Other viral proteins

Besides its three enzymes needed for replication, HIV-1 also uses four regulatory proteins , Nef, Rev, Tat, and Vpr (or Vpx for HIV-2). These proteins regulate the speed and efficiency of viral replication. HIV-1 also has two accessory proteins, Vif and Vpu; the function of these proteins is not well understood. As with the replication enzymes, researchers have attempted to interfere with HIV’s life-cycle by targeting these other proteins.

The Nef protein is involved in several processes critical to both viral entry and ‘budding’ of new virions. The protein seems to both promote HIV production and contribute to CD4 cell destruction, so blocking it might have a double benefit, but there are currently no Nef inhibitors in clinical trials.

The Tat protein appears to trigger HIV to produce new viral particles once it enters a cell. Only one Tat inhibitor, Ro 24-7429, has progressed into human trials, but it was abandoned after it showed little efficacy and had toxic side-effects.

The Rev protein shuttles HIV DNA from the outer part of the cell into the nucleus and then later back out again, where it can be used to produce new virions. A group of compounds known as guanidinoglycosides that target Rev showed some antiviral activity in early studies.¹

Vpr, another regulatory protein, seems to have no effect on viral replication within CD4 cells, but does appear to play a role in viral reproduction within other types of HIV-infected cells such as macrophages. Studies have shown that glucocorticoid antagonists such as mifepristone can prevent Vpr-induced HIV replication in the test tube.²

Studies of potential drugs that target the HIV regulatory and accessory proteins have not progressed very far, but they offer future targets for antiretroviral therapy.