Feline immunodeficiency virus pathogenesis and development of a dual-subtype feline-immunodeficiency-virus vaccine (2007)

Introduction Feline immunodeficiency virus (FIV) infection is a natural infection of domestic felid populations which results in a chronic and progressive acquired immunodeficiency syndrome [1–3]. FIV was discovered in the autumn of 1986 and reported in 1987 shortly after the discovery of HIV-1 in 1983 and HIV-2 in 1986 [1,4,5]. Although sequence comparisons between human and feline AIDS lentiviruses show distant relationship, similarities exist in the structural gene organization of these lentiviruses (gag–pol–env) as well as the presence of a few regulatory genes (rev, vpr, vif) commonly present in advanced primate retroviruses such as HIV-1 and HIV-2 [6,7] (Fig. 1). Much like HIV-1 infection, FIV infection of domestic cats is found throughout the world. The major characteristic of FIV infection is the CD4+ T-cell loss followed by immunodeficiency syndrome, which is clinically and immunologically similar to the immunopathogenesis of HIV infection [1–3]. Moreover, in 2002, a commercial dual-subtype FIV vaccine was released as an outcome of extensive international collaborations among FIV researchers [8]. The successes and failures of FIV vaccine trials are described in this review and hopefully provide insights into the development of effective HIV vaccines.Fig. 1: Proviral genome organization of HIV-1, HIV-2, and feline immunodeficiency virus (FIV). Open reading frame (orf)-A, also called orf-2, was initially reported to express 79 amino acid Tat-like protein. However, recent studies suggest this gene to be vpr based on its gene product promoting the transport of the DNA pre-integration complex into the cell nuclei. FIV resembles HIV by having LTR–gag–pol–env–LTR genomic organization, while missing few regulatory genes (tat, vpu, vpx, nef).FIV pathogenesis compared to HIV-1 infection Virology, transmission, and epidemiology of FIV similar to HIV In addition to having advanced genomic organization like HIV, FIV has virological and immunological features resembling both HIV-1 and HIV-2. When compared with HIV-1 infection, HIV-2 and FIV infections have longer asymptomatic stage, a higher cell-proviral load, a slower CD4+ T-cell decline, a lower frequency of vertical transmission, and a lower mortality (Tables 1 and 2; [9–55]). The high cell/proviral load relative to plasma vRNA load in HIV-2 and FIV infections suggests less shedding into plasma and lower transmission rate of HIV-2 and FIV than HIV-1.Table 1: Feline immunodeficiency virus (FIV) with virological features similar to HIV-1 and HIV-2.Table 2: Feline immunodeficiency virus (FIV)–cat model for HIV immunopathogenesis and neuropathogenesis.FIV infection is similar to HIV-1 infection by having a broad worldwide prevalence of the predominant subtypes, a high plasma vRNA load in naturally infected animals, similar neuropathology and neurological signs, and the use of similar modality (in utero, intrapartum, and colostrum/milk) for vertical transmission. Although FIV is prevalent throughout the world, the transmission rates of FIV in prevalent areas are much lower than those of HIV-1 but above those of HIV-2 (Table 1). Natural FIV transmission is reported to occur during fighting via biting and wound exposure to contaminated blood [8,41,56]. FIV transmission by contaminated blood is thought to be by infected cells rather than plasma in blood based on more consistent recovery of provirus from infected cells than virus from plasma (Table 1) [8,42,57,58]. Such transmission mode may simulate perhaps the HIV infection of intravenous (IV) drug users. FIV transmission by saliva occurs more readily in cats with oral lesions due to higher levels of infected cells in the contaminating blood than in the saliva [8,42,57]. Hence, the low natural transmission rate is thought to be due to the lower infectious FIV levels in saliva of cats that are free of oral lesions found in asymptomatic phase. Experimental transmission studies using intravenous (IV), intramuscular (IM), intrarectal, and intravaginal inoculations have demonstrated FIV infection with both cell-free and cell-associated viruses [8,41,55,58–60]. Immunopathogenesis of FIV similar to HIV In comparison to HIV-1 infection, FIV has a broader range of susceptible cells due to its use of chemokine receptors as both coreceptor and minor primary receptors (Table 1). In addition to infecting feline CD4+ T cells, monocyte/macrophages, and glial cells, FIV infects CD8+ T cells and B cells (Table 2) [61–63]. FIV infection of CD4+CD25+ feline T regulatory (Treg) cells from infected cats was reported [64,65], prior to the recent report on in-vitro infection of human Treg cells with HIV-1 [66]. However, infection of Treg cells in humans has been more difficult to determine due to the decreased Treg cells in HIV-1-positive subjects [66]. FIV uses feline CD134 (not human CD134) as its primary receptor and both feline and human CXCR4, a chemokine receptor, can serve as co-receptor [37,38,67]. CD134, also called OX40, is a member of tumor necrosis factor receptor family transiently expressed on activated T cells and serves as a key co-stimulatory molecule involved in regulation of CD4+ memory T cells [68,69]. In addition, a number of FIV strains can infect CXCR4-positive cells without the presence of CD134 [38,39]. In preliminary studies, some FIV strains were found to use CXCR4 and CCR5 as minor primary receptors or co-receptors [36,39,40]. However, confirmation of these observations needs to be made for CCR5 by other laboratories. The immunological hallmark of FIV infection is depletion of CD4+ peripheral T cells and reduced CD4/CD8 ratios, leading to B- and T-cell dysfunctions [70–73]. T-cell dysfunctions include decreased proliferative responses and decreased interleukin-2 (IL-2) production [2,72,73]. However, even with the loss of CD4+ T cells, CD8+ cytotoxic T lymphocyte (CTL) activities to FIV group-specific-antigens (Gag) and to whole virus develop early in the infection