Equine infectious anemia (EIA) is a disease caused by the equine infectious anemia virus (EIAV), a virus that is restricted in host range to members of the Equidae family. The virus causes persistent lifelong infection in its hosts. The infection is not found in other members of the Perissodactyla, suggesting the virus entered equids sometime following divergence from rhinoceroses and tapirs, a separation thought to have occurred 8 to 9 million years ago in evolutionary theory. Equine infectious anemia virus is a relative of the human and simian immunodeficiency viruses, although unlike its more famous relatives, it does not infect CD4+ helper T cells (TH) and therefore does not induce chronic immunodeficiency or acquired immunodeficiency disease syndrome (AIDS)–like signs. In fact, clinical signs following exposure to EIAV are highly variable and, with the exception of extreme cases, are likely to be missed or incorrectly interpreted, except by the most observant owner or veterinarian. Furthermore, there may be significant differences between equid species in susceptibility to EIAV-induced pathology, with donkeys (Equus asinus) being far more resistant to disease than horses (Equus caballus). However, this conclusion may be biased by the fact that experimental infections conducted to date have used viruses derived from and propagated in horses or ponies rather than donkeys. Therefore it is possible that, instead of donkeys having innate resistance to EIAV-induced disease, the virus must undergo adaptation for optimal growth in each equid species.
In addition to variation among individual animals in clinical presentation following exposure, one of the most important factors in the epidemiology and spread of EIAV is the fact that most infected animals acquire the ability to control viral replication for prolonged periods of time, resulting in an absence of all overt disease signs. In this state, the “inapparent carrier” remains a potential reservoir for transmission but cannot be readily distinguished from noninfected cohorts without the use of specific diagnostic tests. Considering the inherent difficulties involved in the differential diagnosis of EIA based on clinical signs, it is perhaps not surprising that most newly discovered cases of the disease involve equids that have attained inapparent carrier status. In many countries (with the exception of Italy, which recently [2007 to 2012] undertook a national surveillance program), mandatory testing for EIA is limited to equids that are to be sold or bred or that are participating in competitive equestrian events involving transportation from one location to another. Where such regulations are enforced, the rate of EIA detection in the tested population is usually very low, and new cases are only discovered when, for example, previously untested equids are offered for sale. EIA is a blood-borne disease, and hematophagous insects (especially horse flies, deerflies, and stable flies) are believed to be the most important vectors for natural transmission. However, the most efficient vector for this infection or disease is humans. Volumes of residual blood in a hypodermic syringe and needle are at least 1000-fold greater than they are on the mouthparts of a horse fly. Furthermore, when EIAV is contained within the relatively protected environment of a hypodermic syringe, it can survive longer than when exposed to rapid drying on insect mouthparts. Consequently, the adoption of strict standard or universal precautions by all equine practitioners should be encouraged to reduce their impact on transmission of EIAV and other blood-borne pathogens.
