Integrin α4β7 in HIV-1 infection: A critical review

Liu, Qingbo; Lusso, Paolo

doi:10.1002/jlb.4mr0120-208r

Cited by 12 publications

(7 citation statements)

References 41 publications

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“…The HIV envelope protein GP120 binds to and signals by α4β7 460 ; thus, targeting α4β7 might be a new therapeutic method to prevent and treat HIV infection. 461 …”

Section: Integrin Roles In Physiology and Pathologymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

323

111

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Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

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“…The HIV envelope protein GP120 binds to and signals by α4β7 460 ; thus, targeting α4β7 might be a new therapeutic method to prevent and treat HIV infection. 461 …”

Section: Integrin Roles In Physiology and Pathologymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

323

111

View full text Add to dashboard Cite

show abstract

“…Surface proteins of some viruses, such as the capsid protein VP1 of coxsackievirus A9, contain commonly known integrin-binding sequences, such as RGD, that bind integrins to gain entry into cells or modulate downstream signaling pathways, while other viruses have acquired novel integrin-binding mechanisms, for example the binding of human echovirus 1 outside of the known ligand-binding site on α 2 β 1 integrin ( Roivainen et al, 1994 ; Jokinen et al, 2010 ; Hussein et al, 2015 )⁠. Other viruses are known to bind integrins, such as HIV-1 binding to α 4 β 7 , but the specific residues involved in the interactions are still unknown ( Liu and Lusso, 2020 )⁠. Thus, further investigation of the evolution of integrin-binding for viral pathogens is important for a better understanding of viral cell entry and cell signaling perturbations during infection.…”

Section: Introductionmentioning

confidence: 99%

Can the SARS-CoV-2 Spike Protein Bind Integrins Independent of the RGD Sequence?

Beaudoin

Hamaia

Huang

et al. 2021

Front. Cell. Infect. Microbiol.

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The RGD motif in the Severe Acute Syndrome Coronavirus 2 (SARS-CoV-2) spike protein has been predicted to bind RGD-recognizing integrins. Recent studies have shown that the spike protein does, indeed, interact with αVβ3 and α5β1 integrins, both of which bind to RGD-containing ligands. However, computational studies have suggested that binding between the spike RGD motif and integrins is not favourable, even when unfolding occurs after conformational changes induced by binding to the canonical host entry receptor, angiotensin-converting enzyme 2 (ACE2). Furthermore, non-RGD-binding integrins, such as αx, have been suggested to interact with the SARS-CoV-2 spike protein. Other viral pathogens, such as rotaviruses, have been recorded to bind integrins in an RGD-independent manner to initiate host cell entry. Thus, in order to consider the potential for the SARS-CoV-2 spike protein to bind integrins independent of the RGD sequence, we investigate several factors related to the involvement of integrins in SARS-CoV-2 infection. First, we review changes in integrin expression during SARS-CoV-2 infection to identify which integrins might be of interest. Then, all known non-RGD integrin-binding motifs are collected and mapped to the spike protein receptor-binding domain and analyzed for their 3D availability. Several integrin-binding motifs are shown to exhibit high sequence similarity with solvent accessible regions of the spike receptor-binding domain. Comparisons of these motifs with other betacoronavirus spike proteins, such as SARS-CoV and RaTG13, reveal that some have recently evolved while others are more conserved throughout phylogenetically similar betacoronaviruses. Interestingly, all of the potential integrin-binding motifs, including the RGD sequence, are conserved in one of the known pangolin coronavirus strains. Of note, the most recently recorded mutations in the spike protein receptor-binding domain were found outside of the putative integrin-binding sequences, although several mutations formed inside and close to one motif, in particular, may potentially enhance binding. These data suggest that the SARS-CoV-2 spike protein may interact with integrins independent of the RGD sequence and may help further explain how SARS-CoV-2 and other viruses can evolve to bind to integrins.

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“…There is also a need for additional studies aimed at understanding the composition of the replication-competent viral reservoir within sorted α4β7 + CD4 + T cells and accompanying subsets in different tissue compartments. This is important because there are differences in α4β7 + expression in CD4 + T cells with higher frequencies observed within the gut in comparison to blood and various lymph nodes, except mesenteric lymph nodes [72,73]. Understanding how these differences will affect the measures of the viral reservoir following RA supplementation remains to be fully evaluated.…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Improves the Recovery of Replication-Competent Virus from Latent SIV Infected Cells

Olwenyi

Acharya

Routhu

et al. 2020

Cells

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The accurate estimation and eradication of Human Immunodeficiency Virus (HIV) viral reservoirs is limited by the incomplete reactivation of cells harboring the latent replication-competent virus. We investigated whether the in vitro and in vivo addition of retinoic acid (RA) enhances virus replication and improves the detection of latent virus. Peripheral blood mononuclear cells (PBMCs) from naive and anti-retroviral therapy (ART)-treated SIV-infected rhesus macaques (RMs) were cultured in vitro with anti-CD3/CD28 + IL-2 in the presence/absence of RA. Viral RNA and p27 levels were quantified using RT-qPCR and ELISA, respectively. Viral reservoirs were estimated using the Tat/Rev-Induced Limited Dilution Assay (TILDA) and Quantitative Viral Outgrowth Assay (QVOA). In vitro and in vivo measures revealed that there was also an increase in viral replication in RA-treated versus without RA conditions. In parallel, the addition of RA to either CD3/CD28 or phorbol myristate acetate (PMA)/ionomycin during QVOA and TILDA, respectively, was shown to augment reactivation of the replication-competent viral reservoir in anti-retroviral therapy (ART)-suppressed RMs as shown by a greater than 2.3-fold increase for QVOA and 1 to 2-fold increments for multi-spliced RNA per million CD4+ T cells. The use of RA can be a useful approach to enhance the efficiency of current protocols used for in vitro and potentially in vivo estimates of CD4+ T cell latent reservoirs. In addition, flow cytometry analysis revealed that RA improved estimates of various viral reservoir assays by eliciting broad CD4 T-cell activation as demonstrated by elevated CD25 and CD38 but reduced CD69 and PD-1 expressing cells.

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Integrin α4β7 in HIV-1 infection: A critical review

Cited by 12 publications

References 41 publications

Targeting integrin pathways: mechanisms and advances in therapy

Targeting integrin pathways: mechanisms and advances in therapy

Can the SARS-CoV-2 Spike Protein Bind Integrins Independent of the RGD Sequence?

Retinoic Acid Improves the Recovery of Replication-Competent Virus from Latent SIV Infected Cells

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