Equine Herpesvirus 1 Bridles T Lymphocytes To Reach Its Target Organs

Abstract

Equine herpesvirus 1 (EHV1) replicates in the respiratory epithelium and disseminates through the body via a cell-associated viremia in leukocytes, despite the presence of neutralizing antibodies. “Hijacked” leukocytes, previously identified as monocytic cells and T lymphocytes, transmit EHV1 to endothelial cells of the endometrium or central nervous system, causing reproductive (abortigenic variants) or neurological (neurological variants) disorders. In the present study, we questioned the potential route of EHV1 infection of T lymphocytes and how EHV1 misuses T lymphocytes as a vehicle to reach the endothelium of the target organs in the absence or presence of immune surveillance. Viral replication was evaluated in activated and quiescent primary T lymphocytes, and the results demonstrated increased infection of activated versus quiescent, CD4+versus CD8+, and blood- versus lymph node-derived T cells. Moreover, primarily infected respiratory epithelial cells and circulating monocytic cells efficiently transferred virions to T lymphocytes in the presence of neutralizing antibodies. Albeit T-lymphocytes express all classes of viral proteins early in infection, the expression of viral glycoproteins on their cell surface was restricted. In addition, the release of viral progeny was hampered, resulting in the accumulation of viral nucleocapsids in the T cell nucleus. During contact of infected T lymphocytes with endothelial cells, a late viral protein(s) orchestrates T cell polarization and synapse formation, followed by anterograde dynein-mediated transport and transfer of viral progeny to the engaged cell. This represents a sophisticated but efficient immune evasion strategy to allow transfer of progeny virus from T lymphocytes to adjacent target cells. These results demonstrate that T lymphocytes are susceptible to EHV1 infection and that cell-cell contact transmits infectious virus to and from T lymphocytes.IMPORTANCEEquine herpesvirus 1 (EHV1) is an ancestral alphaherpesvirus that is related to herpes simplex virus 1 and causes respiratory, reproductive, and neurological disorders in Equidae. EHV1 is indisputably a master at exploiting leukocytes to reach its target organs, accordingly evading the host immunity. However, the role of T lymphocytes in cell-associated viremia remains poorly understood. Here we show that activated T lymphocytes efficiently become infected and support viral replication despite the presence of protective immunity. We demonstrate a restricted expression of viral proteins on the surfaces of infected T cells, which prevents immune recognition. In addition, we indicate a hampered release of progeny, which results in the accumulation of nucleocapsids in the T cell nucleus. Upon engagement with the target endothelium, late viral proteins orchestrate viral synapse formation and viral transfer to the contact cell. Our findings have significant implications for the understanding of EHV1 pathogenesis, which is essential for developing innovative therapies to prevent the devastating clinical symptoms of infection.

Identification of a New Equid Herpesvirus 1 DNA Polymerase (ORF30) Genotype with the Isolation of a C2254/H752 Strain in French Horses Showing no Major Impact on the Strain Behaviour

“…In addition, a study showed that N 752 strains (isolated from abortion) could infect equally monocytic CD172a+ cells and T lymphocytes, whereas D 752 strains (isolated from neurological cases) could infect CD172a+ cells in a larger proportion than T lymphocytes. In accordance with other studies, the authors suggested that N 752 had adapted its immune evasion strategy after co-evolving from D 752 strains with the host immune system [ 52 , 54 , 55 ]. Concerning the genotype/pathotype association suggested by Nugent et al (2006), it was followed by a statistical report by Perkins et al performed on 176 EHV-1 isolates, showing a strong but not strict association between G 2254 /D 752 strains and neurological disease, and A 2254 strains and abortion disease.…”

Equine Herpesvirus Type 1 Modulates Cytokine and Chemokine Profiles of Mononuclear Cells for Efficient Dissemination to Target Organs

“…The viral and host factors responsible for cell-to-cell spread have not yet been fully identified for EHV-1. It was postulated that EC infection is established upon close contact of infected PBMC with EC upon which cell-to-cell virus transfer can take place [ 28 , 29 ]. Factors favoring adhesion of the two cell types and establishing cell-to-cell contact are essential for viral spread [ 30 , 31 ].…”

Viral Load and Cell Tropism During Early Latent Equid Herpesvirus 1 Infection Differ Over Time in Lymphoid and Neural Tissue Samples From Experimentally Infected Horses

“…Subsequently, EHV-1 infects mononuclear cells, enters the blood circulation and is thereby disseminated widely to secondary infection sites, such as the central nervous system (CNS) or the uterus ( 1 – 3 ). The main cell type infected during cell-associated viremia are monocytes and T-lymphocytes (T-cells), followed by B-lymphocytes (B-cells) ( 4 – 7 ).…”

“…For VZV, which, like EHV-1, belongs to the subfamily of Varicellovirinae, it is thought that VZV is transported to the sensory ganglia during viremia and in VZV-infected T-cells, as well as by axonal transportation ( 24 , 25 ). EHV-1 tropism for T-cells is also well described and it is proposed to be important for viral dissemination throughout the host and for bypassing viral clearance by the immune system ( 7 , 22 , 26 ). Interestingly, while EHV-1 gene transcription and protein expression is active during viral replication in epithelial cells, during viremia, the virus seems to be carried in a non-replicative state, until secondary locations, such as CNS or uterine endothelium, are reached and virus transfer occurs ( 7 ).…”

“…EHV-1 tropism for T-cells is also well described and it is proposed to be important for viral dissemination throughout the host and for bypassing viral clearance by the immune system ( 7 , 22 , 26 ). Interestingly, while EHV-1 gene transcription and protein expression is active during viral replication in epithelial cells, during viremia, the virus seems to be carried in a non-replicative state, until secondary locations, such as CNS or uterine endothelium, are reached and virus transfer occurs ( 7 ). However, it is unclear if EHV-1 is also transported to ganglia in the same manner and uses this route for successful latency establishment.…”