scholarly journals Roles of Virion-Incorporated CD162 (PSGL-1), CD43, and CD44 in HIV-1 Infection of T Cells

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1935
Author(s):  
Tomoyuki Murakami ◽  
Akira Ono
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Transmembrane Proteins ◽  
Cell Polarization ◽  
Viral Envelope ◽  
Target Cells ◽  
Virus Attachment ◽  
Virion Incorporation ◽  
Trans Infection ◽  
Hiv 1

Nascent HIV-1 particles incorporate the viral envelope glycoprotein and multiple host transmembrane proteins during assembly at the plasma membrane. At least some of these host transmembrane proteins on the surface of virions are reported as pro-viral factors that enhance virus attachment to target cells or facilitate trans-infection of CD4+ T cells via interactions with non-T cells. In addition to the pro-viral factors, anti-viral transmembrane proteins are incorporated into progeny virions. These virion-incorporated transmembrane proteins inhibit HIV-1 entry at the point of attachment and fusion. In infected polarized CD4+ T cells, HIV-1 Gag localizes to a rear-end protrusion known as the uropod. Regardless of cell polarization, Gag colocalizes with and promotes the virion incorporation of a subset of uropod-directed host transmembrane proteins, including CD162, CD43, and CD44. Until recently, the functions of these virion-incorporated proteins had not been clear. Here, we review the recent findings about the roles played by virion-incorporated CD162, CD43, and CD44 in HIV-1 spread to CD4+ T cells.

scholarly journals The Inhibition of HIV-1 Entry Imposed by Interferon Inducible Transmembrane Proteins Is Independent of Co-Receptor Usage

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 413 ◽  
Author(s):  
Jingyou Yu ◽  
Shan-Lu Liu
Keyword(s):  
T Cells ◽  
Viral Entry ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Transmembrane Proteins ◽  
Target Cells ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Receptor Usage ◽  
Hiv 1

Interferon inducible transmembrane proteins (IFITMs) are one of several IFN-stimulated genes (ISGs) that restrict entry of enveloped viruses, including flaviviruses, filoviruses and retroviruses. It has been recently reported that in U87 glioblastoma cells IFITM proteins inhibit HIV-1 entry in a co-receptor-dependent manner, that is, IFITM1 is more inhibitory on CCR5 tropic HIV-1 whereas IFITM2/3 confers a greater suppression of CXCR4 counterparts. However, how entry of HIV-1 with distinct co-receptor usage is modulated by different IFITM orthologs in physiologically relevant CD4+ T cells and monocytes/macrophages has not been investigated in detail. Here, we report that overexpression of IFITM1, 2 and 3 in human CD4+ HuT78 cells, SupT1 cells, monocytic THP-1 cells and U87 cells expressing CD4 and co-receptor CCR5 or CXCR4, suppressed entry of CXCR4 tropic viruses NL4.3 and HXB2, CCR5 tropic viruses AD8 and JRFL, dual tropic 89.6 virus, as well as a panel of 32 transmitted founder (T/F) viruses, with a consistent order of potency, that is, IFITM3 > IFITM2 > IFITM1. Consistent with previous reports, we found that some CCR5-using HIV-1 isolates, such as AD8 and JRFL, were relatively resistant to inhibition by IFITM2 and IFITM3, although the effect can be cell-type dependent. However, in no case have we observed that IFITM1 had a stronger inhibition on entry of any HIV-1 strains tested, including those of CCR5-using T/Fs. We knocked down the endogenous IFITMs in peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells and observed that, while this treatment did greatly enhance the multiple-round of HIV-1 replication but had modest effect to rescue the single-round HIV-1 infection, reinforcing our previous conclusion that the predominant effect of IFITMs on HIV-1 infection is in viral producer cells, rather than in target cells to block viral entry. Overall, our results argue against the idea that IFITM proteins distinguish co-receptors CCR5 and CXCR4 to inhibit entry but emphasize that the predominant role of IFITMs on HIV-1 is in producer cells that intrinsically impair the viral infectivity.

scholarly journals Th1/17 Polarization of CD4 T Cells Supports HIV-1 Persistence during Antiretroviral Therapy