The causative agent of EIA was defined as a filterable agent or virus in 1904 and was shown to be a member of the Retroviridae family in the 1970s. It is now classified in subfamily Orthoretrovirinae within the Lentivirus genus, and as such is related to human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), bovine immunodeficiency virus (BIV), and the small ruminant lentiviruses (SRLVs). Consequently, the Equidae are included within the relatively small number of mammalian species (African nonhuman primates, cattle, cats, sheep, goats, and, most recently, humans) that constitute natural hosts for lentiviruses. An unusual feature of these viruses is that cells of the monocyte-macrophage lineage are the primary host cell type. These are nondividing cells and, as such, provide a hostile environment for many viruses because they contain very low levels of deoxynucleotides, with the exception of deoxyuridine 5′-triphosphate (dUTP). This nucleotide can produce mutational effects because it has a propensity to mispair with guanine. Furthermore, mammals have evolved sophisticated intracellular defense systems against retroviruses, such as the apolipoprotein β editing complex 3 (APOβEC3) series of molecules, in addition to innate and adaptive immune responses. To counteract both the hostile environment of nondividing host cells and the so-called retroviral restriction factors, lentiviral genomes contain a number of short open reading frames (ORFs) in addition to prototypical gag, pol, and env genes that are possessed by all retroviruses. Consequently, lentiviruses are termed complex retroviruses; EIAV is the simplest living representative of the genus in that it contains just three additional ORFs compared with the six ORFs in HIV-1. As a result of its relative genetic simplicity, EIAV has been dubbed the “country cousin” of primate lentiviruses such as HIV-1 and SIV. The EIAV gag gene encodes the group-specific antigens comprising the matrix (p15), major capsid (p26), nucleocapsid (p11), and late domain (p9) proteins. Polymerase (pol) gene products are produced in much lower quantities within infected cells and include protease, reverse transcriptase, RNase H, dUTPase, and integrase, whereas env encodes the surface unit (SU or gp90) and transmembrane (TM or gp45) envelope glycoproteins that are important in attachment and entry to host cells. The structural antigens, which induce the strongest immune responses in infected equids and therefore are important in the serologic diagnosis of EIA, are (p26), along with gp90 (SU) and gp45 (TM).
The term retrovirus was coined to reflect the mode of replication in which the single-stranded RNA genome is reverse-transcribed into double-stranded proviral DNA. In these viruses, the flow of genetic information is opposite to the standard biologic paradigm found in all living cells, wherein double-stranded genomic DNA is transcribed into various single-stranded RNA molecules. Furthermore, this proviral DNA molecule can be integrated into host cell chromatin by the virally encoded integrase protein. After integration, it is treated as a “normal” cellular gene and transcribed by host transcription factor complexes into messenger RNA for the production of viral proteins or full-length genomic RNA for packaging into progeny virions. One of the cardinal features of lentiviruses is that they induce persistent infections in their hosts. This is effected by the proviral integration strategy and an error-prone reverse transcriptase process that promotes high mutation rates, enabling evasion of adaptive immune responses to the major antigenic determinants.
Clinical responses of equid host species are dependent on multiple virus and host factors that have not been completely characterized. Viral strains that have been serially passaged in horses are noted to have marked increases in pathogenicity in that species. Similarly, strains that have been adapted to replicate in cultured equid cells become attenuated in adults, but not in fetuses. Some of the genetic changes in the virus associated with these alterations have been mapped to specific alterations in host cell transcription factor–binding motifs contained within the long terminal repeat (LTR), along with mutations in the envelope glycoproteins and the ORF encoding Rev, a protein that is essential for export of viral RNA molecules from the host cell nucleus.
In a typical infection of horses with a horse-adapted strain of virus, early or acute virus replication leads to high viral loads in plasma, which is associated with marked febrile responses and, often, mild to severe thrombocytopenia sometimes associated with petechial hemorrhages on oral mucous membranes. In some individuals, this febrile response is unabated, and peracute or acute death results. In others, this initial febrile response is resolved, and the horse develops repeated clinical episodes over time, leading to more characteristic clinical signs of the chronic form of EIA: fever, dependent edema, cachexia, anemia, depression, lassitude, and a general unthrifty appearance.
Many equids in which EIA is detected today are clinically normal and generally are only discovered as a result of required testing. These inapparent carriers of EIAV may have had a mild fever episode associated with initial exposure to the virus or may have remained clinically normal throughout the infection. It is tempting to hypothesize that the relatively mild strains of EIAV found today in many countries have emerged because of our culling of equids infected with more pathogenic strains. Suffice it to say, however, that it is thought that the genetic plasticity of the virus would permit any strain to regain virulence and induce serious disease signs. That potential has convinced the regulatory community to treat all EIAV-infected horses with the same guidelines, regardless of clinical status at the time of detection. That position is justified because each inapparent carrier may respond with clinical signs of EIA after immunosuppression from stress or treatment with immunosuppressive drugs.