Joseph J Eron Jr MD
from HIV/AIDS Annual Update 2
Antiretroviral medication development has grown out of an understanding of the HIV life cycle. The more detailed our knowledge about the steps in the viral life cycle, the greater potential there is to develop effective therapies. Steps in the life cycle that are specific for the virus and distinct from ongoing processes in human cells may represent therapeutic targets that have a greater likelihood of success and a lower incidence of toxicity.
Thus, HIV-1 enzymes such as reverse transcriptase (RT), protease, and integrase have been logical targets for inhibition. Success in these areas can be measured by the number of RT and protease inhibitors currently available, although the lack of integrase inhibitors highlights the potential limitations even when a step in the HIV life cycle is fairly well understood.
The interaction of HIV-1 with the cell membrane of CD4+ cells is a process involving several specific interactions between the virus and host and within the viral envelope, and therefore has been an intended target for antiretroviral therapy for many years.
The first interaction between virus and cell is the specific binding of the HIV envelope protein, gp120, to the CD4 molecule, and early attempts to target this interaction held promise in vitro; however, they failed dismally when inhibition of viral replication in the clinical setting was attempted.
In recent years there has been rapid progress towards understanding that the process of HIV-1 attachment and entry into a CD4+ cell can be divided into three basic steps:
- HIV-1 attaches to the CD4 molecule on the cell surface via envelope gp120
- a conformational change occurs in gp120, allowing it to bind to the chemokine coreceptor (CCR5 or CXCR4)
- the HIV envelope fuses with the cell membrane via a structural change in the gp41 envelope protein.
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