scholarly journals Markov Chain-Based Stochastic Modelling of HIV-1 Life Cycle in a CD4 T Cell

Mathematics ◽  
2021 ◽  
Vol 9 (17) ◽  
pp. 2025
Author(s):  
Igor Sazonov ◽  
Dmitry Grebennikov ◽  
Andreas Meyerhans ◽  
Gennady Bocharov
Keyword(s):  
Markov Chain ◽  
Life Cycle ◽  
T Cell ◽  
Phenotypic Diversity ◽  
Cd4 T Cell ◽  
Statistical Characteristics ◽  
Model Parameters ◽  
Cell Infection ◽  
Viral Progeny ◽  
Infected Cells

Replication of Human Immunodeficiency Virus type 1 (HIV) in infected CD4+ T cells represents a key driver of HIV infection. The HIV life cycle is characterised by the heterogeneity of infected cells with respect to multiplicity of infection and the variability in viral progeny. This heterogeneity can result from the phenotypic diversity of infected cells as well as from random effects and fluctuations in the kinetics of biochemical reactions underlying the virus replication cycle. To quantify the contribution of stochastic effects to the variability of HIV life cycle kinetics, we propose a high-resolution mathematical model formulated as a Markov chain jump process. The model is applied to generate the statistical characteristics of the (i) cell infection multiplicity, (ii) cooperative nature of viral replication, and (iii) variability in virus secretion by phenotypically identical cells. We show that the infection with a fixed number of viruses per CD4+ T cell leads to some heterogeneity of infected cells with respect to the number of integrated proviral genomes. The bottleneck factors in the virus production are identified, including the Gag-Pol proteins. Sensitivity analysis enables ranking of the model parameters with respect to the strength of their impact on the size of viral progeny. The first three globally influential parameters are the transport of genomic mRNA to membrane, the tolerance of transcription activation to Tat-mediated regulation, and the degradation of free and mature virions. These can be considered as potential therapeutical targets.

scholarly journals Infection of HLA-DR1 Transgenic Mice with a Human Isolate of Influenza A Virus (H1N1) Primes a Diverse CD4 T-Cell Repertoire That Includes CD4 T Cells with Heterosubtypic Cross-Reactivity to Avian (H5N1) Influenza Virus

2009 ◽  
Vol 83 (13) ◽  
pp. 6566-6577 ◽  
Author(s):  
Katherine A. Richards ◽  
Francisco A. Chaves ◽  
Andrea J. Sant
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Cd4 T Cells ◽  
Cross Reactivity ◽  
Cd4 T Cell ◽  
Ns1 Protein ◽  
Infected Cells

ABSTRACT The specificity of the CD4 T-cell immune response to influenza virus is influenced by the genetic complexity of the virus and periodic encounters with variant subtypes and strains. In order to understand what controls CD4 T-cell reactivity to influenza virus proteins and how the influenza virus-specific memory compartment is shaped over time, it is first necessary to understand the diversity of the primary CD4 T-cell response. In the study reported here, we have used an unbiased approach to evaluate the peptide specificity of CD4 T cells elicited after live influenza virus infection. We have focused on four viral proteins that have distinct intracellular distributions in infected cells, hemagglutinin (HA), neuraminidase (NA), nucleoprotein, and the NS1 protein, which is expressed in infected cells but excluded from virion particles. Our studies revealed an extensive diversity of influenza virus-specific CD4 T cells that includes T cells for each viral protein and for the unexpected immunogenicity of the NS1 protein. Due to the recent concern about pandemic avian influenza virus and because CD4 T cells specific for HA and NA may be particularly useful for promoting the production of neutralizing antibody to influenza virus, we have also evaluated the ability of HA- and NA-specific CD4 T cells elicited by a circulating H1N1 strain to cross-react with related sequences found in an avian H5N1 virus and find substantial cross-reactivity, suggesting that seasonal vaccines may help promote protection against avian influenza virus.

scholarly journals Infection of CD8+CD45RO+ Memory T-Cells by HIV-1 and Their Proliferative Response

2008 ◽  
Vol 2 (1) ◽  
pp. 43-57 ◽  
Author(s):  
Naveed Gulzar ◽  
Sowyma Balasubramanian ◽  
Greg Harris ◽  
Jaime Sanchez-Dardon ◽  
Karen F.T. Copeland
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Proliferative Response ◽  
Cell Infection ◽  
Cellular Target ◽  
Potential Reservoir ◽  
Infected Cells ◽  
Hiv 1

