Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals

Abstract

We estimate the time required for HIV to complete separate stages of its infection cycle in productively infected CD4؉ T cells in vivo by comparing initial delays after administration of single antiretroviral drugs until HIV RNA reduction in peripheral blood. Data were obtained from monotherapy studies of eight antiretroviral drugs from all currently licensed HIV drug classes: CCR5 blockers (maraviroc), fusion inhibitors (enfuvirtide), nucleoside and nonnucleoside reverse transcriptase inhibitors (abacavir, tenofovir, and rilpivirine), integrase inhibitors (raltegravir), and protease inhibitors (ritonavir and nelfinavir). We find that HIV requires an average of 52 h between export of virions in one generation to export in the next, with most of this (33 h) taken up by reverse transcription. Reverse transcription in vivo was three times longer than in vitro and began soon after virion fusion, as we determined no difference in mean times for commencement of reverse transcription and virion fusion as calculated by timing of the effects for tenofovir and maraviroc. Approximately 7 h is required between HIV integration and virion production. First-phase HIV RNA decay (half-life of 17 h over all drugs) seemed to slow as the stage being inhibited by the drug was further from viral production. The mean estimated half-life of plasma virions was 5 min, significantly shorter than previous estimates.

Effect of interferon‐alpha therapy on hepatitis D virus

“…Interestingly, we recently showed 2 that a biphasic viral decline was also observed in patients treated with lonafarnib, a prenylation inhibitor, which was previously shown to block HDV assembly/secretion. 3 The similarity in the pattern of viral decline reinforces our conclusion that an additional effect in blocking viral infection cannot be ruled out, but that the main mechanism of action of IFN is blocking viral production.…”

“…In contrast, inhibition of new infection will take a while to manifest itself on virion levels in serum given that a cell infected just before therapy will take some time to produce virus as the infection progresses through its complete replication cycle within that cell. This difference of effect determined by the length of the initial delay before viremia decreases has been observed in human immunodeficiency virus (HIV) by Murray et al 3 Monotherapy that inhibits fusion of a virion with a cell showed a larger initial delay in response than a drug that inhibited a later stage, such as integration of HIV DNA into the cell genome. All of these results and the long delay before HDV RNA decreases after IFN suggest that this drug impacts on new infection, rather than the much later stage of HDV virion production.…”

Early HIV RNA decay during raltegravir-containing regimens exhibits two distinct subphases (1a and 1b)

“…This model is a simple extension of the basic model of viral infection [1] and similar models have been proposed [12, 23, 26]. Here, as has been done before [1, 6], we assume that the plasma HIV RNA is at set-point before therapy, that the virus and infected cells are in quasi-steady state (i.e., V ≈ p I 2 / c ), and, as we focus on the early viral kinetics, we make the standard approximation that the number of target cells remains constant.…”

Novel Prospective Treatment Options

“…Active targeting exploits these viral components on the cell surface to selectively identify the infected cells from the uninfected ones [13]. Active replication of HIV in vivo, from the point of infection of a CD4 T-cell to release of viral progeny takes an average of 52 hours for completion [14]. This long generation time of HIV could be effectively utilized to specifically deliver the anti-retroviral drugs to the infected cells by nanotechnology methods.…”