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Fifth level
This slide reviews some of the steps in the viral life cycle and highlights the steps targeted by novel antiretrovirals currently in development.
Entry 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.
Once a 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.
Reverse 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.
The next 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.
The viral 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.
Integrase is 1 of 3 enzymes necessary for HIV-1 viral replication. Integrase allows for the integration of HIV-1 DNA into the genome of the host cell. Raltegravir targets this enzyme and blocks strand transfer that is necessary for viral replication.
Phase 2 and 3 data provide evidence of the safety and efficacy of Raltegravir . Specifically, trials 18 and 19 were designed identically and differed by geographic location only. Studies 4 and 5 were phase 2 dose-finding trials in naïve and treatment experienced patients respectively.