CD8+ T-cells are involved in controlling HIV-1 infection by eliminating infected cells and secreting soluble factors that inhibit viral replication. To investigate the mechanism and significance of infection of CD8+ T-cells by HIV-1in vitro, we examined the susceptibility of these cells and their subsets to infection. CD8+ T-cells supported greater levels of replication with T-cell tropic strains of HIV-1, though viral production was lower than that observed in CD4+ T-cells. CD8+ T-cell infection was found to be productive through ELISA, RT-PCR and flow cytometric analyses. In addition, the CD8+CD45RO+ memory T-cell population supported higher levels of HIV-1 replication than CD8+CD45RA+ naïve T-cells. However, infection of CD8+CD45RO+ T-cells did not affect their proliferative response to the majority of mitogens tested. We conclude, with numerous lines of evidence detecting and measuring infection of CD8+ T-cells and their subsets, that this cellular target and potential reservoir may be central to HIV-1 pathogenesis.

scholarly journals Autographa californica Multiple Nucleopolyhedrovirus exon0 (orf141), Which Encodes a RING Finger Protein, Is Required for Efficient Production of Budded Virus

2004 ◽  
Vol 78 (18) ◽  
pp. 9633-9644 ◽  
Author(s):  
Xiaojiang Dai ◽  
Taryn M. Stewart ◽  
Joseph A. Pathakamuri ◽  
Qianjun Li ◽  
David A. Theilmann
Keyword(s):  
Life Cycle ◽  
Ring Finger ◽  
Autographa Californica ◽  
Transcriptional Analysis ◽  
Wild Type Virus ◽  
Efficient Production ◽  
Cell Infection ◽  
Multiple Nucleopolyhedrovirus ◽  
Infected Cells ◽  
Budded Virus

ABSTRACT exon0 (orf141) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is a highly conserved baculovirus gene that codes for a predicted 261-amino-acid protein. Located in the C-terminal region of EXON0 are a predicted leucine-rich coiled-coil domain and a RING finger motif. The 5′ 114 nucleotides of exon0 form part of ie0, which is a spliced gene expressed at very early times postinfection, but transcriptional analysis revealed that exon0 is transcribed as a late gene. To determine the role of exon0 in the baculovirus life cycle, we used AcMNPV bacmids and generated exon0 knockout viruses (Ac-exon0-KO) by recombination in Escherichia coli. Ac-exon0-KO progressed through the very late phases in Sf9 cells, as evidenced by the development of occlusion bodies in the nuclei of the transfected or infected cells. However, production of budded virus (BV) in Ac-exon0-KO-infected cells was reduced at least 3 orders of magnitude in comparison to that in wild-type virus infection. Microscopy revealed that Ac-exon0-KO was restricted primarily to the cells initially infected, exhibiting a single-cell infection phenotype. Slot blot assays and Western blot analysis indicated that exon0 deletion did not affect the onset or levels of viral DNA replication or the expression of IE1, IE0, and GP64 prior to BV release. These results demonstrate that exon0 is required for efficient production of BV in the AcMNPV life cycle but does not affect late occlusion-derived virus.

scholarly journals Anchor sequence-dependent endogenous processing of human immunodeficiency virus 1 envelope glycoprotein gp160 for CD4+ T cell recognition.

1990 ◽  
Vol 171 (3) ◽  
pp. 875-887 ◽  
Author(s):  
M Polydefkis ◽  
S Koenig ◽  
C Flexner ◽  
E Obah ◽  
K Gebo ◽  
...  
Keyword(s):  
T Cell ◽  
Envelope Glycoprotein ◽  
Recombinant Vaccinia Virus ◽  
Cd4 T Cell ◽  
Cellular Transport ◽  
Cell Clones ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Anchor Sequence ◽  
Hydrophobic Anchor

Human CD4+ T cell clones and cell lines were shown to lyse recombinant vaccinia virus-infected cells that synthesize the HIV-1 envelope glycoprotein gp160. The processing of endogenously synthesized gp160 for recognition by CD4+ T cells required that the protein, after synthesis on the rough endoplasmic reticulum and during subsequent cellular transport, remain attached to the luminal/extracellular membrane face by a hydrophobic anchor sequence.

scholarly journals CD4+ T cell-mimicking nanoparticles encapsulating DIABLO/SMAC mimetics broadly neutralize HIV-1 and selectively kill HIV-1-infected cells

