Programmed activation of T-lymphocytes. A theoretical basis for short term treatment of AIDS with azidothymidine.
When its T-lymphocyte host cell is activated, the latent (DNA) form of human immunodeficiency virus (HIV) is activated to produce RNA copies which are liberated as virus particles from the cell. In this process the cell is destroyed together with the latent virus. If administered at this time, 3'-azidothymidine (AZT) would specifically prevent the liberated RNA copies replicating and establishing latency in new host cells. The RNA copies would then be degraded by viral or host ribonucleases. Thus, one DNA copy of HIV and its RNA progeny would be eliminated from the body. However, many DNA copies of HIV would remain in other cells. The main problem of therapy with AZT is that activation of host cells to become permissive for production of virus is random in time. Activation depends on chance encounters of an infected person with the particular foreign antigens to which individual T-cells bearing latent HIV can specifically respond. It is primarily for this reason that AZT must be administered continuously. If all T-cell could be polyclonally stimulated at one time, all HIV-bearing T-cells would be destroyed and concomitant administration of AZT for a short term would prevent the replication of all liberated viruses. Unlike most renewable 'end' cells in the body, the maturation of T cells involves processes of positive and negative selection. To preserve the 'educated' T-cell population, T-cell renewal occurs at the end cell, rather than at the stem cell level. It is possible that normal physiological signals concerned with this homeostatic regulation of T-lymphocyte population size could be harnessed to produce synchronous activation of all T-lymphocytes. Tumor necrosis factor-alpha has some of the properties expected of a postulated polyclonal activator needed for this programmed activation of T-lymphocytes.
Forsdyke
D R
DR
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D004279:DNA, Viral / Q000187:drug effects; D006678:HIV / Q000187:drug effects; D006801:Humans; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000627:therapeutic use*
D004279:DNA, Viral; D015215:Zidovudine