scholarly journals Vaginal Epithelium Transiently Harbours HIV-1 Facilitating Transmission

2021 ◽  
Vol 11 ◽  
Author(s):  
Varsha M. Prabhu ◽  
Varsha Padwal ◽  
Shilpa Velhal ◽  
Sukeshani Salwe ◽  
Vidya Nagar ◽  
...  
Keyword(s):  
Vaginal Epithelium ◽  
Female Reproductive Tract ◽  
T Cell Subsets ◽  
Productive Infection ◽  
Viral Reservoir ◽  
Established Cell Line ◽  
Target Cells ◽  
Trans Infection ◽  
In Trans ◽  
Hiv 1

Vaginal transmission accounts for majority of newly acquired HIV infections worldwide. Initial events that transpire post-viral binding to vaginal epithelium leading to productive infection in the female reproductive tract are not well elucidated. Here, we examined the interaction of HIV-1 with vaginal epithelial cells (VEC) using Vk2/E6E7, an established cell line exhibiting an HIV-binding receptor phenotype (CD4-CCR5-CD206+) similar to primary cells. We observed rapid viral sequestration, as a metabolically active process that was dose-dependent. Sequestered virus demonstrated monophasic decay after 6 hours with a half-life of 22.435 hours, though residual virus was detectable 48 hours’ post-exposure. Viral uptake was not followed by successful reverse transcription and thus productive infection in VEC unlike activated PBMCs. Intraepithelial virus was infectious as evidenced by infection in trans of PHA-p stimulated PBMCs on co-culture. Trans-infection efficiency, however, deteriorated with time, concordant with viral retention kinetics, as peak levels of sequestered virus coincided with maximum viral output of co-cultivated PBMCs. Further, blocking lymphocyte receptor function-associated antigen 1 (LFA-1) expressed on PBMCs significantly inhibited trans-infection suggesting that cell-to-cell spread of HIV from epithelium to target cells was LFA-1 mediated. In addition to stimulated PBMCs, we also demonstrated infection in trans of FACS sorted CD4+ T lymphocyte subsets expressing co-receptors CCR5 and CXCR4. These included, for the first time, potentially gut homing CD4+ T cell subsets co-expressing integrin α4β7 and CCR5. Our study thus delineates a hitherto unexplored role for the vaginal epithelium as a transient viral reservoir enabling infection of susceptible cell types.

scholarly journals Characterization of the Influence of Semen-Derived Enhancer of Virus Infection on the Interaction of HIV-1 with Female Reproductive Tract Tissues

2015 ◽  
Vol 89 (10) ◽  
pp. 5569-5580 ◽  
Author(s):  
Shannon A. Allen ◽  
Ann M. Carias ◽  
Meegan R. Anderson ◽  
Eneniziaogochukwu A. Okocha ◽  
Lorie Benning ◽  
...  
Keyword(s):  
Cell Culture ◽  
Virus Infection ◽  
Reproductive Tract ◽  
Sexual Transmission ◽  
Female Reproductive Tract ◽  
Productive Infection ◽  
Target Cells ◽  
Mucosal Transmission ◽  
Epithelial Barriers ◽  
Hiv 1

ABSTRACTThe majority of human immunodeficiency virus type 1 (HIV-1) transmission events occur in women when semen harboring infectious virus is deposited onto the mucosal barriers of the vaginal, ectocervical, and endocervical epithelia. Seminal factors such as semen-derived enhancer of virus infection (SEVI) fibrils were previously shown to greatly enhance the infectivity of HIV-1 in cell culture systems. However, when SEVI is intravaginally applied to living animals, there is no effect on vaginal transmission. To define how SEVI might function in the context of sexual transmission, we applied HIV-1 and SEVI to intact human and rhesus macaque reproductive tract tissues to determine how it influences virus interactions with these barriers. We show that SEVI binds HIV-1 and sequesters most virions to the luminal surface of the stratified squamous epithelium, significantly reducing the number of virions that penetrated the tissue. In the simple columnar epithelium, SEVI was no longer fibrillar in structure and was detached from virions but allowed significantly deeper epithelial virus penetration. These observations reveal that the action of SEVI in intact tissues is very different in the anatomical context of sexual transmission and begin to explain the lack of stimulation of infection observed in the highly relevant mucosal transmission model.IMPORTANCEThe most common mode of HIV-1 transmission in women occurs via genital exposure to the semen of HIV-infected men. A productive infection requires the virus to penetrate female reproductive tract epithelial barriers to infect underlying target cells. Certain factors identified within semen, termed semen-derived enhancers of virus infection (SEVI), have been shown to significantly enhance HIV-1 infectivity in cell culture. However, when applied to the genital tracts of living female macaques, SEVI did not enhance virus transmission. Here we show that SEVI functions very differently in the context of intact mucosal tissues. SEVI decreases HIV-1 penetration of squamous epithelial barriers in humans and macaques. At the mucus-coated columnar epithelial barrier, the HIV-1/SEVI interaction is disrupted. These observations suggest that SEVI may not play a significant stimulatory role in the efficiency of male-to-female sexual transmission of HIV.

