most likely carried from the Congo to Haiti in the 1960s — a working theory suggests that it could be from a Haitian civil servant recruited by the United Nations to work in the former Belgian Congo after colonial rule collapsed. In Haiti, the few cases were multiplied by unsterile conditions at a private blood-collecting company known as Hemo-Caribbean. This company exported roughly 1,600 gallons of blood plasma to the United States every month throughout the 1970s to be used by American haemophiliacs. At the time, Haiti was also a popular sex-tourism destination for Americans. AIDS was first clinically reported in the USA in June 1981. Several homosexual men and intravenous drug users in New York and San Francisco were diagnosed with a rare form of pneumonia (Pneumocystis pneumonia) that only occurs in individuals with severely compromised immune systems. Soon after, many homosexual men began developing a rare form of skin cancer, Kaposi’s Sarcoma. The Centre for Disease Control formed a taskforce to investigate these unusual outbreaks. By the end of 1981, there were 270 reported cases of severe immune deficiency among homosexual men in the US. From 1982 onwards, as the number of cases began to skyrocket and spread to several European countries, the disease was officially labelled AIDS, despite its exact cause remaining unknown at the time.

The first major breakthrough in understanding the cause of AIDS came in 1984, when researchers in the US and France announced that they had discovered the cause of the syndrome: the retrovirus HTLV-II, later renamed HIV. By the end of 1985, there were more than 20,000 reported cases of AIDS across the globe. The first antiretroviral medication for HIV, azidothymidine (AZT), became available in 1987. However, concerns were raised regarding its toxicity, with many physicians believing that the drug was too potent to administer to AIDS patients. By 1990, it was estimated that between 8 and 10 million people were suffering from AIDS worldwide.

In 1995, doctors introduced triple combination therapy as an antiretroviral treatment. This new treatment, known as “Highly Active Antiretroviral Therapy” (HAART), used specialised drug combinations that inhibited the virus from replicating. In patients who underwent HAART, it was noticed that their red and white blood cell counts had normalised, an important sign that the immune system was starting to work again. Later that year, a new protease inhibitor drug was included in HAART that further bolstered the treatment regime’s effectiveness in combating the virus. In 1997, for the first time in a decade, AIDS fell out of the top 10 causes of death in the United States. However, despite these pivotal advances in AIDS treatment, the majority of these drugs remained out of reach for patients located in the developing world. By 1999, AIDS was the number one cause of death in Africa with astronomical infection rates being reported from countries such as Zimbabwe, Malawi and South Africa. To combat this inequality, in the early 2000s, the Joint United Nations Program on HIV and AIDS (UNAIDS), negotiated with pharmaceutical companies to make more affordable, generic antiretroviral medication available in developing countries.

These advancements in treatment have changed HIV/AIDS from an acute illness to a chronic one. With access to antiviral medication, HIV patients can live normal lives with life expectancies similar to those of people without the virus. Today, treatment comes in the form of a single pill a day. Current antiviral medication can restore T-cell counts to normal levels thereby maintaining a healthy immune system. The viral load (amount of HIV in the body) is reduced to undetectable levels. This means that there is not enough HIV in bodily fluids to pass on the virus during sex. Essentially, patients receiving effective treatment are no longer infectious. Pre-Exposure Prophylaxis (PrEP) has also been very successful in reducing HIV transmission. This method involves HIV-negative people who are engaged in risky behaviours (unprotected sex and intravenous drug use) taking medication before engaging in these activities to reduce the chance of contracting HIV.

Despite making immense progress in managing the disease and its symptoms, medical researchers had, until very recently, been unable to “cure” HIV/AIDS. If the patients in question stopped taking their medication; their T-Cell count would drop, their viral load would return to transmittable levels and they would once again begin experiencing the symptoms of the disease. Essentially, HIV can be managed insofar as that it has little impact on the daily lives of patients but cannot, with current treatment methods, be completely removed from the body. However, in 2007, Timothy Brown inspired hope among HIV/AIDS sufferers. Referred to as the “Berlin Patient” in medical circles, Brown was diagnosed with HIV in 1995. After controlling the virus for many years with antiretroviral therapy, in 2006, Brown was diagnosed with Acute Myeloid Leukaemia. After several rounds of unsuccessful chemotherapy in 2007 and 2008, he underwent two bone marrow transplants, a common treatment for this type of cancer. Doctors chose an unrelated donor who screened positive for the homozygous ?32 mutation on CCR5. Brown stopped taking his antiviral medication shortly after his first transplant. Usually, when HIV-infected people stop taking these drugs, levels of HIV soar within weeks. Yet, in the past ten years, researchers have found only traces of viral genetic material in Timothy Brown’s body, none of which can replicate. Professor Cormac Taylor of UCD’s School of Medicine explains the process as follows: “For HIV to effectively enter the immune cells that it infects and ultimately kills, it requires another protein to be on the surface of these cells called CCR5. A small number of people who have a mutation in the CCR5 gene cannot be infected by HIV as it cannot bind to and enter their immune cells. If a HIV positive patient has their own immune cells removed (by radiation) and replaced (by bone marrow transplant) with cells from a donor who had the CCR5 mutation, then this means that following transplant, the patient’s ‘new’ immune cells are resistant to HIV infection with any virus remaining in the body.” Timothy Brown was the first patient considered “cured” of HIV/AIDS.

