CELLULAR MECHANISMS OF FELINE IMMUNODEFICIENCY VIRUS (FIV)-INDUCED NEUROPATHOGENESIS

Elisabeth Zenger, Evelyn Tiffany-Castiglioni, and Ellen W. Collisson

Department of Medicine, UCSF AIDS Program, San Francisco General Hospital, University of California, San Francisco, California (Zenger) and the Departments of Veterinary Anatomy and Public Health (Tiffany-Castiglioni) and Pathobiology (Collisson), College of Veterinary Medicine, Texas A&M University, College Station, Texas.

Received 10/7/97 Accepted 10/23/97

2. INTRODUCTION

Among the clinically notable and biologically intriguing aspects of lentiviruses are their effects on the central nervous system (CNS). In addition to opportunistic CNS infections and neoplasms associated with immunodeficiency, there is also a unique syndrome of neurologic impairment which appears to result from a more fundamental effect of the lentivirus. The lentiviruses feline immunodeficiency virus (FIV) and human immunodeficiency virus (HIV) are clinically relevant neuropathogens. The syndrome of neurologic dysfunction associated with HIV infection that includes cognitive and motor impairment in both adults and children has been termed acquired immunodeficiency syndrome (AIDS) dementia complex, HIV-1 encephalopathy, or simply NeuroAIDS.

The high incidence of neurologic dysfunction from HIV infection has heightened interest in neuropathogenesis associated with feline retrovirus infections. Feline immunodeficiency virus causes a disease syndrome in cats remarkably similar to that associated with HIV infection in people (1, 2, 3) and is therefore not only an important feline pathogen but also an invaluable small animal model of HIV. Although there has been a surge of new information during the last several years, many questions regarding lentivirus-associated neuropathogenesis still exist. Despite nearly a decade of research, the CNS target cells and alterations responsible for neurologic dysfunction from FIV are yet to be definitively identified. This review highlights major research findings in the area of cellular mechanisms of FIV-mediated neuropathogenesis.

Although not recognized as frequently as in HIV-infected people, a wide range of neurologic deficits has been described in FIV-infected cats and neurologic disease represents an important sequela to naturally- and experimentally-acquired FIV-infection. The nature of FIV-associated neurologic abnormalities tends to be behavioral rather than motor in nature. Reported clinical behavioral abnormalities in adult cats encompass subtle to overt changes including docility, agitation, confusion, loss of litterbox training, dementia or psychotic behavior (hiding, rage, excessive aggression), and compulsive (i.e., repetitive, purposeless) motor movement or roaming (4, 5). Specific neurologic defects have included anisocoria, nystagmus, delayed pupillary reflex, ataxia, paresis, paralysis, delayed or absent righting and other abnormal postural reflexes, intention tremors, and focal or generalized seizures (5, 6).

The seemingly lower incidence of neurologic manifestations of FIV compared to HIV may be a real difference in disease expression between these viruses or may simply represent a decreased ability to detect subtle behavioral or functional alterations in cats. Although a relatively insensitive diagnostic indicator, magnetic resonance imaging reveals subtle but distinct abnormalities in some FIV-infected cats including ventricular enlargement and focal white-matter lesions. A significant decrease in N-acetylaspartate, a marker of neuronal dysfunction has been detected using proton magnetic resonance spectroscopy (MRS) in FIV-infected cats (7). Neuroelectrodiagnostic evaluation has proven to be a sensitive means of detecting neurologic dysfunction in both overtly affected as well as seemingly asymptomatic FIV-infected cats as early as 3 months postinfection (6, 8, 9, 10, 11). Delayed visual evoked potentials (VEP) and brain stem auditory evoked potentials (BAEP), decreased retinocortical times, and decreased evoked spinal potentials suggesting a demyelinating process and/or selective fiber dropout have been detected in many FIV-infected cats. Abnormalities detected by electroencephalography (EEG) range from asymmetrical or diffuse high-amplitude activity to marked alterations in sleep patterns with predominant slow-wave activity. The EEG findings correlate with abnormal behavior in some cats and parallel findings reported in HIV-infected patients.

Although the majority of FIV-infected cats do not manifest clinically observable neurologic dysfunction, a much higher proportion have microscopic CNS lesions. However, as occurs with HIV as well, often there is poor correlation between the histopathologic lesions and detected clinical neurologic abnormalities. Experimental infection with the Petaluma (FIV-Pet) or Pisa-M2 (FIV-Pisa-M2) consistently causes moderate to pronounced gliosis of both gray and white matter, vacuolar myelopathy and inflammatory cell infiltration in the CNS (4, 12, 13). However, these lesions are not associated with clinical disease. In contrast, experimental infection with the phylogenetically distantly related Maryland strain of FIV (FIV-MD) causes rapid onset of neurological signs but only mild CNS lesions (6, 14). Importantly, FIV can be isolated from areas virtually devoid of histologic lesions and extent of virus distribution seems to correlate well with severity of neurologic dysfunction. With neurovirulent strains of FIV, there is significant loss of cortical neurons and evidence of compensatory increases of synaptic terminal densities suggesting that neurodegeneration begins after the early viremia during the asymptomatic stage of disease (9, 15). Compensatory changes likely mask slow and progressive loss of neurons which only becomes clinically significant during AIDS or when there are other factors which accelerate the neurodegenerative process.

It is widely accepted that HIV and FIV gain access to the brain via migration of infected hematogenous cells. However, definitive proof is yet to be brought forward demonstrating this phenomenon. The potentiality of free FIV, instead of or in addition to cell-associated virus, entering the CNS has been suggested by results of studies demonstrating disrupted blood-brain barrier (BBB) integrity during acute FIV infection (7, 9). Increased BBB permeability is correlated temporally with peak viremia and CD4/CD8 ratio inversions (7).

In vivo and in vitro studies suggest that neuroglia, the support cells of the CNS, rather than neurons are the principle cellular targets for lentiviruses. Although neurons are for all intents not infected, a substantial degree of neuronal loss can occur in the cortex (16, 17) and indirect viral effects are presumably responsible for clinical and pathological findings (18, 19, 20, 21). The observed neurologic dysfunction likely involves an intricate web of subcellular pathways and neurotoxic factors affecting neurons but produced by infected neuroglia, specifically microglia and astroglia.