INTRODUCTION
The most prevalent pharmacotherapeutic paradigm for treatment and management of human immunodeficiency virus (HIV)-related disease remains HAART (highly active antiretroviral therapy).
This concurrent administration of multiple antiviral drugs simultaneously targets multiple aspects of the viral life cycle in order to both suppress viral replication and reduce the likelihood of generating viable escape mutants in treated individuals. The success of this approach has been well documented1 and is attested to by the thousands of HIV-positive individuals with suppressed levels of viral infection on such regimens, although novel compounds are continuously sought to counter escape mutants and reduce the side effects of medication.Current classes of antiretroviral drugs available for the treatment and management of HIV infection include nucleoside and nonnucleoside reverse transcriptase inhibitors, HIV protease inhibitors (PIs), and fusion inhibitors. The two predominant viral targets for anti-HIV therapeutics have been reverse transcriptase (RT) and HIV protease (PR). Both are essential enzymes in the viral life cycle, and inhibition of either or both have proven to be an effective strategy to suppress viral replication and extend the lives of those infected.
Compounds targeting reverse transcriptase interfere with viral deoxyribonucleic acid (DNA) production, preventing all downstream events, including viral genome integration and messenger ribonucleic acid (mRNA) transcript production. This occurs either through the inhibition of catalytic activity (nonnucleoside reverse transcriptase inhibitors) or through induction of DNA chain termination by incorporation of nonnatural nucleotides that lack further linkage potential (nucleoside reverse transcriptase inhibitors).
Protease inhibitors exert their primary effect through the inhibition of HIV polyprotein cleavage, preventing virion maturation at the end of the life cycle.
This results in production of noninfectious particles as well as interferes in the initial polyprotein cleavages necessary for production of individual viral proteins.Entry inhibitors, broadly defined to include all drugs that interfere with virion attachment and fusion, have only recently come to market, and the first fusion inhibitor T-20 (fuzeon) received U.S. Food and Drug Administration (FDA) approval in 2003. This compound acts to competitively inhibit HIV gp41 from self-associating and prevents the mechanical formation necessary to enable virion-cell fusion. Results to date show this class of drugs to be quite effective, with reduced side effect profiles2,3 in many respects compared with traditional classes of antiretrovirals, and thus this class of therapeutics is expected to receive increased attention and grow significantly in coming years.
Finally, there are several “miscellaneous” drugs currently prescribed for the treatment of HIV disease. These include hydroxyurea, which acts to reduce the available nucleotide pool for use in DNA synthesis, thereby serving to antagonize viral replication; interleukin (IL)-2, currently used to stimulate lymphocyte replication and activate remaining lymphocytes; and thalidomide, an antitumor necrosis factor (TNF) medication that prevents TNF-induced inflammatory processes and TNF-induced cell death, thereby sparing additional lymphocytes and increasing T cell numbers.
Although an ideal pharmacological drug has high selectivity and specificity, the reality is that most compounds in use have multiple targets for interaction. Anti-HIV medications are no different, and in addition to their predominant effects on viral targets, also act on a variety of cellular targets. In this chapter, we will address the current understanding of each of the four major classes of HIV therapeutics with regard to their apoptotic impact. We will discuss likely mechanisms for the impacts of these drugs, and highlight specific activities of compounds, when known.