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 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 one 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 one 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. IMPORTANCE: Most current data suggest that Cytotoxic T cells (CTL) mediate their control of HIV-1 infection by non-lytic mechanisms, i.e., 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 re-analyze 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 that the killing rate should balance the viral replication rate, we estimate both parameters from a large set of published experiments depleting CD8(+)T cells in SIV infected monkeys. This confirms that the killing rate can be much faster than is currently appreciated.