Title: The HIV Life Cycle: Multiple Targets for Antiretroviral Agents
Volume: 1
Issue: 1
Author(s): Massimo Alfano and Guido Poli
Affiliation:
Keywords:
hiv, aids, fusion, viral protease
Abstract: Twenty years ago, the identification of an exogenous human pathogenic retrovirus, named human immunodeficiency virus (HIV), as the causative agent of the acquired immunodeficiency syndrome (AIDS) inaugurated a novel era in pharmacological research. The first antiretroviral agent developed, commonly referred to as AZT, targeted the very nature of this class of viruses, i.e. the RNA-dependent DNA polymerase or reverse transcriptase (RT), an enzyme not present in eukaryotic cells. In addition to AZT, other classes of RT inhibitors have been discovered and are currently employed in the treatment of this disease. In the mid 90s, a novel class of agents specific for the viral protease, an enzyme crucial for the maturation of Gag core proteins that are essential for the infectivity of new progeny virions, was discovered. The combination of inhibitors of the viral protease and of the RT determined a quantum leap in the potency and efficacy of anti-HIV therapy in protocols of “highly active antiretroviral therapy (HAART)”. Introduction of HAART in the industrialized countries has significantly curtailed the mortality associated with AIDS, although the prolonged life expectancy of infected individuals may determine an increased prevalence of HIV infection in the general population. At the level of single individuals, HAART has not tackled the ability of HIV, as a retrovirus, to remain silently integrated as a DNA provirus in the host genome of resting T cells and mononuclear phagocytes. In this regard, no agents are currently effective in preventing or significantly curtailing the number of latently infected cells. Another pharmacological frontier was recently born from the delineation of the precise modality through which HIV infects CD4+ cells. Upon interaction with CD4, the primary receptor (R), a conformational change of the viral gp120 envelope protein enables it to interact with a second R (also referred to as coreceptor) belonging to the family of 7-transmembrane domain chemokine R, mostly CCR5 or CXCR4. This class or molecules represents a favorite target for the development of small molecule inhibitors; indeed, agents antagonizing HIV infection by interfering with binding of the virus to either CD4 or the chemokine R are currently been tested with encouraging results. In addition, inhibitors of the membrane fusion process triggered by gp41, a second component of the viral envelope, are in advance phase of clinical testing and represent an additional weapon for combination therapy. It is conceivable that in the near future other steps of the virus life cycle will be exploited for developing new pharmacological tools.
