Scripps Research Institute scientists have come up with a novel two-punch strategy to combat HIV at the earliest stage of infection.
This unique process is based on latest viral discoveries and scientists have already successfully tested aspects of it in the laboratory. According to the authors of the study, this discovery may reinstate attempts for developing a preventive/therapeutic vaccine against HIV.
More than a dozen candidate vaccines, which have tried to raise immunity against the spiky proteins on the viral envelope, have not
succeeded in clinical testing, till date.
The team of researchers led by Chi-Huey Wong, Scripps Research Chemistry Professor, have created devices known as glycodendrons,
designed to do two things at once: inhibit the transport of HIV from where it traditionally enters the body, preventing it from moving deeper inside where it can infect immune cells; and set up an immune antibody response to a unique carbohydrate structure on the surface of the virus.
"This paper is about a new direction in HIV vaccine design. Results we have so far are very promising," said Wong.
He said that till date, the devices have been able to stimulate the immune system of mice to induce antibodies against HIV surface
glycoprotein, and, in laboratory studies, have been able to block the virus from infecting immune cells.
The new strategy is based on two recent findings in the field of HIV research: First is the discovery that HIV takes a Trojan horse
approach to reach cells it needs to infect deep inside the human body.
It has been explained by some researchers that when the virus enters the body through sexual contact, it steers clear of being interrupted by the dendritic cells of the immune system that stand guard for
invaders at the mucosal lining of tissues. However, the virus fools these cells, and attaches to a particular receptor protein, known as DC-SIGN, on the dendritic cells. In this way, HIV manages to evade immune detection while the dendritic cells travel to the ultimate goal of the virus: immune T-Cells in the lymphoid system, which is later infected by HIV, setting up a deadly infection that spreads.
The second discovery is that there's an antibody that is able to signal immune destruction of the virus. On of the study's first author, Sheng-Kai Wang, a graduate student in Wong's laboratory has said that
this antibody, 2G12, protects people who have it against HIV progression, but there are very few of those who are infected put up such an immune reaction.
The researchers have defined the details of the action of the antibody and found that it recognizes a dense cluster if sugars on one region of the virus's spiky protein coating, which is, strikingly, the same area that HIV uses to bind to the DC-SIGN protein on dendritic cells.
Previously, the researchers designed and tested synthetic constructs to mimic the clusters of sugars recognized by 2G12 that could form a vaccine. They invented a process called programmable one-pot synthesis that made it possible for them to quickly assemble many types of
carbohydrate structures by placing a large number of chemical building blocks into a reaction vessel to make sequential chemical reactions.
Thus, the Scripps Research team built a dendron structure that can bind to the DC-SIGN protein, preventing HIV from doing so, and which also mimics the sugar clusters that 2G12 binds to, prompting the immune system to produce destructive antibodies to the viral coat.
"The sugar structure is able to inhibit HIV from
binding to DC-SIGN on dendritic cells in vitro. But to become a vaccine, as
tested in mice, the sugar structure has to be attached to a carrier as the
sugar structure alone is too small and too weak to be used as a vaccine. The
sugar-carrier conjugate will also inhibit HIV from binding to DC-SIGN,"
The study is
published in a recent issue of the online Early Edition of the Proceedings of
the National Academy of Sciences (PNAS).