Nef-ed off by HIV

Nef-ed off by HIV

News from the British Journal Nature. lifelines : Nef-ed off by HIV

BARBARA MARTE

When a virus infects a cell, the immune system often recognizes and destroys that cell, preventing the virus from spreading. But many viruses, including the AIDS-causing, human immunodeficiency virus (HIV-1), have developed strategies to evade this immune response.

Now a report in Nature Cell Biology1 adds to our understanding of how exactly HIV-1 manages this, and so hints at new ways in which medicine might fight HIV-1.

An important part of the body's immune defence against viral infections are the 'cytotoxic T cells'. These recognize virus-infected cells that display a protein, the 'major histocompatibility class I' protein (or 'class I MHC'), on their surface. The class I MHC of virus-infected cells differs from that of uninfected cells, because it is combined with protein fragments specific for the virus. This system labels infected cells as 'foreign', allowing cytotoxic T cells to spot and eliminate them.

But HIV-1 has developed a trick to circumvent this process: it forces an infected cell to internalize its class I MHC proteins and to redirect them to a compartment within called the Golgi. This evasive manoeuvre allows the virus to persist and replicate.

Didier Trono and colleagues of the University of Geneva, Switzerland, shed new light on how HIV-1 pulls off this MHC-hiding trick. Previously, the team had proposed that a protein made by the virus, known as 'Nef', played some key role in this process.

Now they have discovered that Nef serves as a molecular bridge between class I MHC and another protein, 'PACS-1', that directs proteins to the Golgi. By forming this link, Nef effectively condemns class I MHC to the Golgi, preventing it from stimulating a normal immune response on the cell surface.

These findings suggest the possibility of designing drugs that interfere with this skulduggery and force cells infected with HIV-1 to maintain class I MHC on their surface so that they can be hunted down by the body's immune control suite.

Interestingly, HIV-1 uses the same Nef protein to persuade cells to internalize another important immune receptor, 'CD4'. CD4, displayed on the surface of T-helper cells, allows them to recognize and -- as their name suggests -- to help other cells of the immune system wipe-out virus-infected cells.

The absence of CD4 allows HIV-infected cells to escape the notice of T-helper cells. In this case, however, Nef doesn't redirect CD4 to the Golgi. Internalized CD4 is instead degraded. Thus, HIV-1 has evolved to use a single protein, Nef, in two quite distinct ways to eliminate specific receptors from the cell surface, but in each case the goal is the same: escaping immune
surveillance.

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