Antibody-Induced Internalization of HIV-1 Env Proteins Limits Surface Expression of the Closed Conformation of Env

Anand, Sai Priya; Grover, Jonathan R.; Tolbert, W.D.; Prévost, Jérémie; Richard, Jonathan; Ding, Shilei; Baril, Sophie; Medjahed, Halima; Evans, David T.; Pazgier, Marzena; Mothes, Walther; Finzi, Andrés

doi:10.1128/jvi.00293-19

Cited by 34 publications

(42 citation statements)

References 65 publications

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“…Env Internalization Assay. Env internalization assay was performed as described previously (28). Briefly, infected CD4+ T cells were stained with Env PGT151 Ab (5 μg/mL) and cell viability dye (Zombie UV) for 30 min on ice and then extensively washed in cold buffer.…”

Section: Methodsmentioning

confidence: 99%

“…S5E). To determine if differences in Env retention or internalization from the plasma membrane were also implicated in altered Env surface expression and incorporation into virions, a flow cytometry Env internalization assay (28) and an Env recycling assay were performed (SI Appendix, Fig. S6).…”

Section: Retained Cd3 Expression Correlates With Increased Cell Activmentioning

confidence: 99%

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Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

Mesner

Hotter

Kirchhoff

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Nef is an accessory protein of primate lentiviruses that is essential for efficient replication and pathogenesis of HIV-1. A conserved feature of Nef proteins from different lentiviral lineages is the ability to modulate host protein trafficking and down-regulate a number of cell surface receptors to enhance replication and promote immune evasion. Notably, the inability of Nef to down-regulate CD3 from infected T cells distinguishes HIV-1 Nef and its direct simian precursors from other primate lentiviruses. Why HIV-1 does not employ this potential immune evasion strategy is not fully understood. Using chimeric HIV-1 constructs expressing lentiviral Nef proteins that differ in their ability to down-modulate CD3, we show that retaining CD3 on the surface of infected primary T cells results in increased viral replication and cell-to-cell spread. We identified increased expression of envelope (Env) trimers at the cell surface and increased Env incorporation into virions as the determinants for the Nef-and CD3-dependent enhancement of viral infectivity. Importantly, this was independent of Nef-mediated antagonism of the host restriction factor SERINC5. CD3 retention on the surface of infected primary T cells also correlated with increased T cell signaling, activation, and cell death during cell-tocell spread. Taken together, our results show that loss of an otherwise conserved function of Nef has a positive effect on HIV-1 replication, allowing for more efficient replication while potentially contributing to HIV-1 pathogenesis by triggering T cell activation and cell death during viral spread.HIV | CD3 | Nef | T cell | Env

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Section: Methodsmentioning

confidence: 99%

Section: Retained Cd3 Expression Correlates With Increased Cell Activmentioning

confidence: 99%

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

Mesner

Hotter

Kirchhoff

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…HIV-1 accomplishes this through its Nef and Vpu accessory proteins, which decrease the overall amounts of Env (via Vpu-mediated BST-2 downregulation) and CD4 at the cell surface (23,29,30). In addition, efficient Env internalization also limits ADCC responses (31,32). Motivated by the vulnerability of the CD4-bound conformation of Env to ADCC, new approaches to "force" Env to adopt this conformation using small CD4-mimetic compounds (CD4mc) have been developed (33).…”

mentioning

confidence: 99%

The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site

Prévost

Tolbert

Medjahed

et al. 2020

mBio

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The HIV-1 envelope glycoproteins (Env) undergo conformational changes upon interaction of the gp120 exterior glycoprotein with the CD4 receptor. The gp120 inner domain topological layers facilitate the transition of Env to the CD4-bound conformation. CD4 engages gp120 by introducing its phenylalanine 43 (Phe43) in a cavity (“the Phe43 cavity”) located at the interface between the inner and outer gp120 domains. Small CD4-mimetic compounds (CD4mc) can bind within the Phe43 cavity and trigger conformational changes similar to those induced by CD4. Crystal structures of CD4mc in complex with a modified CRF01_AE gp120 core revealed the importance of these gp120 inner domain layers in stabilizing the Phe43 cavity and shaping the CD4 binding site. Our studies reveal a complex interplay between the gp120 inner domain and the Phe43 cavity and generate useful information for the development of more-potent CD4mc. IMPORTANCE The Phe43 cavity of HIV-1 envelope glycoproteins (Env) is an attractive druggable target. New promising compounds, including small CD4 mimetics (CD4mc), were shown to insert deeply into this cavity. Here, we identify a new network of residues that helps to shape this highly conserved CD4 binding pocket and characterize the structural determinants responsible for Env sensitivity to small CD4 mimetics.

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“…Other complement evasion mechanisms include the incorporation of host membrane complement regulatory proteins by budding enveloped virions, 88 molecular mimicry 89 or recruitment of such host regulatory factors, 87,90 and production of other complement‐disrupting factors such as complement‐cleaving enzymes, 91 and interference with C1q‐associated serine proteases 92 . Another mechanism of complement evasion, and evasion of antibody‐mediated effector function more generally, is antibody‐induced antigen internalization on virally infected host cells 93,94 . These pathogen evasion mechanisms, and others, have been extensively reviewed recently 95 .…”

Section: Role In Infectious Disease: From Elimination To Evasion To Ementioning

confidence: 99%

Antibody‐mediated complement activation in pathology and protection

Goldberg

Ackerman

2020

Immunol Cell Biol

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Antibody-dependent complement activity is associated not only with autoimmune morbidity, but also with antitumor efficacy. In infectious disease, both recombinant monoclonal antibodies and polyclonal antibodies generated in natural adaptive responses can mediate complement activity to protective, therapeutic or disease-enhancing effect. Recent advances have contributed to the structural resolution of molecular complexes involved in antibody-mediated complement activation, defining the avid nature of participating interactions and pointing to how antibody isotype, subclass, hinge flexibility, glycosylation state, amino acid sequence and the contextual nature of the cognate antigen/ epitope are all factors that can determine complement activity through impact on antibody multimerization and subsequent recruitment of complement component 1q. Beyond the efficiency of activation, complement activation products interact with various cell types that mediate immune adherence, trafficking, immune education and innate functions. Similarly, depending on the anatomical location and extent of activation, complement can support homeostatic restoration or be leveraged by pathogens or neoplasms to enhance infection or promote tumorigenic microenvironments, respectively. Advances in means to suppress complement activation by intravenous immunoglobulin (IVIG), IVIG mimetics and complement-intervening antibodies represent proven and promising exploratory therapeutic strategies, while antibody engineering has likewise offered frameworks to enhance, eliminate or isolate complement activation to interrogate in vivo mechanisms of action. Such strategies promise to support the optimization of antibody-based drugs that are able to tackle emerging and difficult-to-treat diseases by improving our understanding of the synergistic and antagonistic relationships between antibody mechanisms mediated by Fc receptors, direct binding and the products of complement activation.

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Antibody-Induced Internalization of HIV-1 Env Proteins Limits Surface Expression of the Closed Conformation of Env

Cited by 34 publications

References 65 publications

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site

Antibody‐mediated complement activation in pathology and protection

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