Postintegration HIV-1 Infection of Cervical Epithelial Cells Mediates Contact-Dependent Productive Infection of T Cells

ABSTRACT The contribution of mammary epithelial cells (MEC) to human immunodeficiency virus type 1 (HIV-1) in breast milk remains largely unknown. While breast milk contains CD4+ cells throughout the breast-feeding period, it is not known whether MEC directly support HIV-1 infection or facilitate infection of CD4+ cells in the breast compartment. This study evaluated primary human MEC for direct infection with HIV-1 and for indirect transfer of infection to CD4+ target cells. Primary human MEC were isolated and assessed for expression of HIV-1 receptors. MEC were exposed to CCR5-, CXCR4- and dual-tropic strains of HIV-1 and evaluated for viral reverse transcription and integration and productive viral infection. MEC were also tested for the ability to transfer HIV to CD4+ target cells and to activate resting CD4+ T cells. Our results demonstrate that MEC express HIV-1 receptor proteins CD4, CCR5, CXCR4, and galactosyl ceramide (GalCer). While no evidence for direct infection of MEC was found, HIV-1 virions were observed in MEC endosomal compartments. Coculture of HIV-exposed MEC resulted in productive infection of activated CD4+ T cells. In addition, MEC secretions increased HIV-1 replication and proliferation of infected target cells. Overall, our results indicate that MEC are capable of endosomal uptake of HIV-1 and can facilitate virus infection and replication in CD4+ target cells. These findings suggest that MEC may serve as a viral reservoir for HIV-1 and may enhance infection of CD4+ T lymphocytes in vivo.

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IL-17A Reprograms Intestinal Epithelial Cells to Facilitate HIV-1 Replication and Outgrowth in CD4+ T-cells

iScience ◽

10.1016/j.isci.2021.103225 ◽

2021 ◽

pp. 103225

Author(s):

Tomas Raul Wiche Salinas ◽

Annie Gosselin ◽

Laurence Raymond Marchand ◽

Etiene Moreira Gabriel ◽

Olivier Tastet ◽

...

Keyword(s):

T Cells ◽

Epithelial Cells ◽

Cd4 T Cells ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Hiv 1

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R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L− CD4+ T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors

Journal of Virology ◽

10.1128/jvi.80.2.854-865.2006 ◽

2006 ◽

Vol 80 (2) ◽

pp. 854-865 ◽

Cited By ~ 8

Author(s):

Françoise Gondois-Rey ◽

Angelique Biancotto ◽

Marcelo Antonio Fernandez ◽

Lise Bettendroffer ◽

Jana Blazkova ◽

...

Keyword(s):

T Cells ◽

Reverse Transcriptase ◽

Lymphoid Tissue ◽

Ex Vivo ◽

Productive Infection ◽

Reverse Transcriptase Inhibitors ◽

Hla Dr ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The persistence of human immunodeficiency virus type 1 (HIV-1) in memory CD4+ T cells is a major obstacle to the eradication of the virus with current antiretroviral therapy. Here, we investigated the effect of the activation status of CD4+ T cells on the predominance of R5 and X4 HIV-1 variants in different subsets of CD4+ T cells in ex vivo-infected human lymphoid tissues and peripheral blood mononuclear cells (PBMCs). In these cell systems, we examined the sensitivity of HIV replication to reverse transcriptase inhibitors. We demonstrate that R5 HIV-1 variants preferentially produced productive infection in HLA-DR− CD62L− CD4+ T cells. These cells were mostly in the G1b phase of the cell cycle, divided slowly, and expressed high levels of CCR5. In contrast, X4 HIV-1 variants preferentially produced productive infection in activated HLA-DR+ CD62L+ CD4+ T cells, which expressed high levels of CXCR4. The abilities of the nucleoside reverse transcriptase inhibitors (NRTI) zidovudine and lamivudine to stop HIV-1 replication were 20 times greater in activated T cells than in slowly dividing HLA-DR− CD62L− CD4+ T cells. This result, demonstrated both in a highly physiologically relevant ex vivo lymphoid tissue model and in PBMCs, correlated with higher levels of thymidine kinase mRNA in activated than in slowly dividing HLA-DR− CD62L− CD4+ T cells. The non-NRTI nevirapine was equally efficient in both cell subsets. The lymphoid tissue and PBMC-derived cell systems represent well-defined models which could be used as new tools for the study of the mechanism of resistance to HIV-1 inhibitors in HLA-DR− CD62L− CD4+ T cells.

