Using potent antiviral agents to perturb the steady state between virus and host, we and Wei et al. Independently described the dynamics of HIV-1 replication and the turnover of CD4 lymphocytes in infected persons. Cell-free virions and virus-producing cells have a composite decay T1/2 of ~2 days, suggesting that HIV-1 replication in vivo must be highly productive, sustained by continuous rounds of de novo infection. Moreover, CD4 lymphocytes also turn over rapidly at an average rate of ~5%, or ~2x109 cells, per day. We have since determined that virus-producing cells are lost with a mean T1/2 of ~1.6 days and that virions are cleared with a mean T1/2 of < 6 hours, which has permitted us to determine that on average, at least 10 x 109 virions are produced and released into the extracellular fluid each day. We now propose to extend our understanding of viral dynamics and lymphocyte turnover by combining experimental studies with theoretical modeling.
Specific aims on viral dynamics include (A) the definition of the kinetics of decay of each crucial HIV-1 or SIV compartment (e.g., virions, productively infected CD4 lymphocytes, cells that latently harbor infectious provirus, and infected tissue macrophages) by using a combination of potent antiviral agents to achieve prolonged, high-level viral suppression in infected persons or macaques; (B) the definition of major tissue sites responsible for SIV clearance (e.g., spleen and liver) and production (e.g., mucosa-associated lymphoid tissues and lymph nodes) in macaques.
Specific aims on lymphocyte turnover include (A) the characterization of CD4 & CD8 lymphocyte phenotypes in patients, before and after treatment with potent antiviral agents, to address the source and mechanism of their regeneration following treatment with antiviral agents, to address the source and mechanisms of their regeneration following effective therapy; (B) a comparison of the cumulative effect of lymphocyte turnover in long-term nonprogres sors, slow progressors, and rapid progressors of HIV-1 infection, by measuring the length of the telomere (which shortens predictably with each division in a normal somatic cell) in sequential samples of CD4 and CD8 lymphocytes; (C) the determination of the extent of CD4 and CD8 lymphocyte turnover by using bromodeoxyuridine incorporation in monkeys with and without SIV infection. The proposed studies should provide a better kinetic picture of HIV-1 pathogenesis, and the theoretical principles to guide future treatment strategies. FUNDING NIH (R01 AI40387) PUBLICATIONS Chen Z., D. Kwon, Z. Jin, S. Monard, P. Telfer, M.S. Jones, R. Aguilar, D.D. Ho, and P.A. Marx. Natural infection of a homozygous 24 CCR5 red-capped mangabey with a 2b-tropc SIV. Journal of Experimental Medicine, 199:2057-2065, 1998. Zhang, L., T. He, A. Talal, G. Wang, S.S. Frankel and D.D. Ho. In vivo distribution of the human immunodeficiency virus/simian immunodeficiency virus coreceptors CXCR4, CCR3 and CCR5. Journal of Virology, 72:5035-5045, 1998. Kostrikis, L.G., Y. Huang, J.P. Moore, S.M. Wolinsky, L. Zhang, Y. Guo, L. Deutsch, J. Phair, A.U. Neumann and D.D. Ho. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nature Medicine, 4:350-353, 1998. Mohri, H., S. Bonhoeffer, S. Monard, A.S. Perelson and D.D. Ho. Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. Science, 279:1223-1227, 1998.
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