HIV replication cycle

De Clercq E. Anti-HIV agents interfering with the initial stages of the HIV replicative cycle. In Morrow WJW, Haigwood NL, eds. HIV Molecular Organization, Pathogenicity and Treatment. Amsterdam Elsevier Science Publishers, 1993 267-292. 

For example, with the crystal structure of the aspartyl protease from human immundeficiency virus (HIV-1) in 1989 came the opportunity to design molecules to block this important enzyme that acts as a molecular scissors. HIV is the virus responsible for AIDS. Essential to viral replication, the HIV protease cuts long strands composed of many proteins into the functional proteins found in mature virus particles. This proteolysis occurs at the very end of the HIV replication cycle (Figure 7-1). The three-dimensional structural information derived from the x-ray crystal structure, combined with computer modeling techniques, allowed chemists to design potent, selective inhibitors of the protease enzyme (Figure... 

Prodrugs of AZT 5 -monophosphate have also been prepared by combination with an antiviral ether lipid [52], with the intention that the derivative would be active against two steps of the HIV replicative cycle. The most active compound was (38) with an IC50 of 0.03 mM and a selectivity of 1793. Although this prodrug is less active than AZT (IC50 0.004 mM), the selectivity for AZT was lower (1281). 

A working knowledge of the HIV replication cycle is essential for understanding the mechanism of action of antiretrovirals [10,75], From the very early hours of its penetration into the body, HIV provokes a cascade of events that will set up the viral clock for the patient s entire life. Several factors are predictors of more rapid HIV disease progression, including the severity of... 

Hitting different targets in the HIV replication cycle hyusing combination therapy can result in a greater than 10 000-fold reduction in the viral load being achieved. Under such conditions, sustained suppression of the virus in the plasma does not necessarily eliminate it from the protected... 

Viral Proteases. Figure 1 Role of virally encoded proteases in the replication cycle of a retrovirus (HIV, part a) and of a (+)-strand RNA virus (HCV, part b). The numbers correspond to the following steps in the infectious cycle ... 

Reverse transcriptase inhibitors prevent DNA from being produced in newly infected cells. They do not, however, prevent the reactivation of HIV from previously infected cells, the reason being that the enzyme is not involved in this process. Thus, agents that act at a later point in the replication cycle, possibly preventing reactivation, would be a major advance in the treatment of AIDs sufferers. The HIV protease inhibitors, which are currently receiving considerable attention, are believed to act in the manner depicted in Fig. 5.24. 

Figure 1. Replication cycle of human immunodeficiency virus (HIV).

Recently, it has been found that NO donors inhibit HIV-1 replication in acutely infected human peripheral blood mononuclear cells (PBMCs), and have an additive inhibitory effect on HIV-1 replication in combination with 3 -azido-3 -deoxythymisylate (AZT) [139, 140]. S-nitrosothiols (RSNOs) inhibit HIV-1 replication at a step in the viral replicative cycle after reverse transcription, but before or during viral protein expression through a cGMP-independent mechanism. In the latently infected U1 cell line, NO donors and intracellular NO production stimulate HIV-1 reactivation. These studies suggest that NO both inhibits HIV-1 replication in acutely infected cells and stimulates HIV-1 reactivation in chronically infected cells. Thus, NO donors may be useful in the treatment of HIV-1 disease by inhibiting acute infection, or reactivating a latent virus. 

There is a need for more effective anti-HIV agents, especially since resistance to all the currently used agents is beginning to develop a combination of different agents targeting different stages of the virus replicative cycle could provide a more effective therapy (348). 

HIV mutates rapidly averaging of 1 to 2 mutations per replication cycle. This means that in a given day, all the potential mutations that can code for single-drug resistance can easily be generated. Multiple mutations can arise in response to selective drug pressure, in which only those viral strains that possess specific mutahons are able to survive in the presence of the drug. 

The group of RNA viruses to which HIV belongs are called retroviruses, because DNA is produced from RNA in their replication cycle—the reverse of the usual direction of transcription (DNA RNA). 

The A-rich loop plays a role in retroviral replication and likely pairs with the complementary tRNA s anticodon. Strnctnral analysis of this A-rich loop shows a U-tum motif, an RNA strnctnre first seen in tRNA , but which is a common structural motif in many tRNAs." If, as evidence suggests, the four adenosines in the A-rich loop of the PBS pairing with the four uridines in the anticodon stem loop of tRNA y is a critical event in the HIV life cycle, this could provide a potential target for therapeutic intervention. 

The replicative cycle of HIV presents many opportunities for the targeting of antiviral agents. The drugs in clinical use are classified as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NTRTIs), and protease inhibitors (PI). 

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