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The Future for the Treatment of HIV

Publié le 1 novembre, 2008 | Pas de commentaires
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2009 marks 25 years since the Acquired Immunodeficiency Syndrome (AIDS) was linked to the transmission of the retrovirus Human Immunodeficiency Virus (HIV). In these years, HIV/AIDS has become one of the largest human health pandemics in recorded history. An estimated 33 million people are infected and AIDS causes approximately two million deaths each year (1). An additional 6500 people are infected everyday.

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HIV is a uniquely persistent disease, evolved to constantly evade the human immune system. Early on in the pandemic, many optimistically declared a vaccine would be developed within a short time-frame. Perhaps the most notorious example came when in 1984 the US Health Secretary, Margaret Heckler, announced the discovery of HIV and claimed a vaccine would be available within two years (2). A vaccine has not been developed, but efforts to create one have yielded many insights into how the virus works.

Efforts to fund-raise for, as well as coordinate and conduct research, has also created an ethical paradox: the disease overwhelmingly affects Sub-Saharan Africa, yet most of the treatment has focused on pharmaceuticals for patients in the Western world.

The virus

HIV is a retrovirus that binds and enters macrophages and CD4+ T-cells, two of the most important components of the human immune system. HIV then incorporates its genome into the DNA of the host cell. In most cases, the virus will enter a period of latency, stunting the immune system’s ability to form a strong response to the virus. Under certain conditions, such as when the immune system is fighting another infection, the HIV DNA will be transcribed, leading to the formation of more virus. In this way, HIV is both able to persist within the host’s cells, and to pervade the host when he is most vulnerable.

Because CD4+ cells are responsible for mediating the immune system, the infection and subsequent takeover by HIV leads to a loss of cell-mediated immunity. The progression of HIV infection to this point can take years. HIV also mutates rapidly, leading to patients who are infected with millions of subtly different strains of virus. This adds to HIV’s persistence, as the vast variability means it can adapt to treatments and become drug-resistant.

HIV also occurs in several groups and subtypes, and patients infected with more than one subtype can produce recombinant strains, further adding to the complexity of the virus (3).

Anti-retroviral treatments

Current treatments for HIV involve using anti-retroviral drugs to block or negate several infection and development points of the virus. Because of the complicated reproductive sequence of HIV, there are many targets for anti-retroviral drugs. The longest available drugs have targeted the synthesis of the viral DNA and the proteins that assemble complete virus particles. There are also drugs which interfere with the fusion of HIV to the host cells, preventing viral entry. Patients with HIV usually take a combination of these drugs, in an approach known as highly active anti-retroviral therapy, or HAART.

Newer drugs target the integration of the viral genome into the host cell (4). Known as ‘integrase inhibitors’, they are considered a more effective and promising treatment because the new drug targets a unique property of HIV. Preventing the virus’ ability to integrate DNA interrupts a key moment in the life-cycle of viral replication. Although unlikely to be totally effective, drugs developed to do this have already shown they are able to significantly decrease the viral load within a patient, over and above what is possible with regular HAART. In cases where patients have HAART-resistant HIV, the drug Raltegravir® has been approved for treatment.

Another new class of anti-retroviral drugs are maturation inhibitors (5,6), none of which are approved for human treatment. These putative drugs prevent the virus from properly assembling before emerging from the host cell. The virus becomes a dysfunctional shell, unable to propagate disease. Although not available for patients, two are in early clinical trials.

These newer classes of drugs could potentially raise the life expectancy of HIV patients, and the integrase inhibitors have had early success. Anti-retroviral drugs still have several drawbacks. Because of the incredible variability, over time HIV will likely become resistant to these newer drugs. Researchers are looking at new strategies to help the body combat the virus.

Anti-retroviral treatments are incredibly expensive. Despite efforts to get lower-cost generic versions of these drugs made for developing countries, HAART remains out of reach for most HIV cases in Sub-Saharan Africa. Here the focus of organizations such as UNAIDS and WHO has been on education and preventing the spread of the disease, although there are efforts now to develop HAART programs in these heavily affected countries. Unfortunately, due to prejudicial trade policies and protectionist pharmaceutical companies, progress has been slow (7).

Researchers are looking at new strategies to help the body combat the virus. Last year, researchers successfully developed an evolved enzyme that could recognize integrated HIV DNA, and remove it from infected cells (8). They evolved this by taking an enzyme called Cre recombinase, which can recognize and excise certain regions of DNA, and selectively modifying it to recognize the regions at either end of integrated HIV DNA. This “Tre” recombinase was able to remove viral DNA from cell culture without harm to the cells. Such a treatment is still highly experimental and many technical barriers remain to this approach becoming a therapy. One idea is to remove stem cells from a patient, program the cells to produce Tre, then re-inject the cells. The patient becomes their own pharmaceutical producer, and, combined with anti-retrovirals, could be a very effective treatment regime. Still, the most effective way of targeting future infection would be the development of an HIV vaccine.

