Research paper
FIV diversity: FIVPle subtype composition may influence disease outcome in African lions

https://doi.org/10.1016/j.vetimm.2011.06.013Get rights and content

Abstract

Feline immunodeficiency virus (FIV) infects domestic cats and at least 20 additional species of non-domestic felids throughout the world. Strains specific to domestic cat (FIVFca) produce AIDS-like disease progression, sequelae and pathology providing an informative model for HIV infection in humans. Less is known about the immunological and pathological influence of FIV in other felid species although multiple distinct strains of FIV circulate in natural populations. As in HIV-1 and HIV-2, multiple diverse cross-species infections may have occurred. In the Serengeti National Park, Tanzania, three divergent subtypes of lion FIV (FIVPle) are endemic, whereby 100% of adult lions are infected with one or more of these strains. Herein, the relative distribution of these subtypes in the population are surveyed and, combined with observed differences in lion mortality due to secondary infections based on FIVPle subtypes, the data suggest that FIVPle subtypes may have different patterns of pathogenicity and transmissibility among wild lion populations.

Introduction

Feline immunodeficiency virus (FIV) is a lentivirus closely related to HIV and SIV. In domestic cats (Felis catus), FIV infection results in immune pathology, secondary infections, and death. The parallels between human and feline AIDS (FAIDS) have been explored for further understanding of HIV/AIDS transmission, infection, and pathology (Bendinelli et al., 1995, Burkhard and Dean, 2003, Elder et al., 1998, Elder et al., 2010, Henriksen et al., 1995, Stump and VandeWoude, 2007). As with HIV and SIV models, there is considerable variation in transmission, course of infection, and outcome of FIV infections in domestic cats. Some variation likely results from host genetic restriction factors that influence the viral life cycle, similar to those described in humans (Lochelt et al., 2005, Munk et al., 2008, Munk et al., 2007, Troyer et al., 2008, VandeWoude et al., 2010). However, differences in pathogenicity have also been demonstrated among genetically distinct subtypes of FIV that circulate in domestic cats (de Monte et al., 2002, Elder et al., 2010, Pedersen et al., 2001, Weaver, 2010).

Most experimental viruses representing FIVFca subtypes are cell-line adapted but nonetheless retain recognized differences in pathogenicity. For example, FIV-CPG derived strains generally result in high initial viral loads and a faster progression to disease, especially in young cats (de Rozieres et al., 2004a, de Rozieres et al., 2004b, de Rozieres et al., 2008). In contrast, cats infected with FIV-A strains often remain asymptomatic for longer periods of time, with lower initial viral loads, though viral growth kinetics are similar in adult cats once the acute stage of infection has passed (de Rozieres et al., 2008, Pedersen et al., 2001, Sparger et al., 1994). FIV subtype A strains are often neurotrophic and neurotoxic, producing CNS symptoms similar to those seen in HIV-1 infection (Gruol et al., 1998, Henriksen et al., 1995, Johnston et al., 2000, Meeker, 2007, Phillips et al., 1994, Phillips et al., 1996, Power et al., 1998).

Species-specific FIV viruses infect other felids and are distributed throughout the world, yet little is known about their immunological and pathological effects in wild populations (Brown et al., 2010, Carpenter et al., 1996, Franklin et al., 2008, Franklin et al., 2007, Olmsted et al., 1992, Troyer et al., 2005). Long term surveillance of non-domestic felids infected with FIV, as well as evidence from free-ranging populations of pumas (Puma concolor) and lions (Panthera leo), suggest that these viruses are ancient, host-adapted, and have little to no negative impact on life-history parameters such as longevity (Biek et al., 2006, Carpenter and O’Brien, 1995, Packer et al., 1999). However, a few clinical studies have revealed that individuals of these same species may demonstrate FIV-associated immune depletion and, in some cases, AIDS-like complications and death (Brennan et al., 2006, Brown et al., 2010, Bull et al., 2002, Bull et al., 2003, Roelke et al., 2006, Roelke et al., 2009). Data on life history and clinical parameters are rare, and seldom collected in the same population.

