By Regina McEnery
The scientific terrain of HIV vaccine research has changed a lot in recent years, as other new preven
tion strategies have come into their own. So, as the four-day conference looks beyond 2013, its agenda will entertain a number of discussions on the possible synergies between vaccines, microbicides, and ARV-based prevention. Jointly sponsored by the Global HIV Vaccine Enterprise and HIVACAT, the Catalan Program for HIV Vaccine Development, the conference is to be held Oct. 7-10 at the International Convention Center in Barcelona.
The fate of adenovirus vector vaccine candidates is likely to dominate discussion as well, beginning with an opening night talk by Magda Sobieszczyk. An assistant professor of clinical medicine at Columbia University Medical Center, Sobieszczyk will be providing highlights and lessons learned from the HVTN 505 trial, which was recently terminated for futility (see IAVI Report blog, Large AIDS Vaccine Trial Shudders to a Halt, April 26, 2013). Duke University scientist Georgia Tomaras will provide antibody profiles from the HVTN 505 study and compare them to those from RV144, the only AIDS vaccine trial to demonstrate any measure of efficacy. In that trial, which had 16,000 participants, a combination of two vaccine candidates administered sequentially in what is called a prime-boost regimen lowered the rate of HIV infection by about 31%.
There will also be a roundtable discussion on the importance of retaining and following clinical trial participants long after the conclusion of a study, a point that became clear following the Phambili study, which was halted in 2007, and drew fresh scrutiny this year (see VAX May 2013 Global News). Finally, the HIV Vaccine Trials Network (HVTN), which sponsored the HVTN 505 trial, will provide a meta-analysis of results from vaccine trials in which adenoviruses have been used as vectors.
Another hot topic at the vaccine conference will be the burgeoning field of structure-based immunogen design. That includes a four-hour satellite session organized by The Scripps Research Institute about the structure of the HIV glycoprotein trimer—or “spike”—which the virus uses to invade its target cell. This extraordinarily complex protein, which protrudes from the surface of HIV, has long resisted structural analysis. But images of this protein complex are becoming clearer, thanks to new imaging technologies and strategies. The satellite session in Barcelona will cover the promise of this structural work—and some related controversies.
And scientists from the Military HIV Research Program are expected to present preliminary data from the RV305 trial, an immunogenicity study that began in 2012 and evaluated the impact of an additional protein boost in volunteers who participated in the RV144 trial (see VAX Sep. 2009 Spotlight article, First Evidence of Efficacy from Large-Scale AIDS Vaccine Trial).
The vaccine conference has broken some new records this year even before it has begun. More than 325 young and early career investigators applied for scholarships, and more than 600 abstracts were submitted for consideration, about 100 more than usual. About 1,000 people are expected to attend the meeting.
Barcelona also brings to a close the single-themed focus of the meeting. Starting in 2014, attendees who converge Oct. 28-31 in Cape Town, South Africa, will get a full course of microbicide and ARV-based prevention research, along with the usual dose of vaccine science the meeting has served up every year.
How does this subset of cells differ from other T cells, where do you find them, and how are they important to AIDS vaccine and cure research?
By Regina McEnery
When a new pathogen enters the body, the immune system uses a variety of defenses to get rid of it. One of the most important responses comes from B cells, which produce antibodies—roughly Y-shaped proteins—to coat the surface of the pathogen and stop the invasion. Antibodies also label the pathogen so that other immune defenses can “see” and attack it.
Other immune cells that are among the first to respond are dendritic cells and macrophages. These cells patrol the body and pick up the pathogen or its fragments. They then migrate to the lymph nodes, which are like the hubs of the immune system. Lymph nodes are a key component of the immune system, found all over the body, most prominently under the jaw, under the arms, in the gut, chest, and groin.
