For those aged 25-44, HIV dropped from the leading cause of death in 1995 to third and fifth leading causes of death in 1996 and 1997 respectively. The age-adjusted HIV death rate of 5.9 deaths per 100,000 is the lowest rate since 1987; the first year mortality data were available for the disease. This dramatic reduction in AIDS related deaths has largely been due to the advent of anti-retroviral agents which prolong AIDS-free HIV infection as well as life-expectancy once AIDS has developed. However, current therapy is not able to eradicate the virus, only suppress it; therefore, long-term treatment is required to control viral load. Most of the problems associated with the HIV therapy are the consequence of this necessity for prolonged treatment. The long-term effectiveness of current inhibitors as therapeutic agents is limited by the rapid development of drug-resistant variants. Furthermore, various side effects have been reported. Thus, despite the success of HIV therapies, there is a demand for new therapies. Current HIV therapies target proteases and reverse transcriptase, both of which are crucial viral proteins. Several other early events in the viral life cycle (stages before the viral genome is inserted into host cell DNA) are also susceptible to drugs, including virus attachment to target cells, membrane fusion and post-entry events such as integration, accessory-gene function and assembly of viral particles. Among these, inhibitors of virus-cell fusion and integration are the most promising candidates. Virion infectivity factors (vif) play an important role at the other end of the viral life-cycle. HIV-1 Vif seems to be required for the suppression of an innate antiviral phenotype that resides in human T lymphocytes. Thus, in the absence of Vif, progeny virions are rendered non-infectious. A trans-atlantic collaboration of researchers has recently described a unique cellular gene, CEM15, whose transient or stable expression in cells that do not normally express CEM15 likewise blocks infectivity, although this is overcome by the presence of Vif. The Vif:CEM15 regulatory circuit is therefore critical for HIV-1 replication, and the pharmaceutical perturbation of this circuit may be a promising target for future HIV/AIDS therapies.

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