and persist during the asymptomatic stage [74,75]. In addition, CD8+ T cells from infected cats produce soluble antiviral factors [76], resembling the CD8-mediated antiviral factor (CAF) produced in HIV-positive individuals. In general, FIV-infected cats possess strong T-helper 1 (TH1) activities during early stages of FIV infection, which gradually decrease with long-term infection [77]. Cats chronically infected with FIV lose their ability to produce naive T cells, which are subsequently replaced by CD4+ and CD8+ cell populations with memory/activated phenotypes of L-selectin-negative but positive for other activation markers [adhesion, integrin and major histocompatibility complex-II (MHC-II) molecules] [78,79]. These T-cell dysfunctions and responses in FIV-infected cats closely mimic those of HIV-positive individuals [78,79]. B-cell dysfunctions are less dramatic than T-cell dysfunctions, and seem to be only in primary antibody responses to T-dependent antigens [72,73], with normal responses to T-independent antigens and normal to some decrease in secondary responses to other feline viral vaccines at acute to asymptomatic stages of infection [80,81]. Virus neutralizing (VN) antibodies to FIV develop shortly after the production of anti-FIV CTL to provide additional immunity against FIV [82]. Infected cats often develop increased serum IgG levels, indicative of FIV-induced virus-specific B-cell hyperactivity similar to that observed in HIV [70,83]. Clinical manifestations include persistent secondary infections which frequently become resistant to antimicrobial therapy and eventually result in the death of the animal [41]. Neurological manifestations and high-grade B-cell lymphomas similar to those observed in HIV-positive patients have also been reported in cats with natural and experimental FIV infections [84–86]. Long-term survivors (LTS) have been reported for FIV-infected cats similar to the human LTS with HIV-1 infection [41,87–89]. In summary, both disease manifestations and clinical progression are similar to HIV, suggesting that the FIV model can be valuable in identifying strategies for developing effective HIV prophylactic therapies and a vaccine [90,91]. Neuropathogenesis of FIV resembles HIV-1 In addition to immunopathogenesis of FIV resembling both HIV-1 and HIV-2, many of the FIV strains cause neuropathology and neurological symptoms that resembles HIV-1-associated dementia complex (HADC) [92]. HADC consists of vacuolar myelopathy, peripheral neuropathies, and cognitive and motor dysfunctions [93]. Like HIV-1, FIV infects CNS macrophages, microglia cells, and astrocytes [62,63,92,93], while HIV-2 has been reported to infect CNS macrophages and microglia cells but does not infect astrocytes or neuronal cells [94]. Extremely low levels of HIV-1 infection in select neuronal cells have been reported [12,95]. A recent report suggests FIV infection of neuronal cells by using CXCR4 and CCR5 as viral receptors [36]. Major histopathology of both HIV-1 and FIV is subcortical white matter pallor, axonal injury, and neuronal loss [36,92,93]. Similar to histopathology of HIV-1-associated vascular myelopathy, FIV causes perivascular mononuclear cell infiltration, glial nodules, and astrogliosis but the multinucleated giant cells are rare in CNS of FIV-infected cats [92]. Peripheral neuropathies of FIV infection include delayed righting reflex and transient limb paresis; while other neurological symptoms include behavior changes (less sociable and more easily frightened), aniscoria, and delayed pupilary reflex [92]. Like HIV-1, delayed auditory and visual evoked responses, and sleep disorder are observed in FIV infected cats [92,96,97]. The use of neurotropic FIV strains enhances the neuropathology and accelerates the manifestation of neurological symptoms to be observed during acute infection [36,92,97]. In light of recent studies suggesting neurological diseases in HIV-1-infected individuals to be over 60% [98], neurotropic FIV infection of domestic cats is an excellent small animal AIDS model for HIV-1 neuropathogenesis and development of anti-HIV/FIV drugs against CNS infection and diseases. Natural pathogenicity and pathogenic strains Domestic cats naturally infected with FIV develop AIDS after 7–9 years of infection (i.e., the equivalent of 42–54 years in human years) and succumb shortly after to the disease (Table 2) [41]. Such slow progression to disease has initially made the FIV–cat model less attractive as an animal AIDS model for vaccine and therapeutic studies. However, long-term studies have determined that HIV-1-positive individuals also develop AIDS after 7–10 years of HIV-1 infection [99,100] and over 10 years of HIV-2 infection [27]. It has been reported that some of the HIV-2 infected individuals even after 10 years of infection may not develop AIDS [27]. The search for more pathogenic FIV strains has determined FIV phylogeny to include not only pathogenic strains but natural recombinants of different subtypes or clades [33,101]. Upon evaluation of all reported FIV sequences, the number of FIV recombinant in nature appears to be small [33,102,103]; suggesting that recombination rate for FIV may be much smaller than those reported for HIV-1 [104]. Thus the extent of circulating FIV appears to be much less than HIV-1. Much like the rapid pathogenesis of SIVmac239 infection of Asian macaques, pathogenic FIV strains cause high virus load and severe CD4+ T-cell loss, leading to acute disease and mortality within a year in a portion of infected cats (Table 2) [101,105]. Hence, the pathogenic FIV strains can accelerate the immunopathogenesis to those observed in HIV-1 infection; while the low-pathogic FIV strains cause immunopathogenesis that resembles those of HIV-2. Similar to the worldwide HIV-1 infection, the global prevalence of natural FIV infection has been reported for domestic cats and so far based on genotype, five subtypes or clades (A–E) have been identified (Fig. 2[34,41,106–130], Table 1), [102,131,132]. 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