The central paradox of HIV pathogenesis is that the viral burden, either free or cellular, seems too low to deplete the CD4 population by direct killing. Until recently, little data could be used to compare direct and indirect pathogenic theories critically. Clinical trials with potent new antiviral agents have measured important kinetic parameters of HIV infection, including viral and infected cell half-lives. This has led to the construction of explicit models of direct killing. Using a worst-case dynamic analysis, we show that such cytopathic models are untenable. Rates of infected cell removal are orders of magnitude too low to suppress steady state CD4 counts significantly in the face of lymphocyte replenishment, especially in early infection. Furthermore, the direct cytopathic models, as proposed, predict an extremely variable disease course across the broad range of observed viral burdens (five orders of magnitude), which is inconsistent with the relatively small differences in disease progression observed between patients. In contrast, immunologic theories of pathogenesis, such as homeostatic dysregulation based on immune activation, do not suffer from these difficulties and are more consistent with the natural history of HIV infection.

September 01 1996 Evolution, Learning, and Instinct: 100 Years of the Baldwin Effect In Special Collection: CogNet Peter Turney, Peter Turney Institute for Information Technology National Research Council Canada Ottawa, Ontario, Canada KIA OR6 peter@ai.iit.nrc.ca Search for other works by this author on: This Site Google Scholar Darrell Whitley, Darrell Whitley Department of Computer Science Colorado State University Fort Collins, CO 80523 whitley@cs.colostate.edu Search for other works by this author on: This Site Google Scholar Russell W. Anderson Russell W. Anderson Research Scientist Smith-Kettlewell Eye Research Institute 2232 Webster Street San Francisco, CA 94115 rwa@milo.berkeley.edu Search for other works by this author on: This Site Google Scholar Author and Article Information Peter Turney Institute for Information Technology National Research Council Canada Ottawa, Ontario, Canada KIA OR6 peter@ai.iit.nrc.ca Darrell Whitley Department of Computer Science Colorado State University Fort Collins, CO 80523 whitley@cs.colostate.edu Russell W. Anderson Research Scientist Smith-Kettlewell Eye Research Institute 2232 Webster Street San Francisco, CA 94115 rwa@milo.berkeley.edu Online Issn: 1530-9304 Print Issn: 1063-6560 © 1996 by the Massachusetts Institute of Technology1996 Evolutionary Computation (1996) 4 (3): iv–viii. https://doi.org/10.1162/evco.1996.4.3.iv Cite Icon Cite Permissions Share Icon Share Facebook Twitter LinkedIn MailTo Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Search Site Citation Peter Turney, Darrell Whitley, Russell W. Anderson; Evolution, Learning, and Instinct: 100 Years of the Baldwin Effect. Evol Comput 1996; 4 (3): iv–viii. doi: https://doi.org/10.1162/evco.1996.4.3.iv Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsEvolutionary Computation Search Advanced Search This content is only available as a PDF. © 1996 by the Massachusetts Institute of Technology1996 Article PDF first page preview Close Modal You do not currently have access to this content.

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.

This is the second in a series of papers modeling human immunodeficiency virus (HIV) infections at four levels: transmission, interaction with the immune system, gene regulation, and selection of mutants. In the previous paper (1) we described and presented a theory of the HIV cytopathic effect based upon the models (and a review of the literature). In this article we give mathematical equations of threshold conditions that connect infectivity, length of host survival, and frequency of acts conducive to transmission. The formula is derived not only for homogeneous populations but also for populations of an arbitrary number of subgroups with varying frequencies of risk behavior, varying rates of infection and latency periods, and varying frequencies of interaction with other groups.