reviews some of the steps in the viral life cycle and highlights the steps
targeted by novel antiretrovirals currently
inhibitors block HIV entry into CD4+ cells. Enfuvirtide is a fusion inhibitor
and is the only approved member of this
entry inhibitor class. Drugs currently in development include TNX-355, an antibody that binds to the CD4+ cell receptor to
block virus entry; CCR5 inhibitors that block
binding to the CCR5 chemokine coreceptor; and CXCR4 inhibitors that block
binding to the CXCR4 chemokine coreceptor.
virus enters a cell, it has to uncoat. Uncoating of the virus may involve a
host protein called cyclophilin A, for
which inhibitors are being developed. Presumably, these inhibitors block the interaction between cyclophilin A and the
virus thereby preventing uncoating.
transcription of the viral RNA genome into double-stranded DNA is the next
step in the viral life cycle. There are
currently several approved reverse transcriptase inhibitors and these are, obviously, not considered novel agents.
step is integration of the double-stranded viral DNA into the host chromosome.
This process is accomplished via the viral
integrase enzyme. Clinical data on 2 integrase inhibitors, MK-0518 and GS-9137, will be discussed later.
genome is then transcribed and translated into proteins. These viral proteins
are cleaved by proteases, including the
proteases carried by the virus itself. The process of protein cleavage followed by assembly of the virus is termed
maturation. A new drug, PA-457, inhibits this
process of maturation or assembly of the virus core without specifically
interfering with protease activity. PA-457
is not a protease inhibitor it is a maturation inhibitor.