At least six genetically distinct strains of lion FIV (FIVPle) circulate in wild populations of African lions (Panthera leo) (Fig. 1; Antunes et al., 2008, O’Brien et al., 2006, Pecon-Slattery et al., 2008b, Troyer et al., 2005). FIVPle subtypes demonstrate distinct phylogeographic distributions, suggesting prolonged host association, perhaps predating the Late-Pleistocene expansions of lions (Antunes et al., 2008). Probably as a result of the highly social nature of lions, FIVPle-infected populations have high prevalence of seropositive individuals, often approaching 100% in adults, while other populations remain completely uninfected (Antunes et al., 2008, Brown et al., 1994, Troyer et al., 2005). This “all or nothing” distribution of FIV in lion population makes appropriate comparisons of infected vs. uninfected lions a challenge. Differences in FIVPle status may be confounded by important environmental parameters affecting lion health including other infectious agents, prey abundance, and water availability.

Epidemiological and life history vs. clinical and immunological studies on FIVPle-infected lions have been collected in different populations with only limited overlap. No evidence has been found of decreased lifespan in FIVPle-endemic populations in the Serengeti National Park and the Ngorongoro crater, where most lions are infected at an early age; no direct comparison with uninfected animals was possible (Packer et al., 1999). By contrast, infected individuals from Botswana and Tanzania demonstrated multiple clinical features of chronic immune depletion similar to human, simian, and domestic cat AIDS (Roelke et al., 2006, Roelke et al., 2009). The phylogeographic distribution of FIVPle raises the question as to whether FIVPle subtypes confer differential pathogenicity. However, to date, no study has correlated FIVPle subtypes with clinical or life history outcomes, in part because of the same geographic and environmental co-factors mentioned above.

Several lines of evidence suggest that FIVPle subtypes may be substantially different from each other. Two FIVPle strains, FIVPle subtype E and FIVPle subtype A, circulate in Botswana while three, FIVPle subtypes A, B, and C, occur in the Serengeti National Park (Antunes et al., 2007, Brown et al., 1994, O’Brien et al., 2006, Troyer et al., 2004, Troyer et al., 2005). Strains representing the predominant subtype in each of these populations, FIVPle-B from the Serengeti and FIVPle-E from Botswana, have been fully sequenced revealing remarkable differences between these subtypes (Pecon-Slattery et al., 2008a). While these two strains form a lion-specific clade when full length viruses are aligned, the envelope (env) sequence by itself displays a different phylogenetic relationship that suggests an historic recombination event between distantly related viruses, making FIVPle-E env seemingly more similar to domestic cat FIV than to FIVPle-B. In contrast, FIVPle-B env groups with other non-domestic cat env gene sequences (Carpenter and O’Brien, 1995, Pecon-Slattery et al., 2008a, Smirnova et al., 2005). The env gene is responsible for several aspects of lentiviral pathogenicity; changes in these sequences can affect receptor binding, antibody affinity, and target cell specificity. Therefore, these differences have been hypothesised to influence disease outcomes (Barlough et al., 1993, Burkhard and Dean, 2003, Elder et al., 2010, Patrick et al., 2002, VandeWoude and Apetrei, 2006).

The FIVPle subtypes circulating in Serengeti lions are more divergent then the FIVPle found in other African lion populations. Specifically, FIVPle-C pol is as different from the other two Serengeti subtypes as from FIV strains that infect other felid species (Troyer et al., 2005). Further, within-subtype diversity is much higher for FIVPle-B than for the other two subtypes. Phylogenetic reconstruction of the three Serengeti FIVPle subtypes suggest different ancestral evolutionary trajectories and/or selection pressures (Troyer et al., 2004). For example, FIVPle-B is representative of a widely distributed East African clade found across Tanzania, Uganda, and Kenya. FIVPle-A appears to have spread from Southern Africa as the most closely related lion viruses are found in South Africa and Botswana. Unique to the Serengeti, FIVPle-C is distantly related to other FIVPle viral subtypes (Antunes et al., 2008, O’Brien et al., 2006) and exhibits relatively low within strain diversity consistent with either recent introduction or stronger selective pressure from the host immune system. This pattern likely arose from three separate introductions of FIVPle to this population in the recent past, a hypothesis supported by population genetic analyses of lion microsatellite loci, autosomal sequences, and mitochondrial sequences (Antunes et al., 2008).