scholarly journals Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility

2008 ◽  
Vol 4 (1) ◽  
pp. 52-62 ◽  
Author(s):  
Weijing He ◽  
Stuart Neil ◽  
Hemant Kulkarni ◽  
Edward Wright ◽  
Brian K. Agan ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Antigen Receptor ◽  
Target Cells ◽  
Duffy Antigen ◽  
Trans Infection ◽  
Hiv 1 ◽  
Hiv Aids

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 Induction of Rapid and Extensive β-Chemokine Synthesis in Macrophages by Human Immunodeficiency Virus Type 1 and gp120, Independently of Their Coreceptor Phenotype

2001 ◽  
Vol 75 (22) ◽  
pp. 10738-10745 ◽  
Author(s):  
Wonkyu Choe ◽  
David J. Volsky ◽  
Mary Jane Potash
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protein Synthesis ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Productive Infection ◽  
Target Cells ◽  
Chemokine Production ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) interacts with its target cells through CD4 and a coreceptor, generally CCR5 or CXCR4. Macrophages display CD4, CCR5, and CXCR4 that are competent for binding and entry of virus. Virus binding also induces several responses by lymphocytes and macrophages that can be dissociated from productive infection. We investigated the responses of macrophages to exposure to a series of HIV-1 species, R5 species that productively infect and X4 species that do not infect macrophages. We chose to monitor production of several physiologically relevant factors within hours of treatment to resolve virally induced effects that may be unlinked to HIV-1 production. Our novel findings indicate that independently of their coreceptor phenotype and independently of virus replication, exposure to certain R5 and X4 HIV-1 species induced secretion of high levels of macrophage inflammatory protein 1α (MIP-1α), MIP-1β, RANTES, and tumor necrosis factor alpha. However two of the six R5 species tested, despite efficient infection, were unable to induce rapid chemokine production. The acute effects of virus on macrophages could be mimicked by exposure to purified R5 or the X4 HIV-1 envelope glycoprotein gp120. Depletion of intracellular Ca2+ or inhibition of protein synthesis blocked the chemokine induction, implicating Ca2+-mediated signal transduction and new protein synthesis in the response. The group of viruses able to induce this chemokine response was not consistent with coreceptor usage. We conclude that human macrophages respond rapidly to R5 and X4 envelope binding by production of high levels of physiologically active proteins that are implicated in HIV-1 pathogenesis.

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

2007 ◽  
Vol 81 (22) ◽  
pp. 12582-12595 ◽  
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.

scholarly journals Endocytic Motif on a Biotin-Tagged HIV-1 Env Modulates the Co-Transfer of Env and Gag during Cell-to-Cell Transmission

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1729
Author(s):  
María Inés Barría ◽  
Raymond A. Alvarez ◽  
Kenneth Law ◽  
Deanna L. Wolfson ◽  
Thomas Huser ◽  
...  
Keyword(s):  
Fluorescent Imaging ◽  
Productive Infection ◽  
Live Cells ◽  
Cell Contact ◽  
Target Cells ◽  
Structural Protein ◽  
Cell Infection ◽  
Virological Synapses ◽  
Hiv 1 ◽  
Cell Cell