2015 ◽  
Vol 89 (22) ◽  
pp. 11284-11293 ◽  
Author(s):  
Hong Sun ◽  
Dhohyung Kim ◽  
Xiaodong Li ◽  
Maja Kiselinova ◽  
Zhengyu Ouyang ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Memory Cell ◽  
Viral Reservoir ◽  
Target Cells ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTThe ability to persist long term in latently infected CD4 T cells represents a characteristic feature of HIV-1 infection and the predominant barrier to efforts aiming at viral eradication and cure. Yet, increasing evidence suggests that only small subsets of CD4 T cells with specific developmental and maturational profiles are able to effectively support HIV-1 long-term persistence. Here, we analyzed how the functional polarization of CD4 T cells shapes and structures the reservoirs of HIV-1-infected cells. We found that CD4 T cells enriched for a Th1/17 polarization had elevated susceptibilities to HIV-1 infection inex vivoassays, harbored high levels of HIV-1 DNA in persons treated with antiretroviral therapy, and made a disproportionately increased contribution to the viral reservoir relative to their contribution to the CD4 T memory cell pool. Moreover, HIV-1 DNA levels in Th1/17 cells remained stable over many years of antiretroviral therapy, resulting in a progressively increasing contribution of these cells to the viral reservoir, and phylogenetic studies suggested preferential long-term persistence of identical viral sequences during prolonged antiretroviral treatment in this cell compartment. Together, these data suggest that Th1/17 CD4 T cells represent a preferred site for HIV-1 DNA long-term persistence in patients receiving antiretroviral therapy.IMPORTANCECurrent antiretroviral therapy is very effective in suppressing active HIV-1 replication but does not fully eliminate virally infected cells. The ability of HIV-1 to persist long term despite suppressive antiretroviral combination therapy represents a perplexing aspect of HIV-1 disease pathogenesis, since most HIV-1 target cells are activated, short-lived CD4 T cells. This study suggests that CD4 T helper cells with Th1/17 polarization have a preferential role as a long-term reservoir for HIV-1 infection during antiretroviral therapy, possibly because these cells may imitate some of the functional properties traditionally attributed to stem cells, such as the ability to persist for extremely long periods of time and to repopulate their own pool size through homeostatic self-renewal. These observations support the hypothesis that HIV-1 persistence is driven by small subsets of long-lasting stem cell-like CD4 T cells that may represent particularly promising targets for clinical strategies aiming at HIV-1 eradication and cure.

scholarly journals Trans-infection but Not Infection from within Endosomal Compartments after Cell-to-cell HIV-1 Transfer to CD4+T Cells

2012 ◽  
Vol 287 (38) ◽  
pp. 32017-32026 ◽  
Author(s):  
Marc Permanyer ◽  
Ester Ballana ◽  
Roger Badia ◽  
Eduardo Pauls ◽  
Bonaventura Clotet ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Trans Infection ◽  
Hiv 1

scholarly journals The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1299-1307 ◽  
Author(s):  
Alexandra A. Lambert ◽  
Caroline Gilbert ◽  
Manon Richard ◽  
André D. Beaulieu ◽  
Michel J. Tremblay
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Productive Infection ◽  
Virus Binding ◽  
Virus Propagation ◽  
Cell Surface Molecule ◽  
Lectin Receptor ◽  
Trans Infection ◽  
Hiv 1

Abstract The dynamic interplay between dendritic cells (DCs) and human immunodeficiency virus type-1 (HIV-1) is thought to result in viral dissemination and evasion of antiviral immunity. Although initial observations suggested that the C-type lectin receptor (CLR) DC-SIGN was responsible for the trans-infection function of the virus, subsequent studies demonstrated that trans-infection of CD4+ T cells with HIV-1 can also occur through DC-SIGN–independent mechanisms. We demonstrate that a cell surface molecule designated DCIR (for DCimmunoreceptor), a member of a recently described family of DC-expressing CLRs, can participate in the capture of HIV-1 and promote infection in trans and in cis of autologous CD4+ T cells from human immature monocyte-derived DCs. The contribution of DCIR to these processes was revealed using DCIR-specific siRNAs and a polyclonal antibody specific for the carbohydrate recognition domain of DCIR. Data from transfection experiments indicated that DCIR acts as a ligand for HIV-1 and is involved in events leading to productive virus infection. Finally, we show that the neck domain of DCIR is important for the DCIR-mediated effect on virus binding and infection. These results point to a possible role for DCIR in HIV-1 pathogenesis by supporting the productive infection of DCs and promoting virus propagation.

scholarly journals Apobec3A maintains HIV-1 latency through recruitment of epigenetic silencing machinery to the long terminal repeat

2019 ◽  
Vol 116 (6) ◽  
pp. 2282-2289 ◽  
Author(s):  
Manabu Taura ◽  
Eric Song ◽  
Ya-Chi Ho ◽  
Akiko Iwasaki
Keyword(s):  
T Cells ◽  
Long Terminal Repeat ◽  
Cd4 T Cells ◽  
Terminal Repeat ◽  
Target Cells ◽  
Mrna Editing ◽  
Latently Infected ◽  
Infected Cells ◽  
Editing Enzyme ◽  
Hiv 1

