It’s time for this year’s second installment of student guest posts for my class on infectious causes of chronic disease. Third one this round is by Jack Walsh. 

The Human Immunodeficiency Virus (HIV) infection is one of the most significant global health challenges of this 21st century. Since the isolation of the virus in 1983, it has infected 70 million people among whom 35 million have died of Acquired Immunodeficiency Syndrome (AIDS).1 Although important progresses have been made in slowing down the pandemic and reducing the morbidity and mortality related to HIV/AIDS with the highly active antiretroviral therapy (HAART) drugs, there are still difficulties in stopping the dissemination of the infection. It is estimated that for every person gaining access to HART, there are two new others infected by the virus.2 An effective and safe vaccine is therefore needed to prevent HIV from spreading, but the development of the vaccine has been proven to be an enormous scientific challenge.

HIV presents particularities that make it very difficult for researchers to find a vaccine. It is a lentivirus from the Retroviridae family, slowly progressive using an enzyme (called reverse transcriptase) for the transformation of its genome or genetic material (RNA in this case) into a new one (proviral DNA) integrated in that of the human host using another enzyme known as integrase. One of the most fascinating characteristics of the virus is its genetic variability in both an infected individual and geographically. In a same person, new mutations can be introduced in almost every new copy, creating up to millions of new particles every day. One antibody could then neutralize one virion, but not another.3 Additionally, super-infection in an individual already HIV infected results in new recombinants increasing further viral genetic diversity. The virus also presents two different types, HIV-1 worldwide and HIV-2 confined to West Africa. HIV-1 is further subdivided into subtypes or clades differently distributed on the globe and further diversified within each clade. Moreover, by integrating proviral DNA in the genome of memory cells of the immune system (CD4+ T cells) the HIV can escape the immune surveillance. To complicate the development of an effective vaccine, the virus envelope is able to hide receptor site to antibody that could potentially inhibit its effect (neutralizing antibodies). This explained the inefficiency of antibodies generated by vaccines targeting the glycoprotein 120 (gp120) located on the surface of virus developed in early vaccine trials.4

However, despite these challenges, encouraging progresses in the development of an effective HIV vaccine have been made. The first HIV vaccine trial was opened at the National Institutes of Health (NIH) Clinical Center in 1987, including 138 healthy volunteers. Other large scale trials included participants from North America and The Netherlands (1998), then Africa and Asia (1999).5 Three main approaches have been used in the development of an HIV vaccine: 1) the induction of neutralizing antibodies against HIV using the virus envelope proteins (gp120 or 140), 2) the use of viral vectors to stimulate responses form killer cells (CD8 T-cells or T cell that would recognize antigens on virus surface of the virus-infected cell, binds to it, and kill it), and 3) the optimization of cellular immunity (activation of killer cells) and humoral immunity (production of antibody) with prime-boosts (administration of one type of vaccine, such as a live-vector vaccine, followed by or together with a second type of vaccine, usually a recombinant).6 Also, to cope with the genetic variability of the virus, multiple strategies are explored, such as mixing envelope immunogens from several HIV subtypes or clades. Unfortunately, most of the tested vaccine models did not significantly reduce HIV infection in participants, except an envelope-based subunits’ vaccine tested in Thailand which showed significant decline by about 30% in HIV infection in 2009.7 Though modest, the results clearly show that HIV/AIDS is a vaccine preventable disease. More recently in 2012, a Spanish study showed promising results in the development of a therapeutic HIV vaccine effective in reducing the viral load by 90% after 12 weeks of therapy, awkwardly the vaccine lost effectiveness within a year.8 Just a few days ago, the Duke Human Vaccine Institute team published an important study, in which it has been able for the first time to map the co-evolutions of antibodies and virus in an infected individual, whose immune system launched a broad attack against the pathogen, using new technologies. They also identified the viral surface glycoprotein, which initiated the neutralizing antibody development.9

Despite two decades of disappointing results on HIV vaccine research, we now have started to see encouraging advances. For the first time a candidate vaccine was successful in significantly reducing the HIV infection. Furthermore, an important progress has been made very recently in identifying neutralizing antibodies initialization and mapping. The study provides crucial insights for the development of a vaccine that could mimic the actual antibody development and elicit non-strain specific antibodies. Progress towards finding an effective vaccine is slow, but we can optimistically say that the future is promising.

 

References

[1] World Health Organization (WHO), Global Health Observatory (GHO). HIV/AIDS, Global situation and trends. 2012. http://www.who.int/gho/hiv/en/

2 Letvin, Norman L. “Progress and obstacles in the development of an AIDS vaccine.” Nature Reviews Immunology 6.12 (2006): 930-939.

3Letvin NL. Progress Toward an HIV Vaccine. Annu. Rev. Med. 2005. 56:213–23

4Marc GP, OsmanovSK, Kieny MP. “A review of vaccine research and development: the human immunodeficiency virus (HIV).” Vaccine 24.19 (2006): 4062-4081.

5 National Institute of Allergy and Infectious Diseases (NIAID). History of HIV Vaccine Research. 2012. http://www.niaid.nih.gov/topics/hivaids/research/vaccines/Pages/history.aspx

6 Ross, Anna Laura, et al. “Progress towards development of an HIV vaccine: report of the AIDS Vaccine 2009 Conference.” The Lancet infectious diseases 10.5 (2010): 305-316.

7 Rerks-Ngarm, Supachai, et al. “Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.” New England Journal of Medicine 361.23 (2009): 2209-2220.

8 García, Felipe, et al. “A Dendritic Cell–Based Vaccine Elicits T Cell Responses Associated with Control of HIV-1 Replication.” Science translational medicine 5.166 (2013): 166ra2-166ra2.

9 Liao HX et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 2013. Epub April 3, 2013

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