Molecular Crosstalk between HIV-1 Integration and Host Proteins – Implications for Therapeutics

Abstract

The human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS), which is one of the leading causes of infectious disease-related mortality worldwide (UNAIDS, 2010). An HIV infection is a chronic disease. While there is no regimen to eradicate the HIV from an infected person, there are more than 20 drugs approved for the treatment of HIV infection, the majority of which target viral reverse transcriptase (RT) and protease (PR). In addition to the development of chemotherapeutic agents such as RT and PR inhibitors (RTI and PI), the advent of the combination therapy of different classes of antiviral drugs, the highly active antiretroviral therapy (HAART), has brought a significant decrease in the morbidity and mortality associated with HIV infections for over a decade. Nowadays, HAART is a standard treatment for HIV infection and AIDS (Palella et al., 1998). However, despite the successful suppression of HIV RNA detected in plasma over prolonged periods of time and a dramatic decrease in patient mortality, HAART is still facing problems, including the emergence of drug resistant viruses and serious side effects in treated individuals. In addition, current treatments only suppress the HIV replication, and eradication of virus from the body cannot be achieved. Therefore, considerable efforts have been made to develop novel anti-HIV drugs that exhibit entirely distinct mechanisms of action. To date, three additional classes of inhibitors have been approved by the US Food and Drug Administration (FDA) as oral antiHIV agents: a fusion inhibitor blocking the fusion step of the viral and cellular membranes, an entry inhibitor targeting coreceptor binding by the virus, and an integrase (IN) inhibitor blocking the integration step of viral DNA. Although many promising inhibitors against HIV replication have arisen over recent years, the current approach in anti-HIV chemotherapy is mostly based on competitive agents targeting the active sites of viral enzymes or the binding pockets of cellular receptors. One of the drawbacks of existing drugs, particularly the antivirals exhibiting allosteric effects, is the rapid emergence of mutant HIV strains resistant to the drugs due to the innately high mutational rate in of viral enzymes. On the other hand, it is becoming increasingly clear that protein-protein interactions (PPIs) could also serve as attractive targets of drugs for human