Theranostics ◽  
2021 ◽  
Vol 11 (18) ◽  
pp. 9009-9021
Author(s):  
Grant R. Campbell ◽  
Jia Zhuang ◽  
Gang Zhang ◽  
Igor Landa ◽  
Luke J. Kubiatowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Cd4 T Cell ◽  
Smac Mimetics ◽  
Infected Cells ◽  
Hiv 1

scholarly journals CD32+and PD-1+Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Alessandra Noto ◽  
Francesco A. Procopio ◽  
Riddhima Banga ◽  
Madeleine Suffiotti ◽  
Jean-Marc Corpataux ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Population ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Populations ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTA recent study conducted in blood has proposed CD32 as the marker identifying the “elusive” HIV reservoir. We have investigated the distribution of CD32+CD4 T cells in blood and lymph nodes (LNs) of HIV-1-uninfected subjects and viremic untreated and long-term-treated HIV-1-infected individuals and their relationship with PD-1+CD4 T cells. The frequency of CD32+CD4 T cells was increased in viremic compared to treated individuals in LNs, and a large proportion (up to 50%) of CD32+cells coexpressed PD-1 and were enriched within T follicular helper (Tfh) cells. We next investigated the role of LN CD32+CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32+and PD-1+CD4 T cells compared to CD32−and PD-1−cells in both viremic and treated individuals, but there was no difference between CD32+and PD-1+cells. There was no enrichment of latently infected cells with inducible HIV-1 in CD32+versus PD-1+cells in antiretroviral therapy (ART)-treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32+PD-1+CD4 T cells were significantly enriched in cell-associated HIV RNA compared to CD32−PD-1−(averages of 5.2-fold in treated individuals and 86.6-fold in viremics), CD32+PD-1−(2.2-fold in treated individuals and 4.3-fold in viremics), and CD32−PD-1+(2.2-fold in ART-treated individuals and 4.6-fold in viremics) cell populations. Similar levels of HIV-1 transcription were found in CD32+PD-1−and CD32−PD-1+CD4 T cells. Interestingly, the proportion of CD32+and PD-1+CD4 T cells negatively correlated with CD4 T cell counts and length of therapy. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and coexpression of CD32 and PD-1, the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.IMPORTANCEThe existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.

scholarly journals Anti-apoptotic clone 11 derived peptides induce in vitro death of CD4+ T cells susceptible to HIV-1 infection

2020 ◽  
Author(s):  
Anastassia Mikhailova ◽  
José Carlos Valle-Casuso ◽  
Annie David ◽  
Valérie Monceaux ◽  
Stevenn Volant ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
T Cell Memory ◽  
Target Cells ◽  
Cell Memory ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTHIV-1 successfully establishes long-term infection in its target cells despite viral cytotoxic effects. We have recently shown that cell metabolism is an important factor driving CD4+ T-cell susceptibility to HIV-1 and the survival of infected cells. We show here that expression of anti-apoptotic clone 11 (AAC-11), an anti-apoptotic factor upregulated in many cancers, increased with progressive CD4+ T cell memory differentiation in association with the expression of cell cycle, activation and metabolism genes and correlated with susceptibility to HIV-1 infection. Synthetic peptides based on the LZ domain sequence of AAC-11, responsible for its interaction with molecular partners, were previously shown to be cytotoxic to cancer cells. Here we observed that these peptides also blocked HIV-1 infection by inducing cell death of HIV-1 susceptible primary CD4+ T-cells across all T-cell subsets. The peptides targeted metabolically active cells and had the greatest effect on effector and transitional CD4+ T cell memory subsets. Our results suggest that AAC-11 survival pathway is potentially involved in the survival of HIV-1 infectable cells and provide a proof of principle that some cellular characteristics can be targeted to eliminate the cells offering the best conditions to sustain HIV-1 replication.IMPORTANCEAlthough antiretroviral treatment efficiently blocks HIV multiplication, it cannot eliminate the cells already carrying integrated proviruses. In the search for a HIV cure the identification of new potential targets to selectively eliminate infected cells is of the outmost importance. We show here that peptides derived from the anti-apoptotic clone 11 (AAC-11), which expression levels correlated with susceptibility to HIV-1 infection of CD4+ T-cells, induced cytotoxicity in CD4+ T-cells showing the highest levels of activation and metabolic activity, conditions known to favor HIV-1 infection. Accordingly, CD4+ T-cells that survived the cytotoxic action of the AAC-11 peptides were resistant to HIV-1 replication. Our results identify a new potential molecular pathway to target HIV-1 infection.

