A study from a Massachusetts General Hospital (MGH) research team has identified the specific function of a protein found in HIV and related viruses that appears to slow down viral spread in the earliest stages of infection. But they also found that, after initially slowing down the spread of infection, that function may help the virus survive later on by evading the immune response. Their report has been published in Cell Host & Microbe.
"Our investigation identified a particular function of the protein Nef as responsible for disrupting the ability of infected T cells to migrate, slowing the rate at which the virus initially spreads after infection. However, that same function allowed the virus to persist at a later time when the adaptive immune response has become activated." says Thorsten Mempel.
Nef help HIV evade the immune response
These findings suggest that this function of Nef evolved to help HIV evade the immune response but at the expense of initially slower spread in an infected animal. Recent studies by Mempel's team and others have suggested that the virus can be transported by infected T cells that travel through tissues and the circulatory system and then spread the infection by direct contact with uninfected cells.
Since Nef has previously been shown both to downregulate the function of several proteins involved in signal transduction and to disrupt processes the MGH team took a detailed look at exactly how Nef and other HIV proteins exert their effects on the motility of infected T cells. Their experiments in mice with key elements of a human immune system supported previous findings that Nef reduces the migration of infected cells by disrupting the assembly and disassembly of actin into branched filaments.
Actin filaments support the shape of cells
Actin filaments support the shape of cells and enable them to move by pushing the outer membrane out on one side while retracting the membrane on the other end. This function of Nef is carried out through the interaction of a "hydrophobic patch" — a group of water-repelling amino acids closely spaced on the surface of the protein — with a group of cellular proteins including an enzyme called PAK2.
The authors found that the benefit conferred by the hydrophobic patch was not seen in cellular studies, suggesting that it had developed in response to the immune system pressures present in a live animal."We know that other functions of Nef appear to have evolved primarily to help HIV evade the immune response, so it makes sense that disruption of the actin cytoskeleton serves a similar purpose," says Mempel,
"The fact that this appears only in living animals clearly suggests that important biological properties of the virus are not apparent in the cell culture systems traditionally used to study HIV. This means its potential weaknesses are. Importantly, if it becomes possible to target the ability of Nef to disrupt the cytoskeleton, we may be able to increase the vulnerability of HIV to antiviral treatment strategies, such as vaccination or broadly neutralizing antibodies."