Immune Reconstitution Prevents Continuous Equine Infectious Anemia Virus Replication in an Arabian Foal with Severe Combined Immunodeficiency: Lessons for Control of Lentiviruses

Abstract

Acute infection with equine infectious anemia virus (EIAV), a lentivirus of horses, results in a persistent high-level viremia in Arabian foals affected with severe combined immunodeficiency (SCID). This observation argues against the idea that the transient nature of acute lentiviral viremia is solely a function of viral population dynamics. To extend these studies, EIAV-specific immune reconstitution was attempted prior to EIAV challenge in 2 SCID foals, using adoptively transferred virus-stimulated lymphocytes derived from persistently EIAV-infected half sibling donors. Following transfer, lymphocyte engraftment occurred in 1 foal, and EIAV-specific cytotoxic T lymphocytes as well as neutralizing antibody activity developed. Following a brief period of plasma viremia in this foal, EIAV replication was controlled and plasma virus could not be detected by RT-PCR or culture. These results provide further direct evidence that a specific immune response is required for termination of plasma viremia in acute lentiviral infections.

Equine Infectious Anemia Virus (EIAV): what has HIV?s country cousin got to tell us?

“…Arabian foals with severe combined immunodeficiency (SCID), lacking both B and T lymphocytes, fail to control the initial viremic episode [33,108,133]. Adoptive transfer by intravenous infusion of EIAV-stimulated donor lymphocytes in SCID foal restores the control of viral replication in the reconstituted animal [112,113]. Studies examining the evolution of plasma-associated viral RNA load together with the development of clinical symptoms suggest that the threshold level for disease induction correlates with an RNA level in plasma of 10 7 to 10 8 copies/mL [29,32,54,83].…”

Presentation and Binding Affinity of Equine Infectious Anemia Virus CTL Envelope and Matrix Protein Epitopes by an Expressed Equine Classical MHC Class I Molecule

“…After infection, viremia and associated clinical signs are usually controlled (1,2), and this requires lymphocyte-specific responses because Arabian foals with SCID do not control the initial viremia, while control occurs in Arabian foals with a normal immune system (3). Further, reconstitution of an SCID foal with immune lymphocytes prevents continuous EIAV replication (4). Recurrence of viremia in infected horses is probably an outcome of antigenic variation, and in fact, antigenic variation of EIAV epitopes recognized by either neutralizing Ab (2,5) or CTL (6) occurs.…”

Cloning and large-scale expansion of epitope-specific equine cytotoxic T lymphocytes using an anti-equine CD3 monoclonal antibody and human recombinant IL-2

“…In horses infected with equine infectious anemia virus (EIAV), a lentivirus with a world-wide distribution, CTL are critical in the control of viral replication and clinical disease (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Several factors contribute to the protective effects of CTL against EIAV, including epitope specificity and functional avidity (15,20,21,23,24).…”

“…We chose to clone CTL specific for the conserved EIAV Rev-QW11 epitope, which is recognized by high avidity CTL (20), and is presented by the equine leukocyte antigen (ELA)-A1 haplotype-associated MHC class I molecules 7-6 and 141 (17,25). Because the ELA-A1 haplotype is well-represented in our research herd of Arabian horses that carry the severe combined immunodeficiency (SCID) trait (33)(34)(35)(36), Rev-QW11-specific CTL clones would be excellent candidates for evaluating protective effects by adoptive transfer to SCID foals (19,37). In addition, this clone would be valuable for investigating the differential recognition efficiencies of Rev-QW11 when presented by the 7-6 and 141 class I molecules (25).…”

“…In addition, this clone would be valuable for investigating the differential recognition efficiencies of Rev-QW11 when presented by the 7-6 and 141 class I molecules (25). The cloning procedure utilized an anti-equine CD3 mAb (38,39) and human recombinant IL-2 (rhuIL-2), which stimulates equine lymphocytes (15,19,22,40), such that autologous APC and specific antigen were not required during expansion in culture. Our results demonstrated that large numbers of CD3+/CD8+ Rev-QW11-specific CTL clones could be generated, and that they retained their phenotype and function following cryopreservation.…”