Hiv1 Infection And Conventional Pharmaceutical Agents

AIDS is caused by HIV-1. This retrovirus primarily infects and destroys cells of the human immune system, in particular, CD4+ T cells and macrophages. The destruction of such cells leads to a severe immunodeficiency (e.g., the inability to fight other infectious agents or tumor cells). Thus, AIDS patients usually die from secondary infections (e.g., tuberculosis, pneumonia) or cancer (e.g., Kaposi's sarcoma). Enormous efforts have been made to study the life cycle and pathogenesis of HIV-1 in order to find potential targets to block the replication of this virus (Fig. 1). A list of potential targets and appropriate control strategies are described in Figure 2. Some viral proteins, such as the protease, reverse transcriptase, and envelope have been crystallized and their 3-dimensional structures revealed (1-6). These studies were performed to design specific compounds, which would irreversibly bind to the active sites of such enzymes, and therefore inhibit their function. Indeed, specific chemical compounds, which efficiently block the activity or function of these viral proteins are now commercially available and in use worldwide (7-11).

Studies have demonstrated that administration of a mixture of 3 antiviral compounds (called combination chemotherapy or highly active retroviral therapy, HAART) can lead to significant reduction of viral load in vivo. Using 2 reverse tran-scriptase and 1 protease inhibitor in treatment naive patients, the serum HIV-1 RNA levels may be reduced to an undetecta-ble level. How long this response will last in these patients remains an open issue. Several reports have described variant strains of HIV-1, among patients receiving combination chemotherapy (12-14).

In particular, patients who have been treated with 1 antiviral inhibitor alone in the past appear to already carry a virus

Figure 1 Life cycle of HIV-1. The life cycle of the human immunodeficiency virus type I is similar to that of all retroviruses studied. HIV-1 attaches to the target cell mainly by binding to the CD4 molecule and chemokine receptors. After fusion of the viral and cellular membranes, retroviral core particles are released into the cytoplasm. The RNA genome is converted into a double-stranded DNA by the viral reverse transcriptase (RT) and ribonuclease H (RNaseH) and actively transported into the nucleus, probably aided by the viral protein vpr. The viral DNA is integrated into the genome of the host cell by the viral integrase (IN). The integrated DNA form of the virus is called the provirus. In contrast to other retroviruses, transcription and RNA splicing of the provirus is regulated by viral accessory proteins. For example, the viral protein Tat must to bind to a specific sequence in the HIV genome (termed TAR) to enable highly efficient transcription of the provirus. Rev is required to control RNA splicing and the transport of RNAs into the cytoplasm. Finally, in the cytoplasm, virus core particles are assembled by encapsidating full-length genomic viral RNAs (recognized by specific encapsidation sequences). At the cell membrane, virus particle assembly is completed by the interaction of the core with the viral membrane proteins and new particles "bud" (are released) from the infected cell. For more details regarding regulatory proteins, see also Fig. 5. Env, envelope; ER, endoplasmatic reticulum.

Figure 1 Life cycle of HIV-1. The life cycle of the human immunodeficiency virus type I is similar to that of all retroviruses studied. HIV-1 attaches to the target cell mainly by binding to the CD4 molecule and chemokine receptors. After fusion of the viral and cellular membranes, retroviral core particles are released into the cytoplasm. The RNA genome is converted into a double-stranded DNA by the viral reverse transcriptase (RT) and ribonuclease H (RNaseH) and actively transported into the nucleus, probably aided by the viral protein vpr. The viral DNA is integrated into the genome of the host cell by the viral integrase (IN). The integrated DNA form of the virus is called the provirus. In contrast to other retroviruses, transcription and RNA splicing of the provirus is regulated by viral accessory proteins. For example, the viral protein Tat must to bind to a specific sequence in the HIV genome (termed TAR) to enable highly efficient transcription of the provirus. Rev is required to control RNA splicing and the transport of RNAs into the cytoplasm. Finally, in the cytoplasm, virus core particles are assembled by encapsidating full-length genomic viral RNAs (recognized by specific encapsidation sequences). At the cell membrane, virus particle assembly is completed by the interaction of the core with the viral membrane proteins and new particles "bud" (are released) from the infected cell. For more details regarding regulatory proteins, see also Fig. 5. Env, envelope; ER, endoplasmatic reticulum.

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