HIV-1 integrates into the genome of target cells and establishes latency indefinitely. Understanding the molecular mechanism of HIV-1 latency maintenance is needed for therapeutic strategies to combat existing infection. In this study, we found an unexpected role for Apobec3A (apolipoprotein B MRNA editing enzyme catalytic subunit 3A, abbreviated “A3A”) in maintaining the latency state within HIV-1–infected cells. Overexpression of A3A in latently infected cell lines led to lower reactivation, while knockdown or knockout of A3A led to increased spontaneous and inducible HIV-1 reactivation. A3A maintains HIV-1 latency by associating with proviral DNA at the 5′ long terminal repeat region, recruiting KAP1 and HP1, and imposing repressive histone marks. We show that knockdown of A3A in latently infected human primary CD4 T cells enhanced HIV-1 reactivation. Collectively, we provide evidence and a mechanism by which A3A reinforces HIV-1 latency in infected CD4 T cells.

scholarly journals Basic Motifs Target PSGL-1, CD43, and CD44 to Plasma Membrane Sites Where HIV-1 Assembles

2014 ◽  
Vol 89 (1) ◽  
pp. 454-467 ◽  
Author(s):  
Jonathan R. Grover ◽  
Sarah L. Veatch ◽  
Akira Ono
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
Membrane Proteins ◽  
Transmembrane Proteins ◽  
Structural Protein ◽  
Virion Incorporation ◽  
Host Membrane ◽  
Cytoplasmic Tails ◽  
Host Plasma Membrane ◽  
Hiv 1

ABSTRACTHIV-1 incorporates various host membrane proteins during particle assembly at the plasma membrane; however, the mechanisms mediating this incorporation process remain poorly understood. We previously showed that the HIV-1 structural protein Gag localizes to the uropod, a rear-end structure of polarized T cells, and that assembling Gag copatches with a subset, but not all, of the uropod-directed proteins, i.e., PSGL-1, CD43, and CD44, in nonpolarized T cells. The latter observation suggests the presence of a mechanism promoting virion incorporation of these cellular proteins. To address this possibility and identify molecular determinants, in the present study we examined coclustering between Gag and the transmembrane proteins in T and HeLa cells using quantitative two-color superresolution localization microscopy. Consistent with the findings of the T-cell copatching study, we found that basic residues within the matrix domain of Gag are required for Gag–PSGL-1 coclustering. Notably, the presence of a polybasic sequence in the PSGL-1 cytoplasmic domain significantly enhanced this coclustering. We also found that polybasic motifs present in the cytoplasmic tails of CD43 and CD44 also promote their coclustering with Gag. ICAM-1 and ICAM-3, uropod-directed proteins that do not copatch with Gag in T cells, and CD46, a non-uropod-directed protein, showed no or little coclustering with Gag. However, replacing their cytoplasmic tails with the cytoplasmic tail of PSGL-1 significantly enhanced their coclustering with Gag. Altogether, these results identify a novel mechanism for host membrane protein association with assembling HIV-1 Gag in which polybasic sequences present in the cytoplasmic tails of the membrane proteins and in Gag are the major determinants.IMPORTANCENascent HIV-1 particles incorporate many host plasma membrane proteins during assembly. However, it is largely unknown what mechanisms promote the association of these proteins with virus assembly sites within the plasma membrane. Notably, our previous study showed that HIV-1 structural protein Gag colocalizes with a group of uropod-directed transmembrane proteins, PSGL-1, CD43, and CD44, at the plasma membrane of T cells. The results obtained in the current study using superresolution localization microscopy suggest the presence of a novel molecular mechanism promoting the association of PSGL-1, CD43, and CD44 with assembling HIV-1 which relies on polybasic sequences in HIV-1 Gag and in cytoplasmic domains of the transmembrane proteins. This information advances our understanding of virion incorporation of host plasma membrane proteins, some of which modulate virus spread positively or negatively, and suggests a possible new strategy to enrich HIV-1-based lentiviral vectors with a desired transmembrane protein.

scholarly journals The B-Oligomer of Pertussis Toxin Deactivates Cc Chemokine Receptor 5 and Blocks Entry of M-Tropic HIV-1 Strains

1999 ◽  
Vol 190 (5) ◽  
pp. 597-606 ◽  
Author(s):  
Massimo Alfano ◽  
Helena Schmidtmayerova ◽  
Carol-Ann Amella ◽  
Tatiana Pushkarsky ◽  
Michael Bukrinsky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Pertussis Toxin ◽  
Chemokine Receptor ◽  
Viral Envelope ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Peripheral Blood Mononuclear ◽  
Hiv 1

