The HIV Envelope but Not VSV Glycoprotein Is Capable of Mediating HIV Latent Infection of Resting CD4 T Cells

Yu, Dongyang; Wang, Weifeng; Yoder, Alyson; Spear, Mark; Wu, Yuntao

doi:10.1371/journal.ppat.1000633

Cited by 73 publications

(90 citation statements)

References 83 publications

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“…There is accumulating evidence that such viruses do not enter cells in the same way as wild-type enveloped viruses and that the infection outcome and replicating properties of those viruses are different (Agosto et al, 2009;Yu et al, 2009). However, in our previous study (Jacque & Stevenson, 2006), we addressed this issue, comparing the replication and integration of VSVG-and wild-type enveloped HIV-1 viruses.…”

Section: Discussionmentioning

confidence: 93%

Lentivirus-associated MAPK/ERK2 phosphorylates EMD and regulates infectivity

Bukong

Hall

Jacqué

2010

Journal of General Virology

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Infection of a cell by lentiviruses, such as human immunodeficiency virus type 1 or feline immunodeficiency virus, results in the formation of a reverse transcription complex, the preintegration complex (PIC), where viral DNA is synthesized. In non-dividing cells, efficient nuclear translocation of the PIC requires the presence of the inner nuclear lamina protein emerin (EMD). Here, we demonstrate that EMD phosphorylation is induced early after infection in primary nondividing cells. Furthermore, we demonstrate that EMD phosphorylation is dependent on virionassociated mitogen-activated protein kinase (MAPK). Specific inhibition of MAPK activity with kinase inhibitors markedly reduced EMD phosphorylation and resulted in decreased integration of the proviral DNA into chromatin. Similarly, when a MEK1 kinase-inactive mutant was expressed in virus-producer cells, virus-induced phosphorylation of EMD was impaired and viral integration reduced during the subsequent infection. Expression of constitutively active MEK1 kinase in producer cells did not result in modulation of EMD phosphorylation or viral integration during subsequent infection. These studies demonstrate that, in addition to phosphorylating components of the PICs at an early step of infection, virion-associated MAPK plays a role in facilitating cDNA integration after nuclear translocation through phosphorylation of target-cell EMD.

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Section: Discussionmentioning

confidence: 93%

Lentivirus-associated MAPK/ERK2 phosphorylates EMD and regulates infectivity

Bukong

Hall

Jacqué

2010

Journal of General Virology

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“…Single-cycle replicating viruses, HIV-1(VSV-G) and HIV-1(Env), were prepared as described previously (23). Levels of p24 in viral supernatant were measured using the PerkinElmer Alliance p24 antigen ELISA kit (PerkinElmer Life Sciences).…”

Section: Preparation Of Resting Cd4 T Cells and Macrophages Frommentioning

confidence: 99%

LIM Kinase 1 Modulates Cortical Actin and CXCR4 Cycling and Is Activated by HIV-1 to Initiate Viral Infection