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gp120-Independent Infection of CD4− Epithelial Cells and CD4+ T-Cells by HIV-1

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/00126334-200205010-00001 ◽

2002 ◽

Vol 30 (1) ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Yen-Hung Chow ◽

Duan Yu ◽

Jun-ying Zhang ◽

Yiming Xie ◽

O. Lu-Chen Wei ◽

...

Keyword(s):

T Cells ◽

Epithelial Cells ◽

Cd4 T Cells ◽

Hiv 1

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Unstimulated Primary CD4+ T Cells from HIV-1-Positive Elite Suppressors Are Fully Susceptible to HIV-1 Entry and Productive Infection

Journal of Virology ◽

10.1128/jvi.01721-10 ◽

2010 ◽

Vol 85 (2) ◽

pp. 979-986 ◽

Cited By ~ 26

Author(s):

S. A. Rabi ◽

K. A. O'Connell ◽

D. Nikolaeva ◽

J. R. Bailey ◽

B. L. Jilek ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Productive Infection ◽

Elite Suppressors ◽

Hiv 1

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Predominant Mode of Human Immunodeficiency Virus Transfer between T Cells Is Mediated by Sustained Env-Dependent Neutralization-Resistant Virological Synapses

Journal of Virology ◽

10.1128/jvi.00381-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12582-12595 ◽

Cited By ~ 296

Author(s):

Ping Chen ◽

Wolfgang Hübner ◽

Matthew A. Spinelli ◽

Benjamin K. Chen

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Productive Infection ◽

Target Cells ◽

Free Virus ◽

Virus Transfer ◽

Immunodeficiency Virus ◽

Virological Synapses ◽

Viral Transfer ◽

Hiv 1

ABSTRACT Cell-free human immunodeficiency virus type 1 (HIV-1) can initiate infections, but contact between infected and uninfected T cells can enhance viral spread through intercellular structures called virological synapses (VS). The relative contribution of VS to cell-free viral transfer has not been carefully measured. Using an ultrasensitive, fluorescent virus transfer assay, we estimate that when VS between HIV-expressing Jurkat T cells and primary CD4+ T cells are formed, cell-associated transfer of virus is 18,000-fold more efficient than uptake of cell-free virus. Furthermore, in contrast to cell-free virus uptake, the VS deposits virus rapidly into focal, trypsin-resistant compartments in target T cells. This massive virus internalization requires Env-CD4 receptor interactions but is resistant to inhibition by patient-derived neutralizing antisera that inhibit homologous cell-free virus. Deleting the Env cytoplasmic tail does not abrogate VS-mediated transfer, but it renders the VS sensitive to neutralizing antibodies, suggesting that the tail limits exposure of VS-neutralizing epitopes on the surface of infected cells. Dynamic live imaging of the VS reveals that HIV-expressing cells are polarized and make sustained, Env-dependent contacts with target cells through uropod-like structures. The polarized T-cell morphology, Env-CD4 coordinated adhesion, and viral transfer from HIV-infected to uninfected cells suggest that VS allows HIV-1 to evade antibody neutralization and to disseminate efficiently. Future studies will discern to what extent this massive viral transfer contributes to productive infection or viral dissemination through the migration of virus-carrying T cells.

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Bowman‒Birk Inhibitor Suppresses Herpes Simplex Virus Type 2 Infection of Human Cervical Epithelial Cells

Viruses ◽

10.3390/v10100557 ◽

2018 ◽

Vol 10 (10) ◽

pp. 557 ◽

Cited By ~ 1

Author(s):

Yu Liu ◽

Xi-Qiu Xu ◽

Biao Zhang ◽

Jun Gu ◽

Feng-Zhen Meng ◽

...

