Biology subjects

Desrosiers, R. C.

Publications and source records attributed to Desrosiers, R. C..

3 recordsLinked to original sources

bioRxiv2021

Molecular insights into antibody-mediated protection against the prototypic simian immunodeficiency virus

SIVmac239 infection of macaques is a favored model of human HIV infection. However, the SIVmac239 envelope (Env) trimer structure, glycan occupancy, and the targets and ability of neutralizing antibodies (nAbs) to protect against SIVmac239 remain unknown. Here, we report the isolation of SIVmac239 nAbs that recognize a glycan hole and the V1/V4 loop. A high-resolution structure of a SIVmac239 Env trimer-nAb complex shows many similarities to HIV and SIVcpz Envs, but with distinct V4 features and an extended V1 loop. Moreover, SIVmac239 Env has a higher glycan shield density than HIV Env that may contribute to poor or delayed nAb responses in SIVmac239-infected macaques. Passive transfer of a nAb protects macaques from repeated low dose intraveneous SIVmac239 challenge at serum titers comparable to those described for protection of humans against HIV infection. Our results provide structural insights for vaccine design and shed light on antibody-mediated protection in the SIV model.

immunology↗

bioRxiv2020

Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)

The rhesus monkey rhadinovirus (RRV), a {gamma}2-herpesvirus of rhesus macaques, shares many biological features with the human pathogenic Kaposis sarcoma-associated herpesvirus (KSHV). Both viruses, as well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family of receptor tyrosine kinases (Ephs). However, the importance of the Eph interaction for RRV entry varies between cell types suggesting the existence of Eph-independent entry pathways. We therefore aimed to identify additional cellular receptors for RRV by affinity enrichment and mass spectrometry. We identified an additional receptor family, the Plexin domain containing proteins 1 and 2 (Plxdc1/2) that bind the RRV gH/gL glycoprotein complex. Preincubation of RRV with soluble Plxdc2 decoy receptor reduced infection by approx. 60%, while overexpression of Plxdc1 and 2 dramatically enhanced RRV susceptibility of otherwise marginally permissive Raji cells. While the Plxdc2 interaction is conserved between two RRV strains, 26-95 and 17577, Plxdc1 specifically interacts with RRV 26-95 gH. The Plxdc interaction is mediated by a short motif at the N-terminus of RRV gH that is partially conserved between isolate 26-95 and isolate 17577, but absent in KSHV gH. Mutation of this motif abrogated the interaction with Plxdc1/2 in in vitro assays and reduced RRV infection in a cell-type specific manner. Taken together, our findings characterize Plxdc1/2 as novel interaction partners and entry receptors for RRV and support the concept of the N-terminal domain of the gammaherpesviral gH/gL complex as a multifunctional receptor-binding domain. Further, Plxdc1/2 usage defines an important biological difference between KSHV and RRV. AUTHORS SUMMARYKSHV is the causative agent of a group of malignancies which account for a substantial disease burden in particular in sub-Saharan Africa. RRV, a related virus of rhesus macaques, has shown promise as model system for KSHV and for the development of immunization strategies. To exploit the full potential of the RRV animal model system, detailed knowledge of commonalities and differences between KSHV and RRV is key. Here, we describe the Plexin domain containing proteins 1 and 2 as a novel receptor family which mediates entry of RRV, but not of KSHV. Infection experiments using RRV mutants deleted of the Plxdc interaction motif suggest a cell type-specific contribution of Plxdc receptors to RRV infection. As information on Plxdc1/2 and its biological function is still sparse, analysis of the RRV-Plxdc interaction will help to characterize the physiological and pathophysiological role of this receptor family.

microbiology↗

bioRxiv2019

EphA7 functions as a receptor for cell-to-cell transmission of Kaposi’s sarcoma-associated herpesvirus into BJAB B cells and for cell-free virus infection by the related rhesus monkey rhadinovirus

Kaposis sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposis sarcoma and is associated with two B cell malignancies, primary effusion lymphoma and the plasmablastic variant of multicentric Castlemans disease. EphA2 functions as a cellular receptor for the gH/gL glycoprotein complex of KSHV for several adherent cell types. KSHV gH/gL was previously shown to also weakly interact with other members of the Eph family of receptors. Whether these interactions are of functional consequence remained unclear so far, even if other A-type Ephs were shown to be able to compensate for absence of EphA2 in overexpression systems. Here, we demonstrate for the first time that endogenously expressed EphA7 in BJAB B cells is critical for the cell-to-cell transmission of KSHV from producer iSLK cells to BJAB target cells. The BJAB lymphoblastoid cell line often serves as a model for B cell infection and expresses only low levels of all Eph family receptors other than EphA7. Endogenous EphA7 could be precipitated from the cellular lysate of BJAB cells using recombinant gH/gL, and knockout of EphA7 significantly reduced transmission of KSHV into BJAB target cells by over 80%. Finally, we demonstrate that receptor function of EphA7 is conserved between cell-to-cell transmission of KSHV and cell-free infection by the related rhesus monkey rhadinovirus (RRV), which is relatively even more dependent on EphA7 for infection of BJAB cells.\n\nIMPORTANCEInfection of B cells is biologically relevant for two KSHV-associated malignancies, the plasmablastic variant of multicentric Castlemans disease (MCD) and primary effusion lymphoma (PEL). Elucidating the process of B cell infection is therefore important to understand the pathogenesis of these diseases. For various types of adherent cells, EphA2 has been shown by several groups to function as an entry receptor that is engaged by the gH/gL glycoprotein complex. Our previous findings indicate that KSHV does not only interact with EphA2, but can also bind to other members of the Eph family of receptor tyrosine kinases with comparatively lower avidity. We now analyzed the requirement of Eph interactions for infection of the BJAB B cell line, a model for infection of B cells by KSHV. We identify EphA7 as the principal Eph receptor for infection of this model B cell line by both KSHV and the related rhesus monkey rhadinovirus.

microbiology↗