HIV-1-Infected CD4+ T Cells Facilitate Latent Infection of Resting CD4+ T Cells through Cell-Cell Contact

Agosto, Luis M.; Herring, Melissa Beth; Mothes, Walther; Henderson, Andrew J.

doi:10.1016/j.celrep.2018.07.079

Cited by 66 publications

(58 citation statements)

References 81 publications

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“…These observations indicate that initial transmission is at a low viral dose, sufficient to infect at most one or few cells. This may also be consistent with initial HIV transmission occurring by cell-free HIV infection, where cell-free virions rely on diffusion to reach an infectable cell and therefore have a low probability to infect [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. In contrast, an infected cell is likely to deliver considerable numbers of virions (10 3 to 10 4 virions are produced per cell [52,53]) if it is at close range.…”

Section: Introductionsupporting

confidence: 60%

Interference with HIV infection of the first cell is essential for viral clearance at sub-optimal levels of drug inhibition

et al. 2020

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HIV infection can be cleared with antiretroviral drugs if they are administered before exposure, where exposure occurs at low viral doses which infect one or few cells. However, infection clearance does not happen once infection is established, and this may be because of the very early formation of a reservoir of latently infected cells. Here we investigated whether initial low dose infection could be cleared with sub-optimal drug inhibition which allows ongoing viral replication, and hence does not require latency for viral persistence. We derived a model for infection clearance with inputs being drug effects on ongoing viral replication and initial number of infected cells. We experimentally tested the model by inhibiting low dose infection with the drug tenofovir, which interferes with initial infection, and atazanavir, which reduces the cellular virion burst size and hence inhibits replication only after initial infection. Drugs were used at concentrations which allowed infection to expand. Under these conditions, tenofovir dramatically increased clearance while atazanavir did not. Addition of latency to the model resulted in a minor decrease in clearance probability if the drug inhibited initial infection. If not, latency strongly decreased clearance even at low latent cell frequencies. Therefore, the ability of drugs to clear initial but not established infection can be recapitulated without latency and depends only on the ability to target initial infection. The presence of latency can dramatically decrease infection clearance, but only if the drug is unable to interfere with infection of the first cells.

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Section: Introductionsupporting

confidence: 60%

Interference with HIV infection of the first cell is essential for viral clearance at sub-optimal levels of drug inhibition

et al. 2020

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“…Furthermore, the use of superantigens during viral entry increases HIV-1 replication [26]. Partial activation, cellular polarization, cell-to-cell contact, and/or infection of resting quiescent cells through perturbation have also been suggested to bias infections towards latency [11,[27][28][29][30][31]. Therefore, the extent of cell activation is a key determinant in regulating the course of HIV-1 infection including the formation of the reservoir.…”

Section: Discussionmentioning

confidence: 99%

Strength of T cell signaling regulates HIV-1 replication and establishment of latency

Gagné

Michaels

Lester

et al. 2018

Preprint

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A major barrier to curing HIV is the long-lived latent reservoir that supports re-emergence of HIV upon treatment interruption. Targeting this reservoir will require mechanistic insights into the establishment and maintenance of HIV latency. Whether T cell signaling at the time of HIV-1 infection influences productive replication or latency is not fully understood. We used a panel of chimeric antigen receptors (CARs) with different ligand binding affinities to induce a range of signaling strengths to model differential T cell receptor signaling at the time of HIV-1 infection. Stimulation of T cell lines or primary CD4+ T cells expressing chimeric antigen receptorssupported HIV-1 infection regardless of affinity for ligand; however, only signaling by the highest affinity receptor facilitated HIV-1 expression. Activation of chimeric antigen receptors that had intermediate and low binding affinities did not support provirus transcription, suggesting that a minimal signal is required for optimal HIV-1 expression. In addition, strong signaling at the time of infection produced a latent population that was readily inducible, whereas latent cells generated in response to weaker signals were not easily reversed. Chromatin immunoprecipitation showed HIV-1 transcription was limited by transcriptional elongation and that robust signaling decreased the presence of negative elongation factor, a pausing factor, by more than 80%. These studies demonstrate that T cell signaling influences HIV-1 infection and the establishment of different subsets of latently infected cells, which may have implications for targeting the HIV reservoir. Author SummaryActivation of CD4+ T cells facilitates HIV-1 infection; however, whether there are minimal signals required for the establishment of infection, replication, and latency has not been explored. To determine how T cell signaling influences HIV-1 infection and the generation of latently infected cells, we used chimeric antigen receptors to create a tunable model. Stronger Gagne, et al. Page 3 signals result in robust HIV-1 expression and an inducible latent population. Minimal signals predispose cells towards latent infections that are refractory to reversal. We discovered that repression of HIV-1 transcription immediately after infection is due to RNA polymerase II pausing and inefficient transcription elongation. These studies demonstrate that signaling events influence the course of HIV-1 infection and have implications for cure strategies. They also provide a mechanistic explanation for why a significant portion of the HIV latent reservoir is not responsive to latency reversing agents which function by modifiying chromatin.

