In Brief

New Global Goals and Guidelines Aim to Eliminate AIDS

September was a busy and ambitious time for global health. In less than a week’s time, three organizations took bold steps intended to slow the spread of AIDS, if not end it entirely.

On September 25, the United Nations General Assembly (UNGA) adopted a sweeping set of 17 Sustainable Development Goals (SDGs), one of which relates to health and aims to end AIDS, tuberculosis, malaria, and neglected tropical diseases by 2030. These broad and ambitious goals, which also aim to end hunger and poverty and combat climate change among other things, replace the soon-to-expire millennium development goals (MDGs) that were adopted in 2000 with a 15-year span.

Two days after the SDGs were endorsed by the UNGA, US President Barack Obama urged world leaders to support the SDGs and announced plans to expand the HIV/AIDS treatment and prevention goals for the President’s Emergency Plan for AIDS Relief (PEPFAR). The US government has already invested US$65 billion in PEPFAR, which now supports antiretroviral therapy (ARV) for about 7.7 million HIV-infected individuals in developing countries. By the end of 2017, PEPFAR plans to support ARV therapy for nearly 13 million HIV-infected individuals in its target countries—almost double the current number. PEPFAR also plans to provide 13 million adult male circumcisions to prevent new HIV infections, and to reduce HIV incidence by 40% among adolescent girls and young women in 10 sub-Saharan African countries with the greatest HIV infection rates by reallocating $300 million of current funding that was secured from improved program efficiencies. “An AIDS-free generation. This is not a distant dream—it is the extraordinary moment before us right now,” said Ambassador Deborah Birx, the US Global AIDS Coordinator who oversees PEPFAR, in a statement.

Capping these announcements, the World Health Organization (WHO) issued revised guidelines on September 30 for HIV treatment and prevention. The updated guidelines call for all HIV-infected individuals to start ARV therapy as soon as possible after their infection is discovered. The guidelines also recommend that high-risk, HIV-uninfected individuals be offered ARVs as a means of HIV prevention, a practice known as pre-exposure prophylaxis (PrEP). Previous guidelines were more limited for both treatment and prevention; viral load determined who received ARV therapy, and PrEP was recommended only for men who have sex with men.

Mitchell Warren, executive director of the global AIDS advocacy organization AVAC, who has been working in the AIDS field for 25 years, says we are entering the most exciting time in HIV science and policy. “But as exciting as the new goals and guidelines are, the gap of where we are and where we need to be is larger than ever,” he acknowledges.

Chris Beyrer, a professor at Johns Hopkins Bloomberg School of Public Health and President of the International AIDS Society, considers the SDGs bold and visionary. “My only concern is that on health, they are very broad, and it may prove that they are too broad and general to serve as foci for advocacy, including around HIV/AIDS,” said Beyrer. “The power of the MDGs was at least in part their specificity.  The SDGS may be harder to advocate around.”

And advocacy will likely be key, given the high price tag that accompanies achieving these goals. Governments, foundations, and public-private partnerships are already investing close to $19 billion a year in programs that provide ARVs in developing countries, and a recent report released by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and Lancet Commission estimates it will cost $36 billion annually to end AIDS by 2030.

If anything, the HIV-related MDGs, which called for halting the spread of HIV/AIDS by 2015 and achieving universal access to ARV treatment for all in need by 2010, illustrate how difficult it can be to reach the finish line. Earlier this year, UNAIDS reported that new infections have declined 35% and 15 million people in developing countries are now receiving ARV therapy. Yet ARV coverage still only accounted for about 41% of the 36 million people estimated to be living with HIV/AIDS, far short of universal access.

Still, Warren remains optimistic. He recalls the 2000 International AIDS Conference in Durban, South Africa, when doubts remained about whether there was enough money to fund ARV treatment outside the US and Europe. “Look what happened,” he said. “Fifteen years later we have 15 million people on ARVs. In 2000, it was zero. The world can change.” —Mary Rushton

Entering the Dark Zone: Scientists Recap Advances and Gaps in Understanding Germinal Center Dynamics

“We don’t know much,” said Barton Haynes, director of the Human Vaccine Institute at the Duke University School of Medicine and a director of the Center for HIV-AIDS Vaccine Immunology. Haynes was referring to the lack of knowledge researchers have about the complex processes and reactions that take place in germinal centers during the induction of broadly neutralizing antibodies (bNAbs) against HIV. Although they may not know much now, this topic is of growing interest.

On August 28, the US National Institute of Allergy and Infectious Diseases (NIAID) held a meeting to discuss the role germinal centers play in antibody maturation, and what strategies researchers can use to exploit this process to further HIV vaccine design and development. The meeting, “Germinal Center Dynamics and Antibody Affinity Maturation for Protective Immunity,” was open only to invited guests but was recapped at a webinar sponsored by the Global HIV Vaccine Enterprise on September 25. The main goals of the NIAID consultation were to identify gaps in knowledge, missing technologies, high-priority issues that need to be addressed by the HIV vaccine field, opportunities to promote multi-disciplinary basic immunology research, and suggestions for funders for short and long-range plans—what Shane Crotty, a professor in the vaccine discovery division of the La Jolla Institute for Allergy and Immunology and a panelist at the webinar, called “an ambitious but appropriate wish list.”

