CCR5 Revisited: How Mechanisms of HIV Entry Govern AIDS Pathogenesis

Brelot, Anne; Chakrabarti, Lisa A.

doi:10.1016/j.jmb.2018.06.027

Cited by 72 publications

(67 citation statements)

References 400 publications

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“…Besides CD4, the CXCR4 and CCR5 (C-C motif chemokine receptor-5) are known HIV coreceptors (21). The expression of CXCR4 on NHBE cells has been amply documented (11,22,23), and we have also previously demonstrated that following infection, NHBE cells produce mucus in response to X4-but not to R5-tropic HIV-gp120 (11); however, the expression CCR5 on these cells is not unequivocal (18,20).…”

Section: Human Bronchial Epithelial Cells Intrinsically Express Cd4 Amentioning

confidence: 99%

Lung Bronchial Epithelial Cells are HIV Targets for Proviral Genomic Integration

Devadoss

Acharya

et al. 2020

Preprint

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In the era of highly active anti-retroviral therapy (HAART), obstructive lung diseases (OLDs) are common among the people living with HIV (PLWH); however, the mechanism by which HIV induces OLDs is unclear. Although human bronchial epithelial cells (HBECs) express HIV coreceptors and are critical in regulating lung immune responses, their role in transmitting HIV remains unclear. Herein, we present evidence that HIV-1 infects normal HBECs and the viral DNA is integrated in the genome to establish the viral latency. To prove that HIV productively infects HBECs, we demonstrate: (a) along with CXCR4, HBECs express the HIV-receptor CD4, and are induced to express CCR5 by IL-13 treatment; (b) following infection with HIV, HBECs produce HIV-p24 and contain the latent HIV provirus, which is activated by endotoxin and/or vorinostat; (c) DNA from HIV-1 infected HBECs contains the HIV-specific gag and nef genes, along with Alu sequences, confirming the integration of HIV in the host DNA; (d) the lung epithelial cells of HIV-infected subjects and SHIV-infected cynomolgus macaques are positive for HIV-specific transcripts. Thus, these studies suggest that HIV establishes latency in lung epithelial cells, making them potential HIV reservoirs. The long-living lung epithelial cells, activated by commonly encountered lung infections, might represent an ideal HIV target/reservoir, contributing to OLDs and other HIV-associated lung comorbidities.

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Section: Human Bronchial Epithelial Cells Intrinsically Express Cd4 Amentioning

confidence: 99%

Lung Bronchial Epithelial Cells are HIV Targets for Proviral Genomic Integration

Devadoss

Acharya

et al. 2020

Preprint

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“…It was revealed that the TXP motif governs the conformation of the extracellular part of TM2, which is closely associated with the chemokine receptor activation. [50][51][52] Thus, the distance of TM2-TM6 in the cytoplasmic side and the RMSD value of the conserved TXP domain with respect to the inactive crystalstructure were chosen as two-dimension reaction coordinates. Table 1 lists the distance of TM2-TM6 and RMSDs of the TXP motif with respect to the crystal structure of CCR5 in the inactive state.…”

Section: Stable States In Conformation Spacementioning

confidence: 99%

Using accelerated molecular dynamics simulation to shed light on the mechanism of activation/deactivation upon mutations for CCR5

Zhang

Yuan

et al. 2018

RSC Adv.

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In this work, accelerated molecular dynamics (aMD) simulations were used to study different effects of G286F and R126 mutations on the activity of CCR5. Potential of Mean Force (PMF) results indicate that there are stable inactive-like states and active-like ones existing in the conformation space of the wild type (WT), confirming that CCR5 could possess to some extent constitutive activity. But the R126N mutation could constrain CCR5 in the inactive state through influencing the TXP motif and limiting the movements of TM5 and TM6. In contrast, the G286F mutation promotes the activity of the receptor by increasing the distance of TM2-TM6 and the flexibility of the intracellular part of TM5 and changing the H-bonding in the TXP motif. The observations from the cross correlation analysis further show that the R126N mutation dramatically reduces the motion correlations between TMs, which should partly contribute to the deactivation of CCR5. Compared with the WT system, TM6 and TM7 in the G286F mutant are loosely correlated with other regions, which should be conducive to drive the movement of TM6 and TM7 toward the active conformation. In addition, the result from the protein structure network (PSN) analysis reveals that the shortest pathways connecting the extracellular and the intracellular domains are highly conserved in the three systems despite the different mutations, in which the hydrogen bond plays a pivotal role. However, the G286F mutation shortens the lifetime of the pathway with respect to the R126N mutation, which may be associated with the different activities of the two mutants. The pathway connecting the ligand-binding site and the G-protein region reveals that the allosteric communication between TM6 and TM7 is enhanced by the R126N mutation while the G286F mutation induces the activation of the G-protein pocket by arousing more residues in the NPxxY region to participate in the pathway.

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“…The most recent findings on other virus-receptor interactions are extensively discussed in the review by Maginnis [5]. The human immunodeficiency virus and its co-receptor CCR5 are taken as an example by Brelot and Chakrabarti [6] to address (i) how viruses can subvert receptors to escape the host immune response and also (ii) how receptors drive the virus-induced pathogenesis. The research article by Shimon et al [7], which reveals the structure of the receptor-binding domain of a non-pathogenic mammarenavirus, further illustrates the discussion.…”

Section: Early Virus-host Cell Interactionsmentioning

confidence: 99%

Early Virus–Host Cell Interactions

Lozach

2018

Journal of Molecular Biology

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CCR5 Revisited: How Mechanisms of HIV Entry Govern AIDS Pathogenesis

Cited by 72 publications

References 400 publications

Lung Bronchial Epithelial Cells are HIV Targets for Proviral Genomic Integration

Lung Bronchial Epithelial Cells are HIV Targets for Proviral Genomic Integration

Using accelerated molecular dynamics simulation to shed light on the mechanism of activation/deactivation upon mutations for CCR5

Early Virus–Host Cell Interactions

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