Lentiviral Nef Proteins Manipulate T Cells in a Subset-Specific Manner

Yu, Hangxing; Khalid, Mohammad; Heigele, Anke; Schmökel, Jan; Usmani, Shariq M.; Merwe, Johannes van der; Münch, Jan; Silvestri, Guido; Kirchhoff, Frank

doi:10.1128/jvi.03104-14

Cited by 9 publications

(8 citation statements)

References 39 publications

(81 reference statements)

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“…1 a). In agreement with our previous finding that TN cells are largely refractory to X4 HIV-1 infection [ 28 ], they were strongly underrepresented in the GFP+ apoptotic lymphocyte population (Fig. 6 b).…”

Section: Resultssupporting

confidence: 92%

Increased susceptibility of CD4+ T cells from elderly individuals to HIV-1 infection and apoptosis is associated with reduced CD4 and enhanced CXCR4 and FAS surface expression levels

et al. 2015

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BackgroundElderly HIV-1 infected individuals progress to AIDS more frequently and rapidly than people becoming infected at a young age. To identify possible reasons for these differences in clinical progression, we performed comprehensive phenotypic analyses of CD4+ T cells from uninfected young and elderly individuals, and examined their susceptibility to HIV-1 infection and programmed death.ResultsPeripheral blood mononuclear cells (PBMCs) from older people contain an increased percentage of central memory and Th17 CD4+ T cells that are main target cells of HIV-1 and strongly reduced proportions of naïve T cells that are poorly susceptible to HIV-1. Unstimulated T cells from elderly individuals expressed higher levels of activation markers, death receptors, and the viral CXCR4 co-receptor than those from young individuals but responded poorly to stimulation. CD4+ T cells from older individuals were highly susceptible to CXCR4- and CCR5-tropic HIV-1 infection but produced significantly lower quantities of infectious virus than cells from young individuals because they were highly prone to apoptosis and thus presumably had a very short life span. The increased susceptibility of T cells from the elderly to HIV-1 infection correlated directly with CXCR4 and inversely with CD4 expression. The levels of apoptosis correlated with the cell surface expression of FAS but not with the expression of programmed death receptor 1 (PD1) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).ConclusionsIncreased levels of activated and highly susceptible HIV-1 target cells, reduced CD4 and enhanced CXCR4 cell surface expression, together with the high susceptibility to FAS-induced programmed cell death may contribute to the rapid CD4+ T cell depletion and accelerated clinical course of infection in elderly HIV-1-infected individuals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0213-1) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 92%

Increased susceptibility of CD4+ T cells from elderly individuals to HIV-1 infection and apoptosis is associated with reduced CD4 and enhanced CXCR4 and FAS surface expression levels

et al. 2015

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“…S1). As expected from published data (16,18), all HIV-1 Nefs (NL4.3 and two primary HIV-1 Nefs, NA7 and SF2), as well as the nef-defective virus, did not down-modulate CD3 ( Fig. 1B and SI Appendix, Fig.…”

Section: Retained Cd3 Expression On Infected Cells Results In Increasedsupporting

confidence: 87%

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

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et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Nef is an accessory protein of primate lentiviruses that is essential for efficient replication and pathogenesis of HIV-1. A conserved feature of Nef proteins from different lentiviral lineages is the ability to modulate host protein trafficking and down-regulate a number of cell surface receptors to enhance replication and promote immune evasion. Notably, the inability of Nef to down-regulate CD3 from infected T cells distinguishes HIV-1 Nef and its direct simian precursors from other primate lentiviruses. Why HIV-1 does not employ this potential immune evasion strategy is not fully understood. Using chimeric HIV-1 constructs expressing lentiviral Nef proteins that differ in their ability to down-modulate CD3, we show that retaining CD3 on the surface of infected primary T cells results in increased viral replication and cell-to-cell spread. We identified increased expression of envelope (Env) trimers at the cell surface and increased Env incorporation into virions as the determinants for the Nef-and CD3-dependent enhancement of viral infectivity. Importantly, this was independent of Nef-mediated antagonism of the host restriction factor SERINC5. CD3 retention on the surface of infected primary T cells also correlated with increased T cell signaling, activation, and cell death during cell-tocell spread. Taken together, our results show that loss of an otherwise conserved function of Nef has a positive effect on HIV-1 replication, allowing for more efficient replication while potentially contributing to HIV-1 pathogenesis by triggering T cell activation and cell death during viral spread.HIV | CD3 | Nef | T cell | Env

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“…The Tdp population, previously described in tonsillar cultures (Picker et al, 1993; Sen et al, 2014), may be particularly susceptible to HIV infection (Yu et al, 2015). Standard 2D dot plot analysis of the expression levels of CD45RA and CD45RO on T cells in fact revealed two subsets of Tdp: one expressing intermediate levels of CD45RA and CD45RO (Tdp intermediate ) and another expressing high levels of both antigens (Tdp high ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mass Cytometric Analysis of HIV Entry, Replication, and Remodeling in Tissue CD4+ T Cells

et al. 2017

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Summary To characterize susceptibility to HIV infection, we phenotyped infected tonsillar T cells by single-cell mass cytometry and created comprehensive maps to identify which subsets of CD4+ T cells support HIV fusion and productive infection. By comparing HIV-fused and HIV-infected cells through dimensionality reduction, clustering, and statistical approaches to account for viral perturbations, we identified a subset of memory CD4+ T cells that support HIV entry but not viral gene expression. These cells express high levels of CD127, the IL-7 receptor, and are believed to be long-lived lymphocytes. In HIV-infected patients, CD127-expressing cells preferentially localize to extrafollicular lymphoid regions with limited viral replication. Thus, CyTOF-based phenotyping combined with analytical approaches to distinguish between selective infection and receptor modulation by viruses can be used as a discovery tool.

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Lentiviral Nef Proteins Manipulate T Cells in a Subset-Specific Manner

Cited by 9 publications

References 39 publications

Increased susceptibility of CD4+ T cells from elderly individuals to HIV-1 infection and apoptosis is associated with reduced CD4 and enhanced CXCR4 and FAS surface expression levels

Increased susceptibility of CD4+ T cells from elderly individuals to HIV-1 infection and apoptosis is associated with reduced CD4 and enhanced CXCR4 and FAS surface expression levels

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

Mass Cytometric Analysis of HIV Entry, Replication, and Remodeling in Tissue CD4+ T Cells

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