Vaccine research

Vaccination is the preeminent medical advance in history. The ability to induce immunity to diseases has consigned smallpox to history, and there are vaccines for everything from polio to the human papillomavirus, the virus implicated in most cervical cancers. Why is an HIV vaccine so elusive? Again, the incredible genetic variability of HIV, and the fact that the virus targets the keystones of the immune system(CD4+ T cells) are the main barriers to vaccine development.

Traditional vaccines use the strategy of providing the immune system a harmless or attenuated template version of a disease. The immune system is able to select antibodies that recognize the disease, guiding the rest of the immune system response. Usually, the part of the virus or bacteria an antibody would recognize is a surface receptor or protein. This is successful when the disease exhibits low variability, but HIV is able to change its surface proteins to evade whatever antibodies an individual immune system has. Then, because the virus targets the memory of the immune system, eventually T cells which recognized one version of the virus succumb to a different version.

To date only one HIV vaccine has been trialled in humans, with a controversial outcome. A vaccine engineered from an adenovirus (like the common cold), carrying three HIV genes, was given to nearly 4000 participants globally. One of the trials, known as STEP, was terminated in September 2007, after preliminary findings raised the possibility that the vaccine actually increased susceptibility to HIV (9,10). Other trials were subsequently halted. The failure of this vaccine candidate led the US National Institutes of Health (NIH) to cancel a large trial of another vaccine based on a similar concept (11). For the moment, HIV vaccine research remains a long way from any practical implementation.

Future prospects for HIV treatments

Due to the relative low cost of administering treatment to developing countries, vaccination will remain the ultimate goal of AIDS prevention work. Annually, nearly one billion US dollars are devoted to vaccine research, with major contributions coming from government health research budgets. However, National Institutes of Health (NIH) budgets for HIV vaccine research have remained static for five years, creating funding pressure due to increase costs of research over this time.

Into this gap have stepped several philanthropic organizations. Perhaps the most well-known is the Bill and Melinda Gates Foundation. In 2006, the Gates Foundation granted $287 million to research teams that were taking
less conventional approaches to HIV vaccine development (12). This included funding computational-biology, where synthetic proteins will be designed to thwart the virus, and studying the properties of less-well known antibodies from animals such as llamas. It is uncertain where these novel approaches will lead.

More certain is that the dynamic of research funding for HIV cures is changing. NIH, long the backbone of HIV research efforts, has been unable to expand its research scope in the last decade. It has contributed enormously in terms of resources and basic knowledge about the disease, yet much remains to be accomplished. Philanthropy offers new funding sources, and exposure to ideas outside the norm, but with less certainty about length and depth. After 25 years much has been learned about HIV, without much visible damage in the progress of the pandemic. Now is the time for new approaches, led by people willing to risk more, to end a tragic era in human health.

References

(1) UNAIDS, WHO. “2007 AIDS Epidemic Update” (2007), available at http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf
(2)Kanabus, Annabel and Fredriksson, Jenni. “The history of AIDS up to 1986.” AVERT 6 October 2008. http://www.avert.org/his81_86.htm
(3) Walker, Bruce D. and Burton, Dennis R. “Towards and AIDS Vaccine” Science 320.5877 (2008) 760-764.
(4) Steigbigel, Roy T., et al. “Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection.” New England Journal of Medicine 359.4 (2008) 339-354.
(5) Salzwedel, Karl, Martin, David E. and Sakalian, Michael. “Maturation Inhibitors: a New Therapeutic Class Targets the Virus Structure” AIDS Rev. (2007) 9:162-172.
(6) Myriad Genetics. “Myriad Genetics Submits IND on Vivecon” Press release 4 December 2007. 20 September 2008 http://www.myriad.com/news/release/1083753
(7)Zaccagnini, Marta. “AIDS, drug prices and generic drugs.” based on an original article by Bonita de Boer, AVERT 19 September 2008. 6 October 2008 http://www.avert.org/generic.htm
(8) Sarkar, Indrani, Hauber, Ilona, Hauber, Joachim, Buchholz, Frank. “HIV-1 Proviral DNA Excision Using an Evolved Recombinase.” Science 316.5833 (2007) 1912-1915.
(9) Steinbrook, Robert. “One Step Forward, Two Steps Back – Will There Ever Be an AIDS Vaccine?” New England Journal of Medicine 357.26 (2007) 2653-2655.
(10) Fauci, Anthony S. et al. “HIV Vaccine Research: The Way Forward” Science 321.5888 (2008) 530-532.
(11) NIH/National Institute of Allergy and Infectious Diseases. « HIV Vaccine Trial Cancelled By NIH. » ScienceDaily 17 July 2008. 21 September 2008 http://www.sciencedaily.com/releases/2008/07/080717110245.htm
(12) Bill and Melinda Gates Foundation. “Foundation Funds Major New Collaboration to Accelerate HIV Vaccine Development” Announcement 19 July 2006. 21 September 2008 http://www.gatesfoundation.org/GlobalHealth/Pri_Diseases/HIVAIDS/Announcements/Announce-060719.htm

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