Pathogenesis of oral FIV infection

Abstract

Feline immunodeficiency virus (FIV) is the feline analogue of human immunodeficiency virus (HIV) and features many hallmarks of HIV infection and pathogenesis, including the development of concurrent oral lesions. While HIV is typically transmitted via parenteral transmucosal contact, recent studies prove that oral transmission can occur, and that saliva from infected individuals contains significant amounts of HIV RNA and DNA. While it is accepted that FIV is primarily transmitted by biting, few studies have evaluated FIV oral infection kinetics and transmission mechanisms over the last 20 years. Modern quantitative analyses applied to natural FIV oral infection could significantly further our understanding of lentiviral oral disease and transmission. We therefore characterized FIV salivary viral kinetics and antibody secretions to more fully document oral viral pathogenesis. Our results demonstrate that: (i) saliva of FIV-infected cats contains infectious virus particles, FIV viral RNA at levels equivalent to circulation, and lower but significant amounts of FIV proviral DNA; (ii) the ratio of FIV RNA to DNA is significantly higher in saliva than in circulation; (iii) FIV viral load in oral lymphoid tissues (tonsil, lymph nodes) is significantly higher than mucosal tissues (buccal mucosa, salivary gland, tongue); (iv) salivary IgG antibodies increase significantly over time in FIV-infected cats, while salivary IgA levels remain static; and, (v) saliva from naïve Specific Pathogen Free cats inhibits FIV growth in vitro. Collectively, these results suggest that oral lymphoid tissues serve as a site for enhanced FIV replication, resulting in accumulation of FIV particles and FIV-infected cells in saliva. Failure to induce a virus-specific oral mucosal antibody response, and/or viral capability to overcome inhibitory components in saliva may perpetuate chronic oral cavity infection. Based upon these findings, we propose a model of oral FIV pathogenesis and suggest alternative diagnostic modalities and translational approaches to study oral HIV infection.

Applications of the FIV Model to Study HIV Pathogenesis

“…In domestic cats, FIV produces progressive immune depletion that eventually results in an acquired immunodeficiency syndrome (AIDS) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. As a consequence, FIV infection is associated with a variety of clinical syndromes, including cachexia, anterior uveitis, chronic rhinitis, gingivostomatitis and periodontitis, encephalitis and neurologic dysfunction, and lymphoma [ 1 , 4 , 9 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. The acute phase of FIV infection, lasting approximately 4–8 weeks, is characterized by a sharp increase in CD4+ T lymphocytes that are accompanied by high levels of FIV viral RNA and proviral DNA in circulation [ 4 , 8 , 22 ].…”

“…During FIV infection, the loss of CD4+ T lymphocytes is directly attributable to a viral-induced cytopathic effect, in addition to an increase in FIV-specific CD8-mediated programmed cell death, lack of thymic regeneration, and spontaneous apoptosis in response to decreased cytokine support [ 10 , 25 , 27 , 28 ]. The most frequent clinical disease syndromes that are associated with FIV infection manifest as a consequence of immune dysfunction, such as oral opportunistic infection (gingivitis, stomatitis, and periodontitis), immune-mediated glomerulonephritis, chronic rhinitis, and dermatitis [ 15 , 16 , 19 , 20 , 29 , 30 ]. Oral opportunistic infections are prevalent in a high proportion of FIV-infected cats, and frequently present as erythematous, inflammatory lesions along the gingival margin (gingivitis), multifocal areas of necrotizing inflammation within the gingival sulcus or periodontal ligament (periodontitis), or ulcerative inflammatory lesions along the buccal mucosa, hard palate, or soft palate (stomatitis) [ 20 , 31 , 32 , 33 ].…”

Canine Distemper Virus Spread and Transmission to Naive Ferrets: Selective Pressure on Signaling Lymphocyte Activation Molecule-Dependent Entry

“…4A) (26). Since the infected animal did not develop signs of disease and frequent fighting was observed in this pair, direct contact between infected circulating immune cells and the oral mucosa of the contact animal during biting is a possible mode of transmission, in a manner similar to the natural transmission of feline immunodeficiency virus (FIV), where a blood-borne virus is transmitted by biting or other aggressive intraspecific behavior (41). Fighting between other animals, however, was infrequent, and no injuries were noted.…”

Immunopathologic Effects of Prednisolone and Cyclosporine A on Feline Immunodeficiency Virus Replication and Persistence

“…Feline immunodeficiency virus (FIV) is a naturally occurring lentivirus of domestic cats that produces progressive immune depletion resulting in an AIDS-like syndrome [1,2,3,4,5,6,7,8,9,10]. Similar to human immunodeficiency virus (HIV), FIV-infected cats may develop secondary or opportunistic infections as a consequence of viral-induced immune dysfunction, including anterior uveitis, chronic rhinitis, gingivostomatitis and periodontitis, encephalitis and neurologic dysfunction, and lymphoma [10,11,12,13,14,15,16,17,18,19]. While antiretroviral therapy (ART) has demonstrated modest success at controlling FIV infection in vivo, the capacity of ART to alleviate symptoms and control the development of secondary disease syndromes has been limited [9,20,21,22].…”