HIV can be transmitted as a free particle, or from cell to cell, for example between CD4+ T cells, through so-called virological synapses. One question is why HIV particles are budding preferentially in such synapses. At today’s session on retroviral entry mechanisms, Clare Jolly from the University College London reported that the reason seems to be that the cell-cell contact induces polarization of the infected donor cell, in that the microtubule organizing center migrates towards the site of cell-cell contact. This suggests that HIV proteins probably migrate along microtubules towards the virological synapse, which could explain why HIV particles preferentially bud there.
This year’s Keystone meeting on HIV Pathogenesis, Therapy and Eradication, which takes place in Whistler, British Columbia from March 26-31, is held jointly with a meeting on Virus Entry, Replication and Pathogenesis, which includes discussion of many viruses other than HIV. The idea of this combination is to strengthen the interaction between HIV researchers and researchers who work on viruses other than HIV, said Michael Farzan, a virologist from Harvard Medical School and one of the organizers of the Virus Entry, Replication and Pathogenesis track. “I hope that what will happen is that more than usual, ideas from virology go to HIV virology, and ideas from HIV virology go to the more conventional virology,” Farzan said, “because HIV researchers frequently reinvent wheels that other virologists have done, but on the other hand HIV is also frequently ahead because [it is] the most studied virus.”
The detrimental effects of chronic immune activation, which is the result of HIV infection, have become increasingly clear. Structural damage to the gut is thought to contribute to this immune activation because of microbial translocation—the leakage of endotoxins and other microbial products across the gastrointestinal barrier and into systemic circulation—but the precise mechanisms driving immune activation, and ways to alleviate among HIV-infected individuals is still not clear.
CD4+ T cells are central players in the body’s immune response. Often called “helper” cells, they orchestrate the assault on invading pathogens: They stimulate the development of antibodies in B cells, and send signals to CD8+ T cells, which detect and kill other infected cells, to make them better killers and to form memory cells. But CD4+ T cells are also the primary targets of HIV, which is why they are not believed to play a leading role in controlling infection by that virus. Instead, CD8+ T cells are thought to be the primary agents of HIV suppression, deploying so-called “death” molecules such as perforin, which pops open infected cells, and granzyme B, which forces them to commit suicide.
Highly active antiretroviral therapy, or HAART, typically combines three antiretroviral drugs (ARVs) as a first line treatment for HIV infection. It is a very effective way to keep HIV replication under control. So effective, in fact, that the best drug combinations suppress HIV to undetectable levels in most patients.
When you have studied HIV’s structure as long as Dennis Burton has, the search for metaphors to describe its unusual architecture becomes irresistible. And so it was that Burton opened his March 22 Keystone Symposia talk by equating the honeycomb of glycans that cover much of HIV’s Envelope protein as HIV’s sweet spot. (Some of us immediately reached for the bowl of candy.)
The Keystone Symposia’s annual meeting on HIV Vaccines, held jointly this year with a meeting on Viral Immunity and Host Gene Influence, kicked off March 21 in Keystone, Colorado, with a keynote about hepatitis A and hepatitis C that could well have been entitled, “A Tale of Two Viruses.”
If you work on vaccines you know the story of British physician Edward Jenner, whose observation that dairymaids infected with cowpox made them resistant to the far more virulent smallpox virus led him to develop, in 1796, the first experimental vaccine. Jenner’s strategy sounded simple: He inoculated an eight-year-old boy with pus scraped from the cowpox blisters of one of those milkmaids and then inoculated the child six weeks later with matter from a fresh smallpox lesion to prove his hypothesis.
The latest issue of IAVI Report is online. Among other things, it features articles on new developments in HIV cure research, recent studies that show promise but also possible pitfalls of using adenovirus vectors in HIV vaccine candidates, and the funding crisis at the Global Fund to Fight AIDS, Tuberculosis and Malaria.
The underperformance of orally administered enteric vaccines in developing countries was the main topic of discussion today, the last day of the conference. In principle, this underperformance can be addressed by delivering vaccines through different routes. However, conventional intramuscular or subcutaneous immunizations often only induce weak immune responses in the gut where the infection occurs, and therefore protect only weakly against enteropathogens on the mucosal surface.