Keyword(s):

Epithelial Cells ◽

Therapeutic Potential ◽

Sexual Transmission ◽

Ubiquitin Proteasome System ◽

Interferon Stimulated Genes ◽

Ubiquitinated Proteins ◽

Ubiquitin Proteasome ◽

Cervical Epithelial Cells ◽

Simplex Virus ◽

Hiv 1

The Bowman‒Birk inhibitor (BBI), a protease inhibitor derived from soybeans, has been extensively studied in anti-tumor and anti-inflammation research. We recently reported that BBI has an anti-HIV-1 property in primary human macrophages. Because HSV-2 infection plays a role in facilitating HIV-1 sexual transmission, we thus examined whether BBI has the ability to inhibit HSV-2 infection. We demonstrated that BBI could potently inhibit HSV-2 replication in human cervical epithelial cells (End1/E6E7). This BBI-mediated HSV-2 inhibition was partially through blocking HSV-2-mediated activation of NF-κB and p38 MAPK pathways. In addition, BBI could activate the JAK/STAT pathway and enhance the expression of several antiviral interferon-stimulated genes (ISGs). Furthermore, BBI treatment of End1/E6E7 cells upregulated the expression of tight junction proteins and reduced HSV-2-mediated cellular ubiquitinated proteins’ degradation through suppressing the ubiquitin‒proteasome system. These observations indicate that BBI may have therapeutic potential for the prevention and treatment of HSV-2 infections.

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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 ◽

10.1182/blood-2008-01-136473 ◽

2008 ◽

Vol 112 (4) ◽

pp. 1299-1307 ◽

Cited By ~ 125

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.

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Mechanisms of Endogenous HIV-1 Reactivation by Endocervical Epithelial Cells

Journal of Virology ◽

10.1128/jvi.01904-19 ◽

2020 ◽

Vol 94 (9) ◽

Author(s):

Germán G. Gornalusse ◽

Rogelio Valdez ◽

Gabriella Fenkart ◽

Lucia Vojtech ◽

Lamar M. Fleming ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex ◽

Epithelial Cells ◽

Genital Tract ◽

Female Genital Tract ◽

Tnf Α ◽

Simplex Virus ◽

Herpes Simplex Virus 2 ◽

Hiv 1 ◽

Female Genital

ABSTRACT Pharmacological HIV-1 reactivation to reverse latent infection has been extensively studied. However, HIV-1 reactivation also occurs naturally, as evidenced by occasional low-level viremia (“viral blips”) during antiretroviral treatment (ART). Clarifying where blips originate from and how they happen could provide clues to stimulate latency reversal more effectively and safely or to prevent viral rebound following ART cessation. We studied HIV-1 reactivation in the female genital tract, a dynamic anatomical target for HIV-1 infection throughout all disease stages. We found that primary endocervical epithelial cells from several women reactivated HIV-1 from latently infected T cells. The endocervical cells’ HIV-1 reactivation capacity further increased upon Toll-like receptor 3 stimulation with poly(I·C) double-stranded RNA or infection with herpes simplex virus 2 (HSV-2). Notably, acyclovir did not eliminate HSV-2-induced HIV-1 reactivation. While endocervical epithelial cells secreted large amounts of several cytokines and chemokines, especially tumor necrosis factor alpha (TNF-α), CCL3, CCL4, and CCL20, their HIV-1 reactivation capacity was almost completely blocked by TNF-α neutralization alone. Thus, immunosurveillance activities by columnar epithelial cells in the endocervix can cause endogenous HIV-1 reactivation, which may contribute to viral blips during ART or rebound following ART interruption. IMPORTANCE A reason that there is no universal cure for HIV-1 is that the virus can hide in the genome of infected cells in the form of latent proviral DNA. This hidden provirus is protected from antiviral drugs until it eventually reactivates to produce new virions. It is not well understood where in the body or how this reactivation occurs. We studied HIV-1 reactivation in the female genital tract, which is often the portal of HIV-1 entry and which remains a site of infection throughout the disease. We found that the columnar epithelial cells lining the endocervix, the lower part of the uterus, are particularly effective in reactivating HIV-1 from infected T cells. This activity was enhanced by certain microbial stimuli, including herpes simplex virus 2, and blocked by antibodies against the inflammatory cytokine TNF-α. Avoiding HIV-1 reactivation could be important for maintaining a functional HIV-1 cure when antiviral therapy is stopped.

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