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“…Despite this, the relative effectiveness of each drug mechanism was clearly predicted by the model. Factors in vivo which may result in deviation from model predictions include transmission by cell-to-cell spread ( Sigal et al ( 2011 ); Boullé et al ( 2016 ); Jackson et al ( 2018 ); Jolly et al ( 2004 ); Duncan et al ( 2014 ); Agosto et al ( 2015 , 2018); Law et al ( 2016 ); Abela et al ( 2012 ); Rudnicka et al ( 2009 ); Sherer et al ( 2007 ); Zhong et al ( 2013 ); Del Portillo et al ( 2011 ); Sowinski et al ( 2008 ); Len et al ( 2017 ); Baxter et al ( 2014 ); Kim et al ( 2018 )). This should reduce the effectiveness of PrEP since the drugs would only act on R 0 and not on λ .…”

Section: Discussionmentioning

confidence: 99%

Interference with HIV infection of the first cell is essential for viral clearance in a pre-exposure prophylaxis model

Sigal

Muelas

Lustig

et al. 2018

Preprint

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Interference with HIV infection of1 the first cell is essential for viral 2 clearance in a pre-exposure 3 prophylaxis model 4 Abstract Pre-exposure prophylaxis (PrEP) uses relatively weak HIV inhibition to reduce 12 transmission between individuals. Why this approach is successful is unclear. Here we derive and 13 experimentally validate a mathematical model for predicting infection clearance with PrEP based 14 on the measured effect of a drug on the HIV replication ratio and number of initial infected cells. 15 We tested the model by inhibiting low dose HIV infection with tenofovir, which reduces infection 16 frequency per cell, and atazanavir, which reduces the cellular burst size of viable virions. Both 17 drugs were at concentrations which allowed similar HIV replication. Reducing infection frequency 18 dramatically increased infection clearance, while reducing burst size did not. This indicates that 19 initial infection is vulnerable to inhibition before it infects the first cell, but not thereafter. Our 20 model explains why PrEP is potent at drug concentrations which are ineffective against established 21 infection, and provides a framework to test drug effectiveness for PrEP. 22 23 33The probability of initial transmission has been shown to be effectively reduced with a single 34 ARV if the ARV is present before exposure takes place, an approach termed PrEP. The ARVs used 35 for PrEP are a subset found in the full treatment regimen. A central agent is tenofovir (TFV), 36 which interferes with viral reverse transcription and is usually delivered as the prodrug tenofovir 37 disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF). TFV is either used by itself or 38 co-administered with emtricitabine (FTC), another HIV reverse transcriptase inhibitor. This approach 39 1 of 16 Manuscript submitted to eLife 0 Treated Untreated Inhibition Key: Transmission Uninfected cell Infected cell X Established infection PI RTI PrEP PI RTI XXXX XXXX X X 333 AS thanks Israel Michael Sigal for extensive discussions, and Deenan Pillay, Mark Siedner, and 334 Brenda Tipper for comments on the manuscript. 335 References 336

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HIV-1-Infected CD4+ T Cells Facilitate Latent Infection of Resting CD4+ T Cells through Cell-Cell Contact

Cited by 66 publications

References 81 publications

Interference with HIV infection of the first cell is essential for viral clearance at sub-optimal levels of drug inhibition

Interference with HIV infection of the first cell is essential for viral clearance at sub-optimal levels of drug inhibition

Strength of T cell signaling regulates HIV-1 replication and establishment of latency

Interference with HIV infection of the first cell is essential for viral clearance in a pre-exposure prophylaxis model

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