During HIV-1 transmission through T cell virological synapses, the recruitment of the envelope (Env) glycoprotein to the site of cell–cell contact is important for adhesion and for packaging onto nascent virus particles which assemble at the site. Live imaging studies in CD4 T cells have captured the rapid recruitment of the viral structural protein Gag to VSs. We explored the role of endocytic trafficking of Env initiated by a membrane proximal tyrosine motif during HIV transfer into target cells and examined the factors that allow Gag and Env to be transferred together across the synapse. To facilitate tracking of Env in live cells, we adapted an Env tagging method and introduced a biotin acceptor peptide (BAP) into the V4 loop of Env gp120, enabling sensitive fluorescent tracking of V4-biotinylated Env. The BAP-tagged and biotinylated HIVs were replication-competent in cell-free and cell-to-cell infection assays. Live cell fluorescent imaging experiments showed rapid internalized cell surface Env on infected cells. Cell–cell transfer experiments conducted with the Env endocytosis mutant (Y712A) showed increased transfer of Env. Paradoxically, this increase in Env transfer was associated with significantly reduced Gag transfer into target cells, when compared to viral transfer associated with WT Env. This Y712A Env mutant also exhibited an altered Gag/biotin Env fluorescence ratio during transfer that correlated with decreased productive cell-to-cell infection. These results may suggest that the internalization of Env into recycling pools plays an important role in the coordinated transfer of Gag and Env across the VS, which optimizes productive infection in target cells.

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 HIV-1 trans-Infection Mediated by DCs: The Tip of the Iceberg of Cell-to-Cell Viral Transmission

Pathogens ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 39
Author(s):  
Daniel Perez-Zsolt ◽  
Dàlia Raïch-Regué ◽  
Jordana Muñoz-Basagoiti ◽  
Carmen Aguilar-Gurrieri ◽  
Bonaventura Clotet ◽  
...  
Keyword(s):  
Immune Responses ◽  
Ebola Virus ◽  
Viral Transmission ◽  
Productive Infection ◽  
Lectin Receptors ◽  
Enveloped Viruses ◽  
Cellular Targets ◽  
Trans Infection ◽  
Antigen Presenting ◽  
Hiv 1

HIV-1 cell-to-cell transmission is key for an effective viral replication that evades immunity. This highly infectious mechanism is orchestrated by different cellular targets that utilize a wide variety of processes to efficiently transfer HIV-1 particles. Dendritic cells (DCs) are the most potent antigen presenting cells that initiate antiviral immune responses, but are also the cells with highest capacity to transfer HIV-1. This mechanism, known as trans-infection, relies on the capacity of DCs to capture HIV-1 particles via lectin receptors such as the sialic acid-binding I-type lectin Siglec-1/CD169. The discovery of the molecular interaction of Siglec-1 with sialylated lipids exposed on HIV-1 membranes has enlightened how this receptor can bind to several enveloped viruses. The outcome of these interactions can either mount effective immune responses, boost the productive infection of DCs and favour innate sensing, or fuel viral transmission via trans-infection. Here we review these scenarios focusing on HIV-1 and other enveloped viruses such as Ebola virus or SARS-CoV-2.

scholarly journals Both Memory and CD45RA+/CD62L+ Naive CD4+ T Cells Are Infected in Human Immunodeficiency Virus Type 1-Infected Individuals

1999 ◽  
Vol 73 (8) ◽  
pp. 6430-6435 ◽  
Author(s):  
Mario A. Ostrowski ◽  
Tae-Wook Chun ◽  
Shawn J. Justement ◽  
Ivette Motola ◽  
Michael A. Spinelli ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
T Cell Subsets ◽  
Viral Reservoir ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Cellular activation is critical for the propagation of human immunodeficiency virus type 1 (HIV-1) infection. It has been suggested that truly naive CD4+ T cells are resistant to productive HIV-1 infection because of their constitutive resting state. Memory and naive CD4+ T-cell subsets from 11 HIV-1-infected individuals were isolated ex vivo by a combination of magnetic bead depletion and fluorescence-activated cell sorting techniques with stringent criteria of combined expression of CD45RA and CD62L to identify naive CD4+ T-cell subsets. In all patients HIV-1 provirus could be detected within naive CD45RA+/CD62L+ CD4+ T cells; in addition, replication-competent HIV-1 was isolated from these cells upon CD4+ T-cell stimulation in tissue cultures. Memory CD4+ T cells had a median of fourfold more replication-competent virus and a median of sixfold more provirus than naive CD4+ T cells. Overall, there was a median of 16-fold more integrated provirus identified in memory CD4+ T cells than in naive CD4+ T cells within a given patient. Interestingly, there was a trend toward equalization of viral loads in memory and naive CD4+ T-cell subsets in those patients who harbored CXCR4-using (syncytium-inducing) viruses. Within any given patient, there was no selective usage of a particular coreceptor by virus isolated from memory versus naive CD4+ T cells. Our findings suggest that naive CD4+ T cells may be a significant viral reservoir for HIV, particularly in those patients harboring CXCR4-using viruses.

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