Germinal centers are unique structures that form within peripheral lymphoid organs, including lymph nodes and the spleen, where activated B cells proliferate and diversify. It is in germinal centers that B cells undergo ongoing rounds of genetic mutation of the cell’s variable region through a process known as somatic hypermutation. This is followed by the affinity selection process in which the mutated cells compete for binding to antigen. The end result of this two-step affinity maturation process is survival of B cells with the greatest affinity for the antigen (see Figure, this page). Germinal centers are also where mature B cells interact with follicular helper T (Tfh) cells—a specialized subset of CD4+ T cells that play a critical role in the selection and survival of B cells and their differentiation into either plasma cells capable of secreting antibodies, or memory B cells that are a vital component of the desired immune response to vaccination. Tfh cells were only identified as a distinct type of T helper cell little more than a decade ago, but since then have become a burgeoning topic of study. These cells play an important role in germinal centers. “Tfh cells are required for germinal centers and therefore the bulk of B-cell memory as well as affinity matured antibody responses,” said Crotty. While HIV vaccine researchers may not know precisely how antibody maturation in germinal centers unfolds, they know it is terribly important.

Inside Germinal Centers

Naive B cells activated by an antigen travel to lymph nodes and the spleen where, together with helper T cells, they establish special structures called germinal centers (GC), pictured in the simplified schematic below. Within germinal centers, B cells multiply and undergo a process known as affinity maturation. Affinity maturation involves ongoing alternating rounds of somatic hypermutation (SHM), during which genetic mutations are introduced into the antibody gene of each cell, and affinity selection—a process through which the somatically mutated B cells compete with each other to bind with antigen that is presented on follicular dendritic cells (FDCs) and to receive signals from follicular T helper (Tfh) cells. Somatic hypermutation occurs in the dark zone of the germinal center, while affinity selection occurs in the light zone. The process of affinity maturation is “still an incredibly active area of research,” said Michael McHeyzer-Williams, a professor at The Scripps Research Institute in La Jolla, CA. If the affinity of the somatically mutated B cell for antigen is weak, the cells will undergo apoptosis. B cells with the highest affinity for the antigen presented on FDCs then either re-enter the dark zone where they will undergo further rounds of expansion and somatic hypermutation, or exit the germinal center either as antibody-secreting plasma cells or as long-lived memory B cells. Researchers are now focusing on how this cycle can be manipulated to enhance the protection afforded by vaccines. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology, copyright 2014.

 

One major goal of HIV vaccine research today is determining what vaccine immunogens will induce antibodies that can neutralize a broad swath of the diverse strains of HIV in circulation, so-called bNAbs. Development of bNAbs is not favored—only a minority of HIV-infected individuals develop them and only after exposure to a rapidly evolving virus. “In every individual we’ve studied, the prerequisite for bNAb breadth is extraordinary virus diversification,” said Haynes.

After isolating and closely studying what now amounts to more than 200 bNAbs against HIV, researchers realize that these antibodies are not just rare, they are unique. For one thing, these antibodies are almost all highly somatically mutated. To achieve this extensive level of somatic mutation, bNAb development must require optimized germinal center responses, according to Crotty. Given this, researchers are increasingly focusing on developing strategies to enhance germinal center dynamics to improve bNAb maturation. One area of investigation is how Tfh cells may enhance somatic hypermutation. Another is how adjuvants may drive germinal center dynamics. According to Haynes there is evidence from animal models that toll-like receptor (TLR) agonists can directly stimulate B cells. Data also indicate that Alum, an aluminum salt adjuvant that is the most widely used in vaccines, drives a slower accumulation of B-cell mutations than TLR agonists.

One hindrance to studying these processes is the difficulty in accessing germinal centers. In some ways when it comes to understanding the complex immune system interactions that occur here, scientists are groping in the dark. Hidden within lymph nodes, these compartments can only be analyzed by biopsy. Their location in germinal centers is one reason it took so long for Tfh cells to be classified. In non-human primates, researchers are now using a type of biopsy procedure referred to as fine-needle aspirates to study the immune responses that occur in response to different antigens.

Despite major gaps in understanding how germinal center reactions occur, “this has been a fantastically successful field of study over the past six years,” said Crotty. He will serve as a scientific organizer of an upcoming Keystone Symposia on “T Follicular Helper Cells and Germinal Centers,” which will be held from February 26 to March 1, 2016, in Monterey, CA; evidence of the topic’s growing research prominence. —Kristen Jill Kresge