Aberrant life cycle of human immunodeficiency virus type 1 CRF15_01B-like clinical isolates from Thailand in human CD4+ T-cell lines

2007 ◽  
Vol 9 (4) ◽  
pp. 449-459 ◽  
Author(s):  
Jiranan Warachit ◽  
Yukie Iwabu ◽  
Yong-Gang Li ◽  
Gui-Mei Li ◽  
Panasda Isarangkura ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Life Cycle ◽  
T Cell ◽  
Cell Lines ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cd4 T Cell ◽  
Immunodeficiency Virus ◽  
T Cell Lines

The role of the human cytomegalovirus UL111A gene in down-regulating CD4+ T-cell recognition of latently infected cells: implications for virus elimination during latency

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4128-4137 ◽  
Author(s):  
Allen K. L. Cheung ◽  
David J. Gottlieb ◽  
Bodo Plachter ◽  
Sandra Pepperl-Klindworth ◽  
Selmir Avdic ◽  
...  
Keyword(s):  
T Cell ◽  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Interleukin 10 ◽  
Cd4 T Cell ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Latently Infected ◽  
Infected Cells

AbstractThe capacity of human cytomegalovirus (HCMV) to establish and maintain a latent infection from which it can later reactivate ensures its widespread distribution in the population, but the mechanisms enabling maintenance of latency in the face of a robust immune system are poorly understood. We examined the role of the HCMV UL111A gene, which encodes homologs of the immunosuppressive cytokine interleukin-10 in the context of latent infection of myeloid progenitor cells. A UL111A deletion virus was able to establish, maintain, and reactivate from experimental latency in a manner comparable with parental virus, but major histocompatibility complex class II levels increased significantly on the surfaces of cells infected with the deletion virus. Importantly, there was an increase in both allogeneic and autologous peripheral blood mononuclear cells and CD4+ T-cell responses to UL111A deletion virus-infected myeloid progenitors, indicating that loss of the capacity to express viral interleukin-10 during latency results in latently infected cells becoming more readily recognizable by a critical arm of the immune response. The detection of a viral gene that suppresses CD4+ T-cell recognition of latently infected cells identifies an immune evasion strategy that probably enhances the capacity of HCMV to persist in a latent state within the human host.

scholarly journals Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection

2021 ◽  
Vol 17 (12) ◽  
pp. e1010105
Author(s):  
Vishakha Sharma ◽  
Matthew Creegan ◽  
Andrey Tokarev ◽  
Denise Hsu ◽  
Bonnie M. Slike ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebrospinal Fluid ◽  
T Cell ◽  
Viral Rna ◽  
Cd4 T Cell ◽  
Cell Infection ◽  
Viral Reservoirs ◽  
Acute Hiv ◽  
Shiv Infection ◽  
Hiv 1

HIV-1 replication within the central nervous system (CNS) impairs neurocognitive function and has the potential to establish persistent, compartmentalized viral reservoirs. The origins of HIV-1 detected in the CNS compartment are unknown, including whether cells within the cerebrospinal fluid (CSF) produce virus. We measured viral RNA+ cells in CSF from acutely infected macaques longitudinally and people living with early stages of acute HIV-1. Active viral transcription (spliced viral RNA) was present in CSF CD4+ T cells as early as four weeks post-SHIV infection, and among all acute HIV-1 specimens (N = 6; Fiebig III/IV). Replication-inactive CD4+ T cell infection, indicated by unspliced viral RNA in the absence of spliced viral RNA, was even more prevalent, present in CSF of >50% macaques and human CSF at ~10-fold higher frequency than productive infection. Infection levels were similar between CSF and peripheral blood (and lymph nodes in macaques), indicating comparable T cell infection across these compartments. In addition, surface markers of activation were increased on CSF T cells and monocytes and correlated with CSF soluble markers of inflammation. These studies provide direct evidence of HIV-1 replication in CD4+ T cells and broad immune activation in peripheral blood and the CNS during acute infection, likely contributing to early neuroinflammation and reservoir seeding. Thus, early initiation of antiretroviral therapy may not be able to prevent establishment of CNS viral reservoirs and sources of long-term inflammation, important targets for HIV-1 cure and therapeutic strategies.

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