Eric Hopton for redOrbit.com – Your Universe Online
Research into the use of HIV vaccines in primates has discovered that the vaccines can “backfire” and result in even higher rates of infection. This unwelcome effect has been found in more than one clinical trial for HIV vaccines. The primate model study therefore suggests that vaccines should avoid viral target cells.
This is important work in the battle to tackle the continuing global HIV/AIDS epidemic. As a result of that global spread of HIV and AIDS, more than 30 million individuals worldwide have been infected. The need to develop a safe and effective HIV/AIDS vaccine is paramount. However, the development of an AIDS vaccine has proved to be a major problem and, to this day, it still presents a huge challenge for the scientific community due to some of the very specific aspects of HIV biology. These include the extreme genetic heterogeneity and structural plasticity of the virus and the ability of the virus to persist as integrated proviral DNA in an immunologically silent form (i.e., latent infection).
The new work was carried out by scientists at Yerkes National Primate Research Center, Emory University. The results propose a straightforward explanation for the backfire effect: vaccination itself may lead to an increase in the number of immune cells that serve as viral targets. In a primate model of HIV transmission, it was found that higher levels of viral target cells in gateway mucosal tissues were associated with an increased risk of infection.
The report, published in the journal Proceedings of the National Academy of Sciences, concludes that, when vaccine researchers are evaluating potential HIV/AIDS vaccines, they may need to steer away from those that activate too many viral target cells in mucosal tissues.
“One of the reasons why it has been so difficult to make an AIDS vaccine is that the virus infects the very cells of the immune system that any vaccine is supposed to induce,” said senior author Guido Silvestri, chief of microbiology and immunology at Yerkes National Primate Research Center.
Silvestri is also a professor of pathology and laboratory medicine at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar. The first author of the paper is senior research specialist Diane Carnathan, PhD, and colleagues from the Wistar Institute, Inovio Pharmaceuticals and the University of Pennsylvania contributed to the study.
Much of the work that has been done on the HIV/AIDS vaccines effort has concentrated on developing vaccines that stimulate antiviral T cells. There are two main types of T cells, defined by the molecules which are found on their surfaces. One type, CD8, is known to be a marker for so-called “killer” cells, while another, CD4, is a marker for what are known as “helper” cells. The “CD4+” T cells are known to be primary targets for HIV and SIV (simian immunodeficiency virus) infection. Other studies have suggested that “CD8+” T cells could have benefits in infection control.
Researchers in the current study immunized rhesus macaques with five different combinations of vaccines encoding SIV proteins found on the inside of the virus only. The scientists used what they termed a “reductionist approach”, an experimental strategy which examined the effects of cell-mediated immunity, without stimulating the production of neutralizing antibodies. The macaques were given an initial immunization which was then followed by two booster shots after 16 and 32 weeks. Next, the monkeys were exposed to repeated weekly low-dose intrarectal challenge with SIV. This was given up to 15 times for each animal. Results showed that this immunization regimen did not prevent SIV infection. Although all the immunized monkeys had detectable levels of circulating “killer” CD8+ T cells, the researchers found that there was no correlation between these cells and the prevention of infection.
Silvestri said that the most important finding was that the monkeys that became infected had higher levels of activated CD4+T cells in rectal biopsies before challenge. This is a major obstacle to the development an effective T-cell–based AIDS vaccine as the immunization may activate CD4+ T cells, possibly making them more susceptible to infection by HIV
“This study shows that if a vaccine induces high levels of activated CD4+ T cells in mucosal tissues, any potential protective effect of the vaccine may be hampered,” he added.
There are immense challenges facing the development of HIV vaccines. This work underlines the importance of pursuing vaccine concepts and products that elicit strong antiviral immune responses without increasing the number of CD4+ T cells in the portals of entry for the virus.