The following is excerpted from an article authored by Cook RF, Cook SJ, and Issel CJ to appear in the Equine Veterinary Journal special publication on Equine Infectious Diseases
Antibodies against EIAV may be detected in a variety of laboratory tests as early as 14-28 days post infection (pi) although most reports indicate they are non-neutralizing. Strain specific neutralizing antibodies are not generally observed until 38-87 days pi and may not reach maximal levels until 90-148 days pi (O'Rourke et al. 1988; Kono et al. 1973; Rwambo et al. 1990; Ball et al. 1992; Hammond et al. 1997), generally long after the acute disease episode has been resolved. As cytotoxic lymphocytes (CTL) can be detected in experimental infections at 14 days pi (Mealey et al. 2005) it is currently believed that cell-mediated and not humoral immune responses are responsible for initial control of EIAV infections. Once acute viral replication has been controlled the animal will remain free of overt clinical signs until a variant virus emerges that can evade immunological surveillance.
If EIAV has seemingly limitless mutational capacity, what terminates the recurring disease cycles and how do animals attain inapparent carrier status?
At one time it was thought there might be selective pressure to limit pathogenicity in the host and to ensure the progressive attenuation of EIAV (Belshan et al. 1998). However, viruses transferred from inapparent carrier equids often produce disease in naive recipients. Furthermore, recrudescence of clinical signs can be induced in carriers by immunosuppression with corticosteroids (Kono et al. 1976; Tumas et al. 1994; Howe et al. 2005; Craigo et al. 2002). These observations suggest the immune system and not viral attenuation is primarily responsible for the eventual cessation of clinical signs in EIAV infected animals. To envisage how this might occur, it is necessary to consider evolution the mammalian immune system in response to lentiviral infections. Cell-mediated and humoral immune responses to new infections are restricted by the phenomenon of immunodominance to just a handful of the many potential epitopes within microbial pathogens (Kedl, Kappler, and Marrack 2003; Borysiewicz et al. 1988; Busch and Pamer 1998; Pamer, Harty, and Bevan 1991; Rodriguez et al. 2002; Yu et al. 2002). Furthermore, immunodominance does not always translate into an effective immune response. EIAV epitopes recognized by high-avidity immunodominant CTL are subject to rapid mutational changes with the original sequences disappearing from the viral population (Mealey et al. 2003). In contrast, low or even moderate avidity immunodominant CTL do not appear to have substantially detrimental effects on the survival of EIAV and epitopes bound by these less efficient T-cells can persist in the viral population (Mealey et al. 2003; Mealey et al. 2005). Therefore, the initial adaptive immune response to EIAV is likely to consist of the eventual appearance of strain specific neutralizing antibodies coupled with a very limited number of effective CTLs. While this is apparently sufficient to resolve acute disease, it is easy to envisage how a highly mutable virus like EIAV could evade these initial immune responses by producing escape mutants with the replicative capacity to induce additional clinical episodes. As such, it appears the immune system is locked into a constant cycle of "catch-up". However, this cycle may be broken by a gradual broadening of the immune responses leading to the recognition of a greater number of epitopes including some that may be conserved because of functional constraints. The result of these enhanced responses is that complete escape from immunological surveillance becomes extremely difficult unless there is suppression of the immune system. For example, the number of CTL epitopes recognized in some HIV positive people increases from 2 during symptomatic acute infection to 27 after 18 months (Yu et al. 2002). The fact that relatively large numbers of T-helper and CTL epitopes can be identified within just the viral envelope glycoproteins 7 months after infection with an attenuated EIAV strain (Tagmyer et al. 2007) suggests a similar broadening of the immune response occur in the horse. An important additional consideration is that unlike HIV, EIAV does not infect T-helper cells and does not produce immunodeficiency. Therefore, in the case of EIAV infected equids broader cell-mediated immune responses are likely to remain protective for very long periods consistent with inapparent carrier status. In addition, antibody responses in EIAV infected animals gradually evolve from low-avidity interactions with linear epitopes to high-avidity binding with predominantly conformational epitopes (Hammond et al. 1997). Neutralizing antibodies also evolve from being highly strain specific to more generally reactive. However, while more broadly reactive cell-mediated and humoral immune responses may eventually restrict EIAV replication and prevent disease they are not sufficient to completely eradicate the virus.
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Updated on: February 17, 2010