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Clinical Microbiology Reviews, October 2006, p. 728-762, Vol. 19, No. 4
0893-8512/06/$08.00+0 doi:10.1128/CMR.00009-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Going Wild: Lessons from Naturally Occurring T-Lymphotropic Lentiviruses
Sue VandeWoude1* and
Cristian Apetrei2,3
Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80538-1619,1
Department of Microbiology, Tulane National Primate Research Center, Covington, Louisiana 70433,2
Department of Tropical Medicine, School of Public Health, Tulane University, New Orleans, Louisiana 701123
Over 40 nonhuman primate (NHP) species harbor species-specific simian immunodeficiency viruses (SIVs). Similarly, more than 20 species of nondomestic felids and African hyenids demonstrate seroreactivity against feline immunodeficiency virus (FIV) antigens. While it has been challenging to study the biological implications of nonfatal infections in natural populations, epidemiologic and clinical studies performed thus far have only rarely detected increased morbidity or impaired fecundity/survival of naturally infected SIV- or FIV-seropositive versus -seronegative animals. Cross-species transmissions of these agents are rare in nature but have been used to develop experimental systems to evaluate mechanisms of pathogenicity and to develop animal models of HIV/AIDS. Given that felids and primates are substantially evolutionarily removed yet demonstrate the same pattern of apparently nonpathogenic lentiviral infections, comparison of the biological behaviors of these viruses can yield important implications for host-lentiviral adaptation which are relevant to human HIV/AIDS infection. This review therefore evaluates similarities in epidemiology, lentiviral genotyping, pathogenicity, host immune responses, and cross-species transmission of FIVs and factors associated with the establishment of lentiviral infections in new species. This comparison of consistent patterns in lentivirus biology will expose new directions for scientific inquiry for understanding the basis for virulence versus avirulence.
In ancient times, citizens sought answers to their most important inquiries by consulting oracles. Myths were part of daily life, and mythological creatures were feared or defeated. Oedipus deciphered the riddle of the Sphinx, a creature that was part primate (human) and part feline (lion). In modern times, many astute scientists have worked diligently to decipher a modern riddle, i.e., understanding human immunodeficiency virus (HIV) and using this knowledge to halt the AIDS pandemic. Although we endeavor to solve this riddle with the tools of science, we should keep in mind that, like Oedipus, we may find clues hidden in the intricate biology of primate and feline lentiviruses.
This review provides an overview of comparative aspects of feline and primate lentiviral infections, highlighting the striking similarities in both natural and cross-species transmission and pathogenicity of these agents. This side-by-side comparison of attributes of lentiviral infections conserved across divergent mammalian families is relevant for understanding the natural course of lentiviral disease. By taking a broader view of viral-host interactions, novel observations can be revealed, framing unanswered questions about HIV/AIDS pathogenesis and lentiviral/host adaptation and suggesting new avenues for mechanistic studies and therapeutic interventions for HIV.
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SIV AND FIV POSITIONS WITHIN THE LENTIVIRUS GENUS
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Simian immunodeficiency virus (SIV) and Feline immunodeficiency virus (FIV) belong to the Lentivirus genus of the Retroviridae. These viruses are morphologically distinct from other retroviruses in that they have a bar- or cone-shaped core (nucleoid). Lentiviruses have a complex structure with numerous accessory genes in addition to gag-, pol-, and env-encoded structural elements. The number of accessory genes (open reading frames [ORFs]) varies according to the strain of virus. All known lentiviruses are exogenous. At least 41 species of primates and 11 felid species have been diagnosed with species-specific lentiviral strains (see below). Besides primates and feline species, lentiviral infections have been identified in horses, goats, sheep, and cattle (253). Infection of certain felid and primate species results in immunodeficiency; however, the majority of these infections appear to be clinically silent. Ovine and caprine lentiviral infections may result in neurological disorders, arthritis, and pneumonia, while equine lentiviral infections result in recurrent fever and blood dyscrasias (253). Pathology has not been reported for cattle infected with bovine immunodeficiency virus (253). All lentiviruses include the accessory genes vif (virus infectivity factor) and rev (regulator of virus gene expression) (231, 253, 413), both of which have been implicated as facilitators of viral transcription and activation. FIVs also carry one or two small open reading frames; ORF 2 has been associated with a vpr-like function in domestic cat FIV (133). Three accessory genes are specific for primate lentiviruses, namely, vpr, vpx, and vpu; SIVs also include a nef gene. Figure 1 illustrates comparative genomic sequence organizations for three families of primate and feline lentiviruses.
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FIG. 1. Genomic organization of SIV and FIV strains belonging to different lineages. The SIV classification demonstrated is based on genomic structure relationships, which are not superimposable on phylogenetic relationships. For references, see Table 1.
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Interestingly, despite the fact that differences in ORF structure exist between FIVs and primate lentiviruses, at least domestic cat FIV has retained similar immunodeficiency-inducing properties, suggesting that immunopathogenicity is either unrelated to these structural components or that FIV has evolved distinct but phenotypically convergent properties resulting in similar biological consequences for its host.
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DETECTION AND NOMENCLATURE
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FIV
Several rapid, sensitive, and specific enzyme-linked immunosorbent assays (ELISAs) are widely available for detection of FIV antibodies from domestic cats (159). Several laboratories offer PCR-based assays for FIV detection, although these are less reliable (221). Serosurveys of nondomestic felids have generally evaluated seroreactivities in captive or free-ranging animal sera versus domestic cat FIV antigens (53, 58, 116, 176, 281, 356). Subsequent studies have demonstrated that using species-specific lentiviral antigen preparations in a Western blot format significantly enhances the sensitivity. Currently, only puma and lion virus-based Western blot assays are available (286, 376, 383, 384); for detection of antibodies from other species, comparison using a multistrain-antigen Western blot approach has provided greater sensitivity (288, 376; S. Franklin et al., Abstr. 7th Int. Feline Retrovir. Res. Symp., p. 69, 2004). The use of a conserved-epitope peptide-based ELISA has been evaluated for rapid screening of puma and lion sera (201, 389), and a flow cytometry-based antibody detection assay has also been reported (40). Despite the fact that available tests often lack sensitivity, 27 of 35 felid species evaluated demonstrated seroreactivity; FIV infection has been confirmed in 11 species by PCR amplification of lentiviral sequences from peripheral blood mononuclear cells (PBMC). Sequence analysis has confirmed nine unique species-specific highly heterologous strains (53, 58, 235, 281, 376). "FIV" is typically used to refer to lentiviruses arising from domestic cats; when more than one feline species of lentivirus is being discussed, the standard nomenclature for designation of strains originating from different species is to append genus and species identifiers for the feline species as a subscript to FIV; for example, domestic cat (Felis cattus) FIV becomes FIVfca, African lion (Panthera leo) FIV is designated FIVple, and puma (also cougar, mountain lion, and panther; Puma concolor) isolates are referred to as FIVpco. As an exception, lion and puma lentiviruses have also been referred to as LLV and PLV to facilitate recognition by readers unfamiliar with felid species designations (281, 386). Five clades (A to E) of FIVfca have been defined based upon env sequence phylogeny (19, 177, 269, 351), and a recent report identified a sixth apparently unique isolate (107). Six infectious FIVfca clones have been characterized, including FIV-GL8 (180), FIV-PPR (355), FIV-PET (365), