Hyaluronic acid is a negative regulator of mucosal fibroblast-mediated enhancement of HIV infection

AbstractThe majority of HIV infections are established through the genital or rectal mucosa. Fibroblasts are abundant in these tissues, and although not susceptible to infection, can potently enhance HIV infection of CD4+ T cells. Hyaluronic acid (HA) is a major component of the extracellular matrix of fibroblasts, and its levels are influenced by the inflammatory state of the tissue. Since inflammation is known to facilitate HIV sexual transmission, we investigated the role of HA in genital mucosal fibroblast-mediated enhancement of HIV infection. Depletion of HA by CRISPR-Cas9 in primary foreskin fibroblasts augmented the ability of the fibroblasts to increase HIV infection of CD4+ T cells. This amplified enhancement required direct contact between the fibroblasts and CD4+ T cells, and could be attributed to both increased rates of trans-infection and the increased ability of HA-deficient fibroblasts to push CD4+ T cells into a state of higher permissivity to infection. This HIV-permissive state was characterized by differential expression of genes associated with regulation of cell metabolism and death. Our results suggest that conditions resulting in diminished cell-surface HA on fibroblasts, such as genital inflammation, can promote HIV transmission by conditioning CD4+ T cells toward a state more vulnerable to infection by HIV.

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Human anogenital monocyte-derived dendritic cells and langerin+cDC2 are major HIV target cells

Nature Communications ◽

10.1038/s41467-021-22375-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jake W. Rhodes ◽

Rachel A. Botting ◽

Kirstie M. Bertram ◽

Erica E. Vine ◽

Hafsa Rana ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Pathogen Detection ◽

Hiv Transmission ◽

Sexual Transmission ◽

Mononuclear Phagocytes ◽

Target Cells ◽

Epithelial Surface ◽

Transmission Studies

AbstractTissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).

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Exogenous and endogenous hyaluronic acid reduces HIV infection of CD4 + T cells

Immunology and Cell Biology ◽

10.1038/icb.2014.50 ◽

2014 ◽

Vol 92 (9) ◽

pp. 770-780 ◽

Cited By ~ 6

Author(s):

Peilin Li ◽

Katsuya Fujimoto ◽

Lilly Bourguingnon ◽

Steven Yukl ◽

Steven Deeks ◽

...

Keyword(s):

T Cells ◽

Hyaluronic Acid ◽

Hiv Infection ◽

Cd4 T Cells

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Identification of HIV-Transmitting Sub-Epithelial Mononuclear Phagocytes in Human Anogenital and Colorectal Tissues

10.1101/2020.05.26.117408 ◽

2020 ◽

Author(s):

Jake W Rhodes ◽

Rachel A Botting ◽

Kirstie M Bertram ◽

Hafsa Rana ◽

Heeva Baharlou ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune System ◽

Target Cell ◽

Cd4 T Cells ◽

Pathogen Detection ◽

Hiv Transmission ◽

Sexual Transmission ◽

Mononuclear Phagocytes ◽

Microbicide Development

AbstractTissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. They are the first cells of the immune system to encounter HIV and play a key role in transmission as they deliver the virus to CD4 T cells, which are the primary HIV target cell in which the virus undergoes replication. Most studies have investigated the role that epithelial MNPs play in HIV transmission but, as mucosal trauma and inflammation are strongly associated with HIV transmission, it is also important to examine the role that sub-epithelial MNPs play. Sub-epithelial MNPs are present in a diverse array of subsets which differ in their function and the pathogens they detect. Understanding how specific subsets interact with HIV and deliver the virus to CD4 T cells is therefore of key importance to vaccine and microbicide development. In this study we have shown that, after topical application, HIV can penetrate to interact with sub-epithelial resident myeloid cells in anogenital explants and defined the full array of MNP subsets that are present in all the human anogenital and colorectal sub-epithelial tissues that HIV may encounter during sexual transmission. In doing so we have identified two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+CD11c+ monocyte-derived dendritic cells and langerin-expressing dendritic cells 2 (DC2).

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Faculty Opinions recommendation of Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1104534.569097 ◽

2008 ◽

Author(s):

Vicente Planelles

Keyword(s):

T Cells ◽

Transcription Factor ◽

Hiv Infection ◽

Cd4 T Cells ◽

Memory Cd4 T Cells

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Faculty Opinions recommendation of Autocrine production of beta-chemokines protects CMV-Specific CD4 T cells from HIV infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1279973.747077 ◽

2009 ◽

Author(s):

Scott Sieg ◽

Nicholas Funderburg

Keyword(s):

T Cells ◽

Hiv Infection ◽

Cd4 T Cells

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The Impact of Exercise Serum on Selected Parameters of CD4+ T Cell Metabolism

Immuno ◽

10.3390/immuno1030008 ◽

2021 ◽

Vol 1 (3) ◽

pp. 119-131

Author(s):

Jana Palmowski ◽

Kristina Gebhardt ◽

Thomas Reichel ◽

Torsten Frech ◽

Robert Ringseis ◽

...

