Dr Hadwen Trust: Aid for AIDS – An anniversary to note but not to celebrate

by Dr Alpesh Patel, Science & Education Officer, Dr Hadwen Trust

Aid for AIDS – An anniversary to note but not to celebrate

Thirty years ago, on 5th June, 1981, the Centre for Disease Control and Prevention in Los Angeles, California, reported the outbreak of an unusual form of pneumonia. This case became the first in a long series that defined a previously unknown syndrome: the Acquired Immune Deficiency Syndrome, more commonly known as AIDS, which was to have a significant effect on worldwide health.

During the past three decades, the disease has claimed over 25 million lives with over 2.5 million new infections reported worldwide each year. It is now estimated that 34 million people are living with HIV and it continues to be one of medicine’s greatest challenges.

Although it is claimed that there has been progress over the past decade in the fight against AIDS, there are two new infections for every new person put on antiretroviral drugs, and the disease continues to claim 1.8 million lives a year.

Treatments have been developed that can slow the course of the disease, but an effective HIV vaccine is yet to be found using current methods. Whilst a “trial and error” approach has been successful for the development of other vaccines, the last few results on HIV trials suggest that this may not be the most effective way to fight this particular disease. Most of the scientific community now agree that the difficulties hindering the development of a vaccine against HIV are fundamental scientific questions, not pharmaceutical ones. Despite much hope and promise, there is still no evidence to indicate that the development of an effective vaccine is imminent.

It is well established within the scientific community that AIDS is caused by the human immunodeficiency virus HIV, a virus that targets the human immune system. HIV has evolved a number of specific immune evasion strategies to avoid the immune response. HIV initially destroys the immune system cells that are meant to fight it. As a result, the condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumours. In addition and soon after infection, HIV inserts its genetic material into human cells, where it remains hidden from the immune system. The virus exists in different subtypes, and can switch between subtypes. This means that HIV is highly variable and constantly changing which makes an immune response more difficult. In order to develop an effective vaccine, all these issues need to be addressed; however, one of the major obstacles in tackling these issues is the lack of a good model for the disease. Despite the vast amount of time and funding currently spent on animal tests, an effective animal model has not yet been identified.

HIV is a retrovirus specific to humans. This means it is not naturally found in any other animal hence the name Human Immunodeficiency Virus. Even though the virus is specific to humans, animal models such as the non-human primate/ Simian Immunodeficiency Virus (SIV) model, the cat/ Feline Immunodeficiency Virus (FIV) model, or Severe Combined Immunodeficiency (SCID) mice implanted with human tissue are still widely used though none of these models replicate the human form of the infection.

Why HIV is not SIV

Some African primates, such as chimpanzees and a few species of monkey, are naturally infected with the Simian Immunodeficiency Virus (SIV) but do not/will not develop AIDS as they have very efficient immune responses to SIV (and HIV), even after many years of infection.

On the other hand, the Asian Rhesus macaque monkey has never been exposed to SIV, so it has no natural immune response to it. When artificially infected with SIV, it will develop an AIDS-like illness. Not only is the SIV virus different from HIV, but macaques have different immune systems to humans, which means they cannot be infected with HIV-1.

In order to overcome this problem, researchers engineered a “hybrid” virus, which fused the SIV and HIV viruses, and is known as SHIV. This hybrid was generated in order to infect macaques whilst attempting to preserve HIV properties. Another variation of SHIV replicated the method that HIV uses to avoid the immune system. Neither hybrid is able to fully replicate the properties of HIV.

There are also major differences between humans and macaques, so that a drug or vaccine that is effective in a macaque may not be effective in humans. This makes the macaque another ineffective model for understanding HIV or for developing drugs or vaccines for HIV. Ironically, a drug or vaccine that might have been effective in an HIV+ human may be dropped because it appears ineffective in animals.

The Future

Although progress has been achieved, based on results over the past five years, the main advances are more likely to come from fundamental research and an in-depth understanding of the infectious mechanism rather than from pursuing the flawed “trial and error” approach.

Key advances, to name a few, include understanding the of the role of mucous as a barrier to sexually transmitted HIV infection, descriptions of the earliest immunological responses in humans after acute HIV infection, and demonstration that HIV infection in humans is usually initiated by one or a very small number of founder viruses. On the vaccine front, the development of computational algorithms is proving very effective in the design of unique immunogens to address the ability to control the virus or prevent virus uptake in certain people. Progress in other areas of biomedicine, such as the development of faster and cheaper DNA sequencing, high-throughput and computational technologies, are showing promise as important tools to reassess our understanding of the diseases.

Although a cure through a vaccine remains the ultimate target, therapeutic treatments that help people to live with the virus have been very useful and should continue to be refined. Therapy can target the infection directly or its secondary effects in humans.

For example, a project on the effect of HIV on the brain, funded by the Dr Hadwen Trust (DHT) and led by Professor Weber at St Mary’s Hospital Medical School in London, developed an alternative to experiments carried out on non-human primates by using human brain cell cultures as a model for HIV infection of the central nervous system.

Another project funded by the DHT investigated Pneumocystic pneumonia (PCP), which is a major problem in immuno-compromised patients such as those with cancer or organ transplant patients, but particularly affects AIDS sufferers. This research, led by Dr Huggett from the Centre of Infectious Disease at University College London, studied the first in vitro culture method for basic research on the human-infecting Pneumocystis jirovecii towards potentially creating a diagnostic test for PCP, and replacing the current animal work conducted to study the condition.

Preventive approaches should also be developed, as shown by Professor’s Weber team who also studied the effects of microbicidal gels that would stop the virus infecting the blood.

The results of 30 years of HIV research indicate the need to search for new tools and ideas and to develop and adopt new technologies arising from all areas of biomedical research. Examples include imaging technologies for studying mucosal immunity and the trafficking of viral or vaccine antigens and immune effectors. Genomic technologies to better understand host factors that regulate the immune response and high-throughput screening methodologies for optimizing vaccine components and vaccination regimens together with new immunogen-design and gene-delivery technologies.

It is in these areas where a single breakthrough could, like the invention of AIDS-suppressing drugs, be critical to one day eradicating AIDS as well as the unnecessary suffering of animals currently being used in HIV/AIDS research.

To learn more about the Dr Hadwen Trust and the work it does to replace the use of animals in medical research, go to www.drhadwentrust.org.