In the lymph nodes, patrolling cells show or “present” the pathogen to CD4+ T cells. These “helper” CD4+ T cells coordinate the activities of antibody-producing B cells and a set of “killer” cells called CD8+ T cells or cytotoxic T lymphocytes. CD4+ and CD8+ T cells work together to eliminate cells that have been infected by pathogens (SeeVAX Feb. 2004 Primer on Understanding the Immune System, Part I).
Scientists have known for quite some time now that HIV preferentially infects and kills CD4+ T cells. While the immune system tries to fight off HIV by sending CD8+ T cells to kill HIV-infected CD4+ T cells, the rapidly replicating virus eventually exhausts and overwhelms the immune system.
CD4+ T cells play a vital role in the antibody response. One of those roles is the delivery of signals that drive the maturation and selection of B cells that generate increasingly potent antibodies. This process, referred to as affinity maturation (see VAX Jan. 2011 Primer on Understanding How Broadly Neutralizing Antibodies Evolve), is critical to the evolution of potent broadly neutralizing antibodies (bNAbs), which have been shown in laboratory studies to neutralize many circulating variants of HIV. Many researchers believe a vaccine would have to elicit such antibodies to provide broad coverage against the virus.
A specialized subset of CD4+ T cells help B cells generate increasingly effective antibodies against their target pathogens. This subset is known as the T follicular helper (Tfh) cell, so named for the B-cell follicles or cavities where most Tfh cells reside. The follicles are found in germinal centers, where mature B cells proliferate and differentiate in orde
r to make antibodies.
One reason Tfh cells eluded identification for some time is that they are primarily found in these B-cell follicles, unlike most helper T cells. Nonetheless, scientists have learned quite a lot about how these elusive cells function, and how they are affected by HIV infection.
For instance, they know that Tfh cells express high levels of certain proteins that HIV uses to enter target cells, making them a major site of HIV replication. At the same time, Tfh cells also express proteins that in some instances are helpful for B-cell survival and the production of antibodies, but in others prove to be detrimental.
Additionally, scientists have identified two types of interactions between Tfh cells and B cells—one brief and on the fringes of the germinal center, the other a much longer interaction within the germinal center. In different ways, these interactions support the development of bNAbs, many of which have recently been isolated from the serum of chronically infected HIV-positive individuals.
Unfortunately, the development of bNAbs is a relatively rare event, arising in only about 15-20% of all people infected with HIV. Scientists believe one reason this may be the case is that HIV drives an abnormal expansion of Tfh cells, thus impairing their function.
Based on this accumulating data, scientists believe a better understanding of Tfh cells and their interaction with B cells could be essential to the design of an effective vaccine.
Curing HIV
Tfh cells are not just important in vaccine science, however. They are also important factors in the hunt for a cure for HIV. A relatively young subfield of HIV science, cure research is an area with lots of missing pieces. But it has lately shown great promise, thanks, in part, to what scientists have learned from 17 years of studying patients on highly active antiretroviral therapy (HAART) (see VAX March 2013 Primer on Understanding Therapeutic Vaccination).
HAART regimens potently suppress viral replication in the blood, allowing the body to rebuild its immune system. But such regimens cannot by themselves cure HIV infection, since the virus weaves itself into the chromosomes of resting CD4+ T cells, creating a population of latently infected cells known as the viral reservoir.
Scientists believe one possible way to cure HIV would be to locate and drain reservoirs of latent HIV-carrying cells. Such reservoirs persist even in people whose circulating HIV has been effectively suppressed by drugs. Scientists have been studying the blood and tissue of HIV-infected individuals—some who received HAART and others who have not—and compared them to HIV-uninfected individuals to measure Tfh populations.
Scientists believe that when the virus infects Tfh cells, it probably contributes to viral persistence because the germinal centers that house most of the Tfh cells are inaccessible to CD8+ T cells (killer T-cells), whose job it is to destroy HIV-hosting cells. These germinal centers also seem to serve as a kind of trap for HIV virus particles, which can then infiltrate the Tfh cells housed there.
Scientists are hoping to use what they have learned from these Tfh studies to design drugs that can counter HIV persistence and thus eradicate the virus.