The biology of HIV and antiretroviral therapy

Chapter 1 describes the HIV life cycle and outlines the steps in the life cycle targeted by antiretroviral drugs. The viral targets of antiretroviral agents are outlined in Chapter 1 Fig. 1.3, and Table 1.6. The antiretroviral drugs in current clinical use inhibit either the viral reverse transcriptase, the viral protease, or block the fusion of the virus with the membrane of its would-be future host cell. Additional viral targets (e.g., the viral integrase or chemokine receptors) are the subject of drug development efforts, but there are no currently approved antiviral drugs directed at these other targets

There are two classes of reverse transcriptase inhibitors (RTIs), the nucleoside analogue RTIs (NRTIs) and the non-nucleoside RTIs (NNRTIs). Nucleoside-analogue reverse transcriptase inhibitors (NRTIs) are modified nucleosides that are designed to lack a 3′OH group (see Chapter 1, Fig. 1.4). (Tenofovir is a nucleotide analagon, see below.) They are phosphorylated by host cell kinases and then incorporated into the elongating polynucleotide chain. Their incorporation produces a prematurely terminated cDNA molecule because another nucleotide cannot add to the chain due to the absent 3′OH. The viral reverse transcriptase has a greater relative affinity for the modified nucleosides than does the human DNA polymerase, which is why nucleoside analogues have a tolerable therapeutic index. The non-nucleoside RT inhibitors, NNRTIs, act through a different mechanism than the NRTIs. The NNRTIs interfere with binding at the active site of the reverse transcriptase.