Keyword(s):

T Cells ◽

Oxygen Consumption ◽

T Cell ◽

Real Time ◽

Cd4 T Cells ◽

Cell Metabolism ◽

Cd4 T Cell ◽

Autologous Serum ◽

Cell Phenotype ◽

The Impact

CD4+ T cells are sensitive to peripheral changes of cytokine levels and metabolic substrates such as glucose and lactate. This study aimed to analyze whether factors released after exercise alter parameters of human T cell metabolism, specifically glycolysis and oxidative phosphorylation. We used primary human CD4+ T cells activated in the presence of autologous serum, which was collected before (CO) and after a 30-min exercise intervention (EX). In the course of activation, cells and supernatants were analyzed for cell viability and diameter, real-time oxygen consumption by using PreSens Technology, mRNA expression of glycolytic enzymes and complexes of the electron transport chain by real-time PCR, glucose, and lactate levels in supernatants, and in vitro differentiation by flow cytometry. EX did not alter T cell phenotype, viability, or on-blast formation. Similarly, no difference between CO and EX were found for CD4+ T cell activation and cellular oxygen consumption. In contrast, higher levels of glucose were found after 48 h activation in EX conditions. T cells activated in autologous exercise serum expressed lower HK1 mRNA and higher IFN-γ receptor 1. We suggest that the exercise protocol used was not sufficient to destabilize the immune metabolism of T cells. Therefore, more intense and prolonged exercise should be used in future studies.

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Circulating integrin α 4 β 7 + CD4 T cells are enriched for proliferative transcriptional programs in HIV infection

FEBS Letters ◽

10.1002/1873-3468.14163 ◽

2021 ◽

Author(s):

Yashavanth S. Lakshmanappa ◽

Jamin W. Roh ◽

Niharika N. Rane ◽

Ashok R. Dinasarapu ◽

Daphne D. Tran ◽

...

Keyword(s):

T Cells ◽

Hiv Infection ◽

Cd4 T Cells

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Identification of novel genes involved in apoptosis of HIV-infected macrophages using unbiased genome-wide screening

BMC Infectious Diseases ◽

10.1186/s12879-021-06346-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Simon X. M. Dong ◽

Frederick S. Vizeacoumar ◽

Kalpana K. Bhanumathy ◽

Nezeka Alli ◽

Cristina Gonzalez-Lopez ◽

...

Keyword(s):

T Cells ◽

Hiv Infection ◽

Respiratory Chain ◽

Cd4 T Cells ◽

Chain Complex ◽

Respiratory Chain Complex ◽

Complex Ii ◽

Genome Wide ◽

Latently Infected ◽

Induced Apoptosis

Abstract Background Macrophages, besides resting latently infected CD4+ T cells, constitute the predominant stable, major non-T cell HIV reservoirs. Therefore, it is essential to eliminate both latently infected CD4+ T cells and tissue macrophages to completely eradicate HIV in patients. Until now, most of the research focus is directed towards eliminating latently infected CD4+ T cells. However, few approaches have been directed at killing of HIV-infected macrophages either in vitro or in vivo. HIV infection dysregulates the expression of many host genes essential for the survival of infected cells. We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages. Methods We applied a pooled shRNA-based genome-wide approach by employing a lentivirus-based library of shRNAs to screen novel gene targets whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Primary human MDMs were infected with HIV-eGFP and HIV-HSA viruses. Infected MDMs were transfected with siRNAs specific for the promising genes followed by analysis of apoptosis by flow cytometry using labelled Annexin-V in HIV-infected, HIV-exposed but uninfected bystander MDMs and uninfected MDMs. The results were analyzed using student’s t-test from at least four independent experiments. Results We validated 28 top hits in two independent HIV infection models. This culminated in the identification of four target genes, Cox7a2, Znf484, Cstf2t, and Cdk2, whose loss-of-function induced apoptosis preferentially in HIV-infected macrophages. Silencing these single genes killed significantly higher number of HIV-HSA-infected MDMs compared to the HIV-HSA-exposed, uninfected bystander macrophages, indicating the specificity in the killing of HIV-infected macrophages. The mechanism governing Cox7a2-mediated apoptosis of HIV-infected macrophages revealed that targeting respiratory chain complex II and IV genes also selectively induced apoptosis of HIV-infected macrophages possibly through enhanced ROS production. Conclusions We have identified above-mentioned novel genes and specifically the respiratory chain complex II and IV genes whose silencing may cause selective elimination of HIV-infected macrophages and eventually the HIV-macrophage reservoirs. The results highlight the potential of the identified genes as targets for eliminating HIV-infected macrophages in physiological environment as part of an HIV cure strategy.

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