IgA antibodies are better than IgG at protecting macaques from mucosal challenge

We know that most cases of HIV transmission occur at the mucosal surfaces of the genitals or the rectum (seeThe Great Barrier, IAVI Report, Mar.-Apr. 2008). What we know less about is the types of antibodies that are best at blocking the virus at those surfaces. Studies have shown that antibodies belonging to a class called IgG1 play a role: passive infusion of such broadly neutralizing anti-HIV antibodies into the blood can protect animals from mucosal challenge. 

But antibodies of another class known as IgA are also common at mucosal surfaces. Now, researchers led by Ruth Ruprecht of Harvard Medical School report for the first time that rectally applied IgA antibodies not only protect primates from rectal challenge with a simian immunodeficiency virus (SIV)/HIV hybrid, or SHIV, but do so better than IgG (AIDS 2013, doi: 10.1097/QAD.0b013e328360eac6). 

The researchers made an IgG1 version of a human broadly neutralizing antibody called HGN194, along with two dimeric IgA versions called dimeric IgA1 (dIgA1) and dimeric IgA2 (dIgA2). They applied the antibodies in the rectum of different rhesus macaques and rectally challenged the animals 30 minutes later with SHIV-1157ipEL-p. This version of SHIV carries an HIV clade C Envelope that was isolated from an African infant six months after it acquired infection. 

They found that the dIgA1 version of HGN194 protected the animals better than dIgA2 and IgG1: Five out of the six animals treated with the dIgA1 version remained uninfected. In contrast, only one of the six dIgA2-treated animals and two of the six IgG1-treated animals remained virus free. All 11 untreated animals got infected. 

The better protection observed in the dIgA1-treated animals initially puzzled the researchers because all three HGN194 versions neutralized the challenge virus equally well. But then their studies hinted at an explanation: The dIgA1 version could bind twice as many virus particles as the dIgA2 version. “That was a Eureka moment,” Ruprecht says, adding that the dIgA1 version can bind more virions because of its shape. Its antigen binding sites, which are located at the end of the arms of the “Y” of the antibody molecule, are further apart from each other than the antigen binding sites of dIgA2. As a result, dIgA1 can accommodate four viruses between its antigen binding sites, while dIgA2 can only accommodate two. 

This also explains why dIgA1 fared best in another experiment: In contrast to dIgA2 and IgG1, only dIgA1 was able to keep most HIV particles from crossing a cultured epithelial cell layer in a so-called “transcytosis” assay, which simulates the crossing of HIV through the kind of epithelial cell layer found at mucosal surfaces. 

These results suggest that vaccine developers should try to find vaccines that can coax the body’s immune system to produce mucosal HIV-specific dimeric and multimeric IgA1 antibodies, says Ruprecht. Such antibodies don’t necessarily have to be neutralizing, because it was dIgA1’s ability to bind more HIV particles—not to better neutralize the virus—that was responsible for the better protection by dIgA1 in the study.

“The very next question is, how can you best induce these types of protective mucosal responses?” says Ruprecht.