Infection of target cells by HIV-1 requires initial binding interactions between the viral envelope glycoprotein gp120, the cell surface protein CD4, and one of the members of the seven-transmembrane G protein–coupled chemokine receptor family. Most primary isolates (R5 strains) use chemokine receptor CCR5, but some primary syncytium-inducing, as well as T cell line–adapted, strains (X4 strains) use the CXCR4 receptor. Signaling from both CCR5 and CXCR4 is mediated by pertussis toxin (PTX)-sensitive Gi proteins and is not required for HIV-1 entry. Here, we show that the PTX holotoxin as well as its binding subunit, B-oligomer, which lacks Gi-inhibitory activity, blocked entry of R5 but not X4 strains into primary T lymphocytes. Interestingly, B-oligomer inhibited virus production by peripheral blood mononuclear cell cultures infected with either R5 or X4 strains, indicating that it can affect HIV-1 replication at both entry and post-entry levels. T cells treated with B-oligomer did not initiate signal transduction in response to macrophage inflammatory protein (MIP)-1β or RANTES (regulated upon activation, normal T cell expressed and secreted); however, cell surface expression of CCR5 and binding of MIP-1β or HIV-1 to such cells were not impaired. The inhibitory effect of B-oligomer on signaling from CCR5 and on entry of R5 HIV-1 strains was reversed by protein kinase C (PKC) inhibitors, indicating that B-oligomer activity is mediated by signaling events that involve PKC. B-oligomer also blocked cocapping of CCR5 and CD4 induced by R5 HIV-1 in primary T cells, but did not affect cocapping of CXCR4 and CD4 after inoculation of the cultures with X4 HIV-1. These results suggest that the B-oligomer of PTX cross-deactivates CCR5 to impair its function as a coreceptor for HIV-1.

scholarly journals Optimizing CD4+ T-Cells Transduction Protocol for Gene Therapy of HIV-1 Infected Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4429-4429
Author(s):  
Amani Ouedrani ◽  
Lounes Djerroudi ◽  
Isabelle Hmitou ◽  
Marina Cavazzana ◽  
Fabien Touzot
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
Cd4 T Cells ◽  
Conflicts Of Interest ◽  
Lentiviral Vector ◽  
Ex Vivo ◽  
Effector Memory ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Hiv 1

Abstract Gene therapy represents an alternative and promising strategy that could provide a path to a curative therapy for HIV-1 infection. One approach involves the introduction of protective gene into a cell, thereby conferring protection against HIV. We plan to conduct an open label phase I/II gene therapy trial for HIV-1 infected patients presenting with lymphoma. The patients will received autologous hematopoietic stem cells transplantation with gene modified CD34+ cells and CD4+ T-cells. CD34+ and CD4+ will be ex vivo transduced by the LVsh5/C46 lentiviral vector (Cal-1, Calimmune, Inc. Tucson, USA). LVsh5/C46 is a SIN lentiviral vector that inhibits two crucial steps of CD4+ T cell infection by the HIV virus: (i) attachment of the virus to its target by downregulation of CCR5 via a short hairpin RNA, (ii) fusion of the virus to the target cell through expression of the C46 inhibitor. We developed a transduction process for CD4+ T-cells using the TransAct™ reagent (Miltenyi Biotec, Bergisch Gladbach , Germany) for CD4+ T-cells activation. Compared to previously published T-cells transduction protocols, the use of Miltenyi TransAct™ permits an equivalent efficacy of transduction - evaluated by measurement of vector copy number through quantitative PCR - without major phenotypic modification. Indeed, CD4+ T-cells ex vivo transduced after activation with the TransAct™ reagent display very few changes in their surface marker with conservation of naive (CCR7+CD62L+CD45RA+), central memory (CCR7+CD62L+CD45RA-) and effector memory (CCR7-CD62L-CD45RA-) subsets in superimposable proportions as initially. Moreover, expression of CD25 remains below 15-25% of cells suggesting a more "gentle " activation of the transduced CD4+ T-cells. Our transduction process had no significant impact in TCRβ repertoire diversity as evaluated by high-throughput sequencing and analyzis of diversity through the Gini-Simpson index or the Shannon index. Finally, transduced CD4 + T-cells retained the ability to to be primed towards the TH1, TH2 and TH17 pathways suggesting that the transduction protocol used did not alter the functional properties of the target cells. Disclosures No relevant conflicts of interest to declare.

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