The HIV cytopathic effect: potential target for therapy?
HIV kills activated infected CD4+ T cells after a burst of replication and the release of large numbers of virions. From a review of the literature on HIV regulatory genes and from preliminary mathematical models of HIV dynamics at four levels (host population epidemiology, the immune system, gene regulation within infected cells, and selection of mutants) we have arrived at the theory that in the etiology of HIV the HIV cytopathic effect may actively be caused by a viral regulatory gene product. The most likely candidate is the rev regulatory protein. Rev and the analogous rex protein from HTLV-I (human T cell leukemia virus) both have two active sites with similar function: one site locates the protein in the nucleus/nucleolus, and the other site interacts with viral mRNAs, facilitating their export from the nucleus to the cytoplasm. Rev seems to have a third functional site near the 3' end. We conjecture that this site may be responsible for the cytopathic effect. We think that rev acts on cellular genes that normally induce senescence and cell death during development, or T-cell maturation, or on terminal differentiation. We propose that mathematical and computer models of the immune system could be used to explore whether suppression of the cytopathic action of the rev protein could be of therapeutic benefit in restoring the ability of the immune system to clear HIV or at least to extend latency. We also suggest how immune deficiency disease might be created as laboratory artifact in animal populations.
Bremermann
H J
HJ
Department of Molecular and Cell Biology, University of California, Berkeley 94720.
Anderson
R W
RW
D015704:CD4 Antigens / Q000276:immunology; D003588:Cytopathogenic Effect, Viral; D004195:Disease Models, Animal; D005809:Genes, Regulator; D005814:Genes, Viral; D006678:HIV / Q000235:genetics / Q000502:physiology*; D015658:HIV Infections / Q000635:transmission; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology
D015704:CD4 Antigens