Neutralizing HIV Tat specific antibodies might be involved in protection

When talk turns to the kind of neutralizing antibodies that can prevent HIV infection, it always revolves around one and just one HIV protein: the Envelope (Env) protein that forms the viral spike. That’s because Env is thought to be the only protein HIV carries on its surface, exposed to antibody targeting. 

But a recent study led by Ruth Ruprecht at Harvard Medical School suggests that antibodies to the HIV protein Tat might also be involved in protection (J. Virol. 2013, doi:10.1128/JVI.02888-12). The researchers studied rhesus macaques they had immunized by intramuscular injection of a vaccine that contained the SIV proteins Gag and Pol, and HIV-1 Env and Tat. They then challenged the animals with an SIV/HIV hybrid virus (SHIV) that contained these same proteins except for Env which had been derived from a different HIV strain. After five low-dose rectal challenges, most unvaccinated animals got infected, while four of the 12 vaccinated animals remained virus free. 

In a previous study of the same animals, they had reported that the protected animals differed from the ones that were not protected in that they had higher titers of neutralizing antibodies as well as cellular immune responses to Gag and Tat (PLoS One 6, e22010, 2011). 

To see how the vaccinated animals that were protected differed from the ones that were infected, the researchers used an unbiased approach in the new study: They mixed the serum of the animals with a library of phages that carried billions of different random peptides on their surface. They then isolated the phages that only bound to the antigen binding sites of antibodies in the serum of the protected, but not the unprotected, animals. 

As expected, they found that some of these phages carried Env-related peptides. But they also found peptides that were identical to parts of HIV Tat that are known to be the target of antibodies that neutralize Tat activity. This suggests that neutralizing antibodies (NAbs) to Tat were in part responsible for the protection of these macaques. 

One suggestion for a possible mechanism, Ruprecht says, comes from a study published late last year, which reported that HIV particles carry Tat molecules on their Env spikes, and that these Tat molecules enter the target cell together with Env. Once inside the cell, the study’s authors argued, it jump starts the replication of HIV genes (PLoS One 7, e48781, 2012). So Tat-specific NAbs might attach to Tat before the virus enters a target cell and keep Tat from doing its job after HIV has made its way inside.

For Ruprecht, the message of the study for vaccine development is clear: Include Tat in a vaccine, she says, adding that the vaccine she used to immunize the macaques induced cellular immune responses to Tat as well. “You get two for one,” she says.