HIV's Sweet Spot

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.)

Burton, a professor of immunology and microbial science at The Scripps Research Institute in La Jolla and the director of IAVI’s Neutralizing Antibody Center, which is based at Scripps, devoted his 30-minute talk recapping work on a subset of broadly neutralizing antibodies (bNAbs) that specifically target the regions of HIV’s Envelope that make up the so-called glycan shield because the sugars protect much of the Envelope surface, including conserved regions.

“We’re developing sweet solutions to sticky situations,” said Burton. “There, see, I couldn’t resist.”

About a year ago, Burton’s lab isolated a family of monoclonal bNAbs known as PGTs that are glycan-dependent. The antibodies were found in the serum of four individuals who are part of IAVI’s cohort of chronically HIV-infected individuals that also yielded in recent years other potent bNAbs, including PG9 and PG16. Scientists subsequently crystallized a section of one of the PGT antibodies known as 128. The antibody was shown to engage two glycans and part of the V3 loop, which the virus needs to bind to receptors and infect cells (see A Bangkok Surprise, IAVI Report, Sep.-Oct. 2011).

Burton noted that the glycans targeted by these PGT antibodies are in a conserved region known as the high mannose patch, and that the antibodies appear to be able to reach through the glycans to make contact with the protein surface underneath. “For the CD4 binding site, it is clear you have to have quite a precise angle of approach,” noted Burton. “This does not seem to apply to the glycan shield. The virus has not made glycans so dense as to evade antibody recognition.”

The End of the Beginning

Gary Nabel, director of the Vaccine Research Center (VRC) at the US National Institute of Allergy and Infectious Diseases (NIAID), immediately followed Burton’s talk with a recap on work being conducted by his lab and others at the VRC in structure-assisted design of HIV immunogens.

He described the discovery and elucidation of a growing arsenal of monoclonal bNAbs—he suggests there are at least 100 now—as tremendous tools. As he was preparing his talk, Nabel said he was reminded of the famous quote by British Prime Minister Sir Winston Churchill following the Allied victory at the Second Battle of El Alamein in 1942 in North Africa: “This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.”

Nabel said the structure-assisted design of HIV immunogens at the VRC is primarily focused on the CD4 binding site—the focus of the highly potent VRC01 bNAb, so much of the work by researchers at the VRC has been focused on altering or modifying parts of the HIV Envelope trimer that prevent antibodies from binding to this region. Nabel said plans are also underway to conduct passive immunization trials in infants and adults.

A bNAb’s novel target

While most of the bNAbs discovered in recent years target the CD4 binding site, Jinghe Huang, a researcher in the laboratory of Mark Connors, chief of the HIV-specific immunity section at NIAID, detailed the isolation of a new bNAb from a chronically HIV-infected individual that was later determined to target the membrane-proximal external region (MPER) that lies at the base of HIV’s Envelope trimer jutting from the virus’ surface. This is not the first bNAb to target this region of the virus. But unlike those other bNAbs that target MPER—such as 4E10 or Z13—Huang noted that this new bNAb, which is called 10E8, exhibits novel binding characteristics. She said mapping studies found that the 10E8 epitope overlaps both of the known 4E10 and Z13 epitopes. She also noted that the 10E8 epitope was resistant to washing, meaning that it remained bound to the antibody, and that it did not bind to phospholipids, which can interfere with antibody binding. The 10E8 antibody was also found to have greater breadth and potency than other MPER neutralizing antibodies.

The genetic bottleneck

Designing and developing an AIDS vaccine capable of overcoming HIV’s astonishing degree of viral diversity remains one of the biggest challenges of modern-day science. One of the ways researchers have been attempting to reach this goal is by studying the virus that is transmitted and establishes infection during sexual transmission—which accounts for the majority of HIV infections globally.

It is thought that in heterosexual transmission, a single virus leads to infection about 80% of the time despite the fact that the transmitting partners have multiple HIV variants circulating in their bodies. Researchers believe this is due to a bottleneck during HIV transmission that allows only the fittest viruses to get through and establish infection.

But there is still much that isn’t known about these transmitted and early founder viruses and so some researchers have been focusing more on the use of next-generation sequencing technology, notably 454 sequencing methods, to better characterize them. An early morning talk March 22 by Ragon Institute researcher Damien Tully detailed how the use of 454 sequencing revealed the entire viral genome of 35 clade B transmitted early founder viruses from a cohort of men who have sex with men. Tully said the analysis combined two different algorithms that, he said, improved the sensitivity of the findings and gave them a deeper image of acute HIV infection. Their results show that in the majority of cases analyzed from the MSM cohort, a single variant was responsible for infection, but about 15 percent of the infections were the result of at least two viruses. They also found that four of the infections were caused by variants that used the less common CXCR4 when infecting cells.