Cycle of HIV

The immune system defends the body against invading organisms, foreign antigens, and host cells that have become neoplastic. In addition, the immune system is an active participant in autoimmune diseases, hypersensitivity reactions, and transplant tissue rejections. 

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Basically, AZT is anabohcaHy phosphorylated to AZT mono-, di-, and tri-phosphates by various enzymes (kinases) of a target ceU (159). AZT-triphosphate competes with other phosphorylated pyrimidine nucleosides for incorporation into HIV DNA by the viral reverse transcriptase. Incorporation of the AZT-triphosphate into reverse transcriptase results in viral DNA chain termination. Reverse transcriptase is essential in the repHcative cycle of HIV. 

FIGURE 84-1. Life cycle of HIV and targets for antiretroviral drugs. (From Fletcher CV, Kakuda TN. Human immunodeficiency virus infection. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy A Pathophysiologic Approach. 6th ed. New York McGraw-Hill 2005 2258, with permission.)... 

The life cycle of HIV is typical of an enveloped retrovirus. As with other viruses, HIV requires a cellular receptor to infect a cell. The receptor for HIV is known as the CD4 antigen. The life cycle for HIV is outlined in Fig. 3. Virus replication is regulated by the products of six genes. 

Schematic illustration of the life cycle of HIV-1. See text for full caption.

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). 

At the beginning of the replication cycle of HIV, before the Rev protein is present, primarily regulatory proteins are formed. If, in the framework of this expression pattern, enough Rev protein is present, then imspliced or incompletely spliced viral mRNAs appear in e cytosol and structural proteins are formed. 

Success in treating AIDS may depend upon better understanding of the complex life cycle of HIV-1,722,730,735 w -,jc -, js summarized in Fig. 28-27. The cycle begins with the binding of the virion envelope protein to the immunoglobulin-like surface protein CD4, which is found principally on the type T4 helper T cells (Chapter 31). Binding of CD4 to the HIV envelope proteins appears to activate the T cells to enter the cell cycle and to take up and integrate the virus. The virus infection destroys these CD4+ lymphocytes with a half-life of less than two days.735... 

In the life cycle of HIV, its RNA is translated into a polypeptide chain that is composed of several individual proteins including protease, integrase and reverse transcriptase, but in this form these enzymes are not functional. They must be cleaved by viral proteases from the assembled sequence in order for them to become functional. These posttranslational modifications allow the enzymes to facilitate the production of new viruses. The protease itself is made up of two 99-amino-acid monomers, and an aspartic acid residue in the monomer is required for the cleavage. The protease inhibitors inhibit the enzyme protease and consequently interfere with viral replication and maturation by preventing proteases from cleaving proteins into peptides. In humans, these drugs inhibit cleavage of HIV gag and pol polyproteins, which are part of the essential viral structural components, P7, P9, P17 and P24, and... 

A number of products exist that are targeted at any of the successive events implicated in the replicative cycle of HIV virus entry, viral adsorption, virus-cell fusion, reverse (RNA —> DNA) transcription, proviral DNA integration, viral (DNA —> RNA) transcription (transactivation), viral (mRNA —> protein) translation, virus release, viral assembly, budding, and maturation... 

Compounds that are targeted against postintegration events in the replication cycle of HIV can be evaluated in chronically infected cells. The proteinase inhibitors block the late-stage maturation process. If the antiviral activity of this assay is compared with its activity in an acute assay then the site of action of an compound can be shown to be pre- or postintegration (5). 

Adding compounds at increasing times postinfection (1.5-48 h) will also discriminate between compounds that act either early or late in the replication cycle of HIV. Reverse-transcriptase inhibitors will lose activity after about 6 h postinfection, whereas proteinase inhibitors will still retain significant activity at 48 h postinfection (references). The methodology is the same as that described in Subheadings 3.2. and 3.2.1. These experiments are typically only carried out with a single compound of interest together with an appropriate reference compound. A number of replicate assays are set up and dilutions of the compound added at 2, 4, 6, 12, 24, and 48 h. Dose responses are drawn for each time-point or responses are shown for each concentration at all time-points (7). 

FIGURE 123-1. Life cycle of HIV with potential targets where replication may be interrupted and known or putative antiretroviral agents. (Reprinted with permission, Courtney V. Fletcher, 2004.)... 

In mid-1997, the National Institutes of Health Office of AIDS Research convened a panel to define the scientific principles that might serve as a guide for the clinical use of antiretroviral agents. The 11 principles presented below are an amalgamation of knowledge of the life cycle of HIV, the consequences of HTV replication, clinical trials of antiretroviral agents, and scientific opinion. 

Researchers have set out to target almost all stages in the life cycle of HIV, but the drugs currently available fall into two main types. The earliest developed were the reverse transcriptase inhibitors, e.g. AZT (Structure 4.2), which stop the replication of viral genes. Transcription is the process in which the DNA base sequence is... 

Success in treating AIDS may depend upon better understanding of the complex life cycle of HIV-j 722.730,735 is Summarized in Fig. 28-27. The... 

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