Vorster

Guo

Yoder

et al. 2011

Journal of Biological Chemistry

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202

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Almost all viral pathogens utilize a cytoskeleton for their entry and intracellular transport. In HIV-1 infection, binding of the virus to blood resting CD4 T cells initiates a temporal course of cortical actin polymerization and depolymerization, a process mimicking the chemotactic response initiated from chemokine receptors. The actin depolymerization has been suggested to promote viral intracellular migration through cofilin-mediated actin treadmilling. However, the role of the virus-mediated actin polymerization in HIV infection is unknown, and the signaling molecules involved remain unidentified. Here we describe a pathogenic mechanism for triggering early actin polymerization through HIV-1 envelope-mediated transient activation of the LIM domain kinase (LIMK), a protein that phosphorylates cofilin. We demonstrate that HIV-mediated LIMK activation is through gp120-triggered transient activation of the Rack-PAK-LIMK pathway, and that knockdown of LIMK through siRNA decreases filamentous actin, increases CXCR4 trafficking, and diminishes viral DNA synthesis. These results suggest that HIV-mediated early actin polymerization may directly regulate the CXCR4 receptor during viral entry and is involved in viral DNA synthesis. Furthermore, we also demonstrate that in resting CD4 T cells, actin polymerization can be triggered through transient treatment with a pharmacological agent, okadaic acid, that activates LIMK and promotes HIV latent infection of resting CD4 T cells. Taken together, our results suggest that HIV hijacks LIMK to control the cortical actin dynamics for the initiation of viral infection of CD4 T cells.Infection by the human immunodeficiency virus (HIV) causes severe depletion of blood CD4 T cells (1, 2). The early interaction between HIV and T cells, particularly virus binding to its receptors, plays an important role in viral infection and pathogenesis. This interaction mediates viral fusion and entry (3, 4). It also initiates intracellular signaling cascades that are important for the early steps of the HIV life cycle (5-9). For example, it has recently been shown that at the earliest time of HIV infection, viral binding to the chemokine coreceptor, CXCR4, activates an actin depolymerization factor cofilin to increase the cortical actin dynamics in resting T cells, facilitating viral intracellular migration (9).The cortical actin is a common structure that is targeted by most viruses for entry and intracellular transport (10, 11). In HIV-1 infection, the direct involvement of the cortical actin in early stages of viral infection has been suggested in HIV-mediated CD4-CXCR4 receptor clustering (5-7, 12-14), subsequent viral DNA synthesis (9, 15), and intracellular migration (9). It has been shown that the initial binding of gp120 to surface CD4 promotes localized aggregation of the CD4 and CXCR4 receptor, which appears to be dependent on the actin-crosslinking protein filamin (7) and the ezrin-radixin-moesin protein moesin (5, 6). Filamin-A interacts directly with the cortical actin and with bot...

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“…More recently, a number of primary cell models have been developed to investigate the molecular mechanisms regulating HIV latency and aid in optimization of elimination strategies (6,12,44,45). However, tractable in vivo systems are still lacking.…”

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confidence: 99%

HIV Latency in the Humanized BLT Mouse

Marsden

Kovochich

Suree

et al. 2012

J Virol

107

115

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Even after extended treatment with powerful antiretroviral drugs, HIV is not completely eliminated from infected individuals. Latently infected CD4 ؉ T cells constitute one reservoir of replication-competent HIV that needs to be eliminated to completely purge virus from antiretroviral drug-treated patients. However, a major limitation in the development of therapies to eliminate this latent reservoir is the lack of relevant in vivo models that can be used to test purging strategies. Here, we show that the humanized BLT (bone marrow-liver-thymus) mouse can be used as both an abundant source of primary latently infected cells for ex vivo latency analysis and also as an in vivo system for the study of latency. We demonstrate that over 2% of human cells recovered from the spleens of HIV-infected BLT mice can be latently infected and that this virus is integrated, activation inducible, and replication competent. The non-tumor-inducing phorbol esters prostratin and 12-deoxyphorbol-13-phenylacetate can each induce HIV ex vivo from these latently infected cells, indicating that this model can be used as a source of primary cells for testing latency activators. Finally, we show activation-inducible virus is still present following suppression of plasma viral loads to undetectable levels by using the antiretroviral drugs zidovudine, indinavir sulfate, and didanosine, demonstrating that this model can also be used to assess the in vivo efficacy of latency-purging strategies. Therefore, the HIV-infected BLT mouse should provide a useful model for assessment of HIV latency activators and approaches to eliminate persistent in vivo HIV reservoirs.

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The HIV Envelope but Not VSV Glycoprotein Is Capable of Mediating HIV Latent Infection of Resting CD4 T Cells

Cited by 73 publications

References 83 publications

Lentivirus-associated MAPK/ERK2 phosphorylates EMD and regulates infectivity

Lentivirus-associated MAPK/ERK2 phosphorylates EMD and regulates infectivity

LIM Kinase 1 Modulates Cortical Actin and CXCR4 Cycling and Is Activated by HIV-1 to Initiate Viral Infection

HIV Latency in the Humanized BLT Mouse

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