Intracellular Dynamics of HIV Infection

Petravic, Janka; Ellenberg, Paula; Chan, Ming-Liang; Paukovics, Geza; Smyth, Redmond P.; Mak, Johnson; Davenport, Miles P.

doi:10.1128/jvi.02038-13

Cited by 19 publications

(23 citation statements)

References 31 publications

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“…Detailed studies of viral reactivation kinetics are essential for understanding both the mechanisms of viral suppression by antiviral drugs and the mechanisms leading to HIV-1 reactivation in latently infected cells (36). The major strength of the fluorescence in situ hybridization assay (PrimeFlow RNA assay) used here is the ability to simultaneously and specifically quantify intracellular viral mRNA and protein expression levels as well as the expression of cell surface molecules by flow cytometry on the single-cell level.…”

Section: Resultsmentioning

confidence: 99%

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique

Martrus

Niehrs

Cornelis

et al. 2016

J Virol

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O ne major obstacle toward an effective human immunodeficiency virus type 1 (HIV-1) cure is the establishment of a pool of long-lived latently infected cells early after infection (1). Using the rhesus macaque model of simian immunodeficiency virus (SIV) infection, it was recently shown that latent reservoirs could be seeded as early as 3 days after SIV exposure and before the detection of viremia in blood (2). The vast majority of cells infected with HIV-1 will die as a consequence of the infection or will be eliminated by the immune system. A minority of infected cells, however, turns into latently infected resting cells. These cells can either be reactivated and release de novo HIV-1 particles (3) or persist and homeostatically proliferate as long-lived memory T cells (4, 5). While current antiretroviral treatments (ARTs) can efficiently suppress HIV-1 replication and have dramatically improved the life expectancy and life quality of infected individuals, ART cannot eradicate the latent viral reservoir.Several different biological processes have been described to maintain latency in HIV-1-infected cells. Host transcription factors (TFs) such as nuclear factor kappa light-chain enhancer of activated B cells (NF-B) have multiple binding sites in the 5= long terminal repeat (LTR) of the HIV-1 genome, and their binding has been demonstrated to be necessary to initiate HIV-1 transcription (6). Sequestration of these TFs in the cytoplasm is one of the mechanisms enabling viral latency (7). Another described HIV-1 latency mechanism involves histone deacetylase (HDAC)-mediated epigenetic silencing (8). During latency establishment, HDAC molecules are recruited toward the 5= LTR of HIV-1 (9, 10) and therefore maintain the LTR in a repressed state (11). Several HDAC inhibitors (HDACis) targeting HDAC molecules have been tested for their ability to reactivate latently HIV-1-infected cells, including vorinostat, panobinostat, entinostat, and romidepsin (RMD). These HDACis proved to efficiently induce HIV-1 expression in latently infected resting CD4 ϩ T cells from HIV-1-infected individuals (8,12,13). RMD, a drug that has been used for the treatment of peripheral T-cell lymphoma,

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Section: Resultsmentioning

confidence: 99%

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique

Martrus

Niehrs

Cornelis

et al. 2016

J Virol

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“…Another possibility is that the cells with reactivated HIV are dividing, in addition to dying at a natural rate. We did not consider this possibility, because we assumed that virus transcription would lead to cell cycle arrest (29,30).…”

Section: Implications Of the Model For Interpreting Clinical Trial Datamentioning

confidence: 99%

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Petravic

Rasmussen

Lewin

et al. 2017

J Virol

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Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latencyreversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3-to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life Ͼ 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment.IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.KEYWORDS latency, reactivation, human immunodeficiency virus C ombination antiretroviral therapy (ART) suppresses plasma HIV RNA below the detection limit of laboratory assays and restores the immune systems of infected patients by preventing new rounds of productive infection. However, ART cannot eradicate the infection, and virus replication starts again within weeks of ART cessation

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“…Note that the measurement units of virus (RNA copies or TCID 50 ) used in our analysis changes both the units and physical meaning of the virus production ‫)(‬ and cell infection (ߚ) rates, changes the meaning and value of the virus loss (ܿ), and the value of the infectious cell lifespan estimated from the experimental data (ߜሻ. (Holder and Beauchemin, 2011;Petravic et al, 2014;Pinilla et al, 2012 . In the case of a non-lytic virus (i.e., ߜ ൌ 0), the burst size becomes infinity, which implies these two terms become 0 and Eq.…”

Section: Derivation Of a Conservation Law For Viral Infectionsmentioning

confidence: 99%

A conservation law for virus infection kinetics in vitro

Kakizoe

Morita

Nakaoka

et al. 2015

Journal of Theoretical Biology

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Conservation laws are among the most important properties of a physical system, but are not commonplace in biology. We derived a conservation law from the basic model for viral infections which consists in a small set of ordinary differential equations. We challenged the conservation law experimentally for the case of a virus infection in a cell culture. We found that the derived, conserved quantity remained almost constant throughout the infection period, implying that the derived conservation law holds in this biological system. We also suggest a potential use for the conservation law in evaluating the accuracy of experimental measurements.

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Intracellular Dynamics of HIV Infection

Cited by 19 publications

References 31 publications

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

A conservation law for virus infection kinetics in vitro

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