Following the successful treatment of Timothy Brown, doctors began attempting to replicate the procedure in patients who were also suffering from HIV and late stage cancer. In case after case, the virus came roaring back, often nine months after the patients stopped taking antiretroviral medication, or else the patients died of cancer. The failures stoked fears that the procedure that had cured Timothy Brown had been a “fluke”. In March of this year however, news broke that a second patient, the “London Patient” had been in long-term remission from HIV for a year and a half, without drugs, as a result of a similar procedure. The anonymous “London patient” was suffering from both HIV and Hodgkin’s lymphoma. He received a bone marrow transplant as part of his cancer treatment in 2016 from a donor who had a malfunctioning CCR5 gene and stopped taking antiretroviral medication shortly afterwards. Blood tests have confirmed, 18 months after ceasing antiviral treatment, that this patient is now HIV free.

Despite garnering international attention, as it stands, the procedure in itself can never be offered as a cure for HIV. When asked about his thoughts regarding these developments, Professor Taylor was sceptical: “Any progress in terms of movement towards cure of HIV is highly welcome. However, a stem cell transplant is a difficult, expensive and risky procedure and is highly unlikely to be a widely available treatment for HIV-positive people any time soon. The risk is that members of the public just see the headline and become erroneously informed that HIV infection can be easily cured. This could lead to people taking more risks and paying less attention to the highly effective prevention of infection methods currently used including the use of condoms and Pre-exposure prophylaxis (PrEP).” Bone marrow transplants can only be undertaken when clinically necessary (advanced stage cancers) as they are thought to carry unacceptable risks. Another crucial limitation of this approach is that the patient would still be vulnerable to a strain of HIV known as X4, which employs a different protein, CXCR4, to enter cells. However, these cases still signify a remarkable step forward.

It is hoped that with new gene editing technologies such as CRISPR/CAS9, a patient’s own genes coding for CCR5 receptors could be altered to deliver a similar outcome. Medical researchers have theorised that these modified HIV resistant cells could eventually clear the body of the virus. Several companies are pursuing CCR5 gene therapies, hoping to be the first to bring any possible cure to the market. The genetic modification must target the right number of cells, in the right place (only the bone marrow) and alter only the genes directing involved in the production of CCR5.

In November 2018, a relatively unknown Chinese scientist, Dr He Jiankui, claimed to have created the world’s first genetically modified babies. Jiankui said that he had altered a gene coding for CCR5 receptors in two twin embryos before having them implanted in a HIV positive mother’s womb. He undertook this experiment with the ultimate goal of making the babies immune to the virus. In doing this, Jiankui defied the unofficial international moratorium on editing human embryos intended for a pregnancy. Even more controversially, he chose to edit out a disease that’s now highly treatable, using a potentially dangerous and unproven technique. When asked about his thoughts the use regarding gene therapy in treating HIV/AIDS, Professor Taylor stated “gene therapy has some potential, but to date, is still very much an experimental approach, the effectiveness of which remains to be determined. Furthermore, this is a highly costly approach unlikely to be available in developing countries such as in sub-Saharan Africa (where the need is highest). I would stress that the effective approaches we have as well as the development of a vaccine is the most likely way in which we will combat HIV on a global scale.” Dr Jiankui’s experimental gene editing drew near universal criticism from within the scientific community, with many high-profile figures expressing their shock at the recklessness of the project. The Chinese government suspended the research and is currently undertaking an official investigation into Dr Jiankui’s activities. The university that Dr He is attached to, the Southern University of Science and Technology, stated that the project was undertaken without their knowledge and that Jiankui had been placed on indefinite unpaid leave from his research post.

Despite the outpouring of criticism directed at Dr Jiankui, perhaps the time has come to take new, revolutionary steps towards eradicating a disease that has caused suffering for millions since its emergence in the early 1980s. Dr George Daley, Dean of Harvard Medical School stated at a Genomic Conference in Hong Kong last year, that the time had come to move past ethical debates and begin pushing ahead with gene editing technology in the clinic. The progress made in HIV treatment over the past thirty years is undoubtedly one of the greatest achievements of the modern age, but there is still a way to go. Medical research relies heavily on the continuous pushing of boundaries, especially in the case of a disease as herculean as HIV/AIDS.