Lessons in AIDS vaccine development learned from studies of equine infectious, anemia virus infection and immunity

Abstract

Equine infectious anemia (EIA), identified in 1843 [1] as an infectious disease of horses and as a viral infection in 1904, remains a concern in veterinary medicine today. Equine infectious anemia virus (EIAV) has served as an animal model of HIV-1/AIDS research since the original identification of HIV. Similar to other lentiviruses, EIAV has a high propensity for genomic sequence and antigenic variation, principally in its envelope (Env) proteins. However, EIAV possesses a unique and dynamic disease presentation that has facilitated comprehensive analyses of the interactions between the evolving virus population, progressive host immune responses, and the definition of viral and host correlates of immune control and vaccine efficacy. Summarized here are key findings in EIAV that have provided important lessons toward understanding long term immune control of lentivirus infections and the parameters for development of an enduring broadly protective AIDS vaccine.

Figure 1

Profile of equine infectious anemia virus (EIAV) clinical disease. A schematic diagram representing a typical clinical profile over elapsed time associated with EIAV infection of equines indicating the characteristic stages of EIA disease. Febrile episodes are defined as rectal temperatures above 39 °C (103 °F), thrombocytopenia is defined as platelet levels below 105000/μL of blood, and a viremia of ≥10⁵ copies RNA/mL plasma.

Figure 2

Schematic of EIAV viral genome. Organization of the EIAV genome indicating viral genes (italic print) and the respective proteins encoded by these genes (block print). V1-V8, indicates the defined Surface Unit, or gp90, variable regions.

Figure 3

EIAV envelope divergence over time. Genetic distance calculations of amino acid sequence divergence of longitudinal isolate Envs from the inoculum Env sequence were calculated and plotted as a function of time. Linear regression (line) analysis revealed a significant linear relationship between the two variables (Figure modified from original published in Craigo et al. [26]).

Figure 4

Temporal evolution of gp90 V3 envelope species demonstrates new species with each population. Temporal evolution of the gp90 Env V3 domain of longitudinal viral populations from an experimentally infected pony is represented graphically. Each distinct gp90 V3 region is depicted as a separate square, or population 1 through 52. Viral plasma species were determined for the acute and chronic stages from fever episodes I through VI, and from the inapparent stage prior to and during immune suppression in both plasma and tissues (lymph node, liver, and spleen). EIAV_PV, lab strain inoculum; Pre-T, pre-immune suppression tissue; Pre, pre-immune suppression plasma; IS-T, immune suppression tissue; IS, immune suppression plasma (Figure modified from original in Craigo et al. [20]).

Figure 5

Schematic representation of lentiviral immune maturation. Development of mature immunity (grey-shaded box) occurs by 6–8 months post-infection. Red, reciprocal endpoint titer; Orange, conformational ratio; Blue, avidity index; Green, reciprocal neutralization titer (Figure modified from original in Montelaro et al. [39]).