title: Notwithstanding Circumstantial Alibis, Cytotoxic T Cells Can Be Major Killers of HIV-1-Infected Cells.
abstract: Several experiments suggest that in the chronic phase of human immunodeficiency virus type 1 (HIV-1) infection, CD8(+) cytotoxic T lymphocytes (CTL) contribute very little to the death of productively infected cells. First, the expected life span of productively infected cells is fairly long, i.e., about 1 day. Second, this life span is hardly affected by the depletion of CD8(+) T cells. Third, the rate at which mutants escaping a CTL response take over the viral population tends to be slow. Our main result is that all these observations are perfectly compatible with killing rates that are much faster than one per day once we invoke the fact that infected cells proceed through an eclipse phase of about 1 day before they start producing virus. Assuming that the major protective effect of CTL is cytolytic, we demonstrate that mathematical models with an eclipse phase account for the data when the killing is fast and when it varies over the life cycle of infected cells. Considering the steady state corresponding to the chronic phase of the infection, we find that the rate of immune escape and the rate at which the viral load increases following CD8(+) T cell depletion should reflect the viral replication rate, ρ. A meta-analysis of previous data shows that viral replication rates during chronic infection vary between 0.5 ≤ ρ ≤ 1 day(-1) Balancing such fast viral replication requires killing rates that are several times larger than ρ, implying that most productively infected cells would die by cytolytic effects.
  
  
  
  Most current data suggest that cytotoxic T cells (CTL) mediate their control of human immunodeficiency virus type 1 (HIV-1) infection by nonlytic mechanisms; i.e., the data suggest that CTL hardly kill. This interpretation of these data has been based upon the general mathematical model for HIV infection. Because this model ignores the eclipse phase between the infection of a target cell and the start of viral production by that cell, we reanalyze the same data sets with novel models that do account for the eclipse phase. We find that the data are perfectly consistent with lytic control by CTL and predict that most productively infected cells are killed by CTL. Because the killing rate should balance the viral replication rate, we estimate both parameters from a large set of published experiments in which CD8(+) T cells were depleted in simian immunodeficiency virus (SIV)-infected monkeys. This confirms that the killing rate can be much faster than is currently appreciated.
authors.affiliation: Theoretical Biology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Saikrishna
authors.initials: S
authors.lastname: Gadhamsetty
authors.affiliation: University College Utrecht, Campusplein, Utrecht, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Coorens
authors.affiliation: Theoretical Biology, Utrecht University, Utrecht, The Netherlands r.j.deboer@uu.nl.
authors.forename: Rob J
authors.identifier: http://orcid.org/0000-0002-2130-691X
authors.initials: RJ
authors.lastname: de Boer
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008253:Macaca mulatta; D008962:Models, Theoretical; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load; D014779:Virus Replication / Q000276:immunology*