All of the licensed influenza vaccines and most of the candidates in clinical or pre-clinical development target the hemagluttinen (HA) antigen on the surface of the virus. This is partly because induction of antibodies against HA is a correlate of immune-mediated protection against influenza, making the surface protein a logical target for the production and quality assessment of vaccines.
One question that keeps coming up at the meeting here is the paradox that compared with developed countries, some oral vaccines are less efficient in malnourished children in developing countries, even though such children show an overstimulation of their immune system in the gut.
For the past 50 years, vaccine manufacturers in the United States have used egg-based technology to develop the seasonal influenza vaccine, and they might have stuck to this method were it not for the emergence of the H5N1 virus in Asia. Since its appearance in the mid-1990s, the highly pathogenic strain of influenza, which jumped directly from birds to humans, has resulted in 500 cases and 300 deaths.
Bacterial infections of the gut are one reason children in the developing world are malnourished, and malnourishment can lead to a poorer response to oral vaccines. One way to protect from the effects of such infections is to add probiotic bacteria to food, but scientists are just beginning to learn how such bacteria actually protect. Today, Shinji Fukuda from the RIKEN Institute in Yokohama, Japan, reported that he and his colleagues showed how a certain type of probiotic bacteria called Bifidobacterium that can be found in yoghurt can protect mice from dying from an otherwise lethal Escherichia coli (E. coli) infection (Nature 469, 543, 2011).
Compared with children in developed countries, children in the developing world show a poorer response to oral vaccines (such as oral polio vaccine), whereas their response to vaccines that are administered systemically by injection (such as measles vaccine) doesn’t appear to be much different.
A healthy gut and good nutrition are important for a healthy immune system and a good immune response to vaccination, so it is not surprising that vaccines have been found to be less efficient in malnourished children. Still, “surprisingly little” is known about the impact nutrition has on the mucosal immune system of the digestive tract, according to the organizers of the Keystone Symposium on Malnutrition, Gut-Microbial Interactions and Mucosal Immunity to Vaccines, which is taking place in New Delhi Nov. 7-11. The meeting focuses on the role nutrition plays in gut immunity, knowledge of which could lead to the development of better vaccines for malnourished children.
This year’s 29th Annual Symposium on Nonhuman Primate (NHP) Models for AIDS, which takes place from October 25-28 in Seattle, has about 50% more registrants than last year, and the number of international registrants has doubled, said David Anderson, conference chair and director of the Washington National Primate Research Center. It could be the beautiful location, but Anderson said part of the reason is that NHP research is becoming more collaborative. “I think part of why we have an increase in attendance this year is because science is getting bigger, more complex and getting characterized by partnerships,” he said, adding that one example is systems biology which involves “pulling people from a lot of different areas together.”
Thomas Hope of Northwestern University started today’s meeting with a talk about his studies of how fluorescently labeled HIV particles enter the mucosal barrier of the macaque reproductive tract. One important topic is to study if and how the menstrual cycle affects this process, Hope said. “[This is] becoming an interesting and important topic that many groups need to consider in prevention science and pathogenesis and transmission,” he said.
The numerous discoveries of potent broadly neutralizing antibodies against HIV that have occurred in the last two years suggest that the human immune system is capable of making such antibodies against the virus more routinely than originally thought. This has made researchers more optimistic about the possibility of inducing antibodies that are capable of neutralizing a wide array of HIV strains at low concentrations. However, whether or not these antibodies, if induced by a vaccine, will actually protect humans against HIV infection is still an open question. And because there are no vaccine candidates yet that can induce these broadly neutralizing antibodies, researchers are instead planning to evaluate the protective efficacy of these antibodies in passive immunization studies.
All of the recently identified broadly neutralizing antibodies against HIV have been isolated from chronically HIV-infected volunteers. In a presentation at AIDS Vaccine 2011, Penny Moore of the National Institute of Communicable Diseases in Johannesburg, South Africa, addressed the question of whether the epitopes that are the targets of these broadly neutralizing antibodies that develop later in the course of infection are present in the transmitted founder virus that establishes infection.