Because these three divergent strains exist in a single population, it is possible to compare both population dynamics and epidemiology of these strains while reducing the influence of confounding environmental factors. Here we present an analysis of FIVPle subtype composition throughout the lifespan of Serengeti lions and during a deadly disease outbreak. In late 1993, an unprecedented number of Serengeti lions died or disappeared; several were observed with neurological disorders including myoclonus ataxia and grand-mal seizures. From November 1993 to August 1994, the lion population in the long-term study area in the southeastern part of the Serengeti National Park plummeted by 39% with 78% of deaths occurring between the beginning of January and the end of March 1994 (Fig. 2). The abruptness and extent of mortality indicated the emergence of a deadly pathogenic agent, initially suspected to be a neurotropic FIV strain. However, comprehensive clinical sampling and an assessment of over 100 lions during the outbreak revealed no relationship between disease and FIV infection, excluding FIVPle as the primary pathogen. The dead and sick lions showed reactivity to canine distemper virus (CDV) monoclonal antibodies, and post mortem immunohistopathology of brain tissue confirmed CDV as the causative agent. PCR detection and CDV viral sequences indicated that the strain had spread from domestic dogs living in villages adjacent to the National Park (Carpenter et al., 1998, Munson et al., 2008, Packer et al., 1999, Packer et al., 2005, Roelke-Parker et al., 1996).

A similar deadly outbreak of CDV occurred in the nearby Ngorongoro Crater in 2001, while 5 other CDV outbreaks in the area over a 20 year time span were not associated with any measureable mortality (Munson et al., 2008). The high-mortality of the 1994 Serengeti and 2001 Ngorongoro CDV outbreaks were apparently linked to co-infection with high levels of Babesia, a tick-borne hemoparasite that proliferated during severe droughts. The associated tick infestations of the primary prey species of lions is believed to have led to the high levels of Babesia observed during the CDV outbreak and to be an important co-factor in these mortality events (Munson et al., 2008).

Although FIVPle was not the primary cause of the fatal outbreaks, the clinical evidence that FIVPle can lead to immune suppression in lions raises the question of whether FIVPle could have played a supportive or interactive role. We therefore treated these die-offs as “naturalistic experiments”: challenges to lions’ health that allowed an opportunity to test whether different strains of FIVPle might have had differential influences on CDV alone or on CDV/Babesia combined pathogenesis.

Section snippets

FIVPle subtype designation

Blood samples from lions, had been used as a source of DNA, with subtype-specific PCR performed (reported in Troyer et al., 2004). The generated FIV sequences had been assigned to subtypes A, B, and C based on phylogenetic analysis of the resultant 300 bp sequences from the pol gene region produced by the strain-specific PCR primers (Troyer et al., 2004, Troyer et al., 2005, Antunes et al., 2008). For the current study, novel analyses used the previously generated FIVPle subtypes that had been

Results

Subtype-specific primers (Troyer et al., 2004) were used to examine FIVPle circulating in blood samples from 216 lions collected over 15 years starting in 1984 and ending in 1999. As seen in a previous study of sixty-nine of these lions (Troyer et al., 2004), there was a high incidence of co-infections with multiple subtypes of FIV; 35% of the animals were infected with more than one subtype at the time of sampling. Overall there was a large difference in subtype frequency, with 12% of the

Discussion

Lentiviruses evolve rapidly and demonstrate strong species fidelity. However, divergent strains infect individual species, sometimes as a result of multiple introductions and sometimes through viral evolution post-introduction. These strains may differ in virulence, host-cell tropism, pathogenicity and clinical outcome. In free-ranging African lions, FIVPle-A, FIVPle-B, and FIVPle-C demonstrated differential pathology and transmission. Older lions (>5 years old) infected with FIVPle-C or A

Conflict of interest statement

All authors declare no conflict of interest.

Acknowledgements

We thank Randy Johnson and Rachel Simmons for statistical assistance and consultation. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and has also been funded in part with federal funds from the National Cancer Institute and National Institutes of Health, under contract HHSN26120080001E. Samples were collected in full compliance with specific federal permits (CITES; Endangered and Threatened Species)

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