LA JOLLA, Calif.—The Scripps Research Institute (TSRI) has had a very productive spring in the field of HIV research, having announced a trio of important advancements and discoveries over the course of two months: a method of “fingerprinting” the shield around the HIV virus, a way of linking antibodies to immune cells that could offer a potential cure and an immunogen that successfully triggered the immune system of non-human primates to produce HIV antibodies.
HIV is an extremely complicated virus, capable of mutating to avoid destruction and of maintaining reservoirs in the body that can allow the virus to recur after seemingly having been in remission. In addition, it also uses glycans, sugar molecules, as a shield to avoid detection and attacks from the immune system. The immune system seeks to produce antibodies to bind to the glycoprotein and stop infection, but the glycans block immune cells. A new “fingerprinting” method allows researchers to analyze the glycan shield on HIV’s outer glycoprotein, as well as opening up a path as a possible candidate for an HIV vaccine.
In this particular effort, the scientists engineered a method for determining the composition of sugars on the glycoprotein, then broke it down with enzymes into smaller peptide chunks. Mass spectrometry was then used to analyze the peptides and determine whether they were high-mannose glycans (a type with a specific kind of sugar), complex-type glycans (more mature glycans) or sites with no glycans. This new method is faster and also was reportedly the first time researchers could see glycan-free sites.
TSRI teams are working to design HIV vaccines that trigger the immune system to create broadly neutralizing antibodies that can get around the glycan shield, and do so by introducing the immune system to HIV-like glycoproteins and teaching it to find holes in the shield. Being able to essentially fingerprint the glycoprotein will make it possible to determine which types of glycans the glycoprotein is comprised of and whether it has any areas vulnerable to attack.
Less than two weeks later, TSRI announced that one of its teams had developed a possible cure: a way to link HIV-fighting antibodies to immune cells, thereby generating a cell population that is resistant to the virus. Tests in the lab demonstrated that the resistant cells can rapidly replace diseased ones, offering a potential method to eliminate HIV infection rather than simply manage it. The team in question—led by study senior author Dr. Richard Lerner, Lita Annenberg Hazen Professor of Immunochemistry at TSRI—intends to work together with a team from City of Hope’s Center for Gene Therapy to evaluate the therapy’s safety and efficacy.
HIV infection occurs when the virus binds with cell surface receptor CD4, so the researchers searched for antibodies that could protect the receptor on immune cells normally killed by HIV. It proved successful—when cells were introduced to the virus, it produced an HIV-resistant population, since the antibodies recognized the CD4 binding site and blocked HIV from linking with the receptor.
The new TSRI technique is said to offer a significant advantage over therapies where antibodies float freely in the bloodstream at a relatively low concentration. Instead, antibodies in the new study hang on to a cell’s surface, blocking HIV from accessing a crucial cell receptor and spreading infection.
Jia Xie, senior staff scientist at TSRI and first author of the study published in the journal Proceedings of the National Academy of Sciences, called it the “neighbor effect.” An antibody stuck nearby is more effective than having many antibodies floating throughout the bloodstream, he says, noting “You don’t need to have so many molecules on one cell to be effective.”
“HIV is treatable but not curable—this remains a disease that causes a lot of suffering,” said Dr. Joseph Alvarnas, director of Value-Based Analytics at City of Hope. “That makes the case for why these technologies are so important.”
Finally, in its latest vaccine-related efforts, TSRI has used previously defined structures of the envelope glycoprotein to engineer a mimic of the viral protein from the subtype C of HIV, which causes the majority of infections globally. This work was published with a second study in Immunity, led by a team at the Karolinska Institute in Stockholm, which demonstrated that the vaccine candidate developed in TSRI’s study is capable of eliciting neutralizing antibodies in non-human primates.
The most common strains of HIV are clades A, B and C. Similar to a flu vaccine, any eventual HIV vaccine will need to inoculate against multiple strains, which will require a cocktail or sequence of such protein mimics, or immunogens.
“Clade C is the most common subtype of HIV in sub-Saharan Africa and India,” explained study co-first author Javier Guenaga, an International AIDS Vaccine Initiative collaborator working at TSRI. “Clade C HIV strains are responsible for the majority of infections worldwide.”
In addition to being the most common, this strain’s envelope glycoprotein is also particularly unstable and the molecules have a tendency to fall apart. Overcoming that issue was complicated, but finally yielded a map of the clade C glycoprotein.
“Despite all the engineering employed to produce a stable clade C protein, these crystals (of clade C protein) were grown in very challenging conditions at 4 degrees Celsius and it took the diffraction of multiple crystals to generate a complete dataset, as they showed high sensitivity to radiation damage,” said co-author Fernando Garces. “Altogether, this highlights the tremendous effort made by the team in order to make available the molecular architecture of this very important immunogen.”
The companion study with the Karolinska Institute team used an immunogen based on Guenaga’s work; when administered to non-human primates, it successfully incited the immune system to produce antibodies that neutralized the clade C HIV strain.
“That was great to see,” said Guenaga. “This study showed that the immunogens we made are not artificial molecules—these are actually relevant for protecting against HIV in the real world.”