Making a successful HIV vaccine

Sugar molecules on HIV envelope are likely target, according to TSRI

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LA JOLLA, Calif.—HIV, which can cause the fatal immune deficiency syndrome known as AIDS, infects about one million people in the United States and 35 million people worldwide. Antiviral drugs can keep AIDS in check, but do not eliminate HIV infection. There is no preventive vaccine.
Scientists at The Scripps Research Institute (TSRI) have discovered that on the HIV envelope protein, at a site important for viral function, a small group of sugar molecules—known as glycans—serve as a key “anchor” for antibodies that can broadly neutralize the virus. This finding, published in the September issue of Immunity, could accelerate efforts to develop a successful HIV vaccine. Researchers determined that future candidate vaccines would be likely to include this glycan cluster among specific viral targets to increase the likelihood of stimulating an effective antibody response.
According to the article in Immunity, “Apex broadly neutralizing HIV antibodies (bnAbs) recognize glycans and protein surface close to the 3-fold axis of the envelope (Env) trimer and are among the most potent and broad Abs described. The evolution of apex bnAbs from one donor (CAP256) has been studied in detail, and many Abs at different stages of maturation have been described. Using diverse engineering tools, we investigated the involvement of glycan recognition in the development of the CAP256.VRC26 Ab lineage.”
The article went on to say, “We found that sialic acid-bearing glycans were recognized by germline-encoded and somatically mutated residues on the Ab heavy chain. This recognition provided an ‘anchor’ for the Abs as the core protein epitope varies, prevented complete neutralization escape and eventually led to broadening of the response. These findings illustrate how glycan-specific maturation enables a human Ab to cope with pathogen escape mechanisms and will aid in optimization of immunization strategies to induce V2 apex bnAb responses.”
The research is part of a broad reverse-engineering effort by scientists around the world to use antibodies isolated from HIV-infected people to develop a successful vaccine. It is a departure from traditional vaccine designs that have been developed and tested against HIV in vulnerable populations since the mid-1980s without success. The HIV virus is challenging, because it has hundreds of thousands of different strains. Because traditional vaccines generally attack only one strain of the virus, they are typically ineffective.
According to principal investigator Dennis R. Burton, professor of immunology and microbiology at TSRI, “We learned in this study that grabbing hold of these glycans can be a very important early step in an effective immune response to HIV, and with this knowledge, we believe we can design better candidate vaccines.”
In the study, TSRI scientists concentrated on an especially potent family of bnAbs, known as VRC26, which were isolated several years ago from blood obtained in South Africa from an HIV-infected person. VRC26 antibodies neutralize HIV by fastening to a region of the viral envelope protein known as the V2 apex, preventing the viral envelope structure from changing its shape to allow for infection of host cells. VRC26 antibodies bind specifically to a viral protein sequence, as well as to two nearby glycans. Because the immune system cannot produce the antibodies right after vaccination, it is difficult to reverse-engineer an HIV vaccine from bnAbs, such as VRC26. A person’s initial pool of B cells may include some that bind weakly to the same V2 apex target on HIV. After engaging the target and adjusting their antigen receptors over many generations this lineage of cells can produce VRC26 bnAbs. A successful vaccine has to stimulate the first B cells in this lineage and then evolve them until they have changed sufficiently to provide effective protection against HIV.
Analyzing how B cells in the VRC26 lineage changed in CAP256’s blood in the course of HIV infection, Raiees Andrabi, a postdoctoral research associate in the Burton Laboratory, explained, “These glycans essentially provided an ‘anchor’ for antibodies in this lineage as the surrounding viral proteins changed. The virus therefore couldn’t escape, and ultimately, as the VRC26 B cells evolved, their antibodies became more and more broadly neutralizing.”
In determining that the V2 apex glycans are important for VRC26 bnAb development, TSRI concluded that vaccines targeting this region should elicit antibodies that bind to these glycans. According to Andrabi, “Maturation of antibody-producing B cells along this glycan-related pathway may be critical for the induction of an effective VRC26 response through vaccination.”
“The proof will come when we test new designs in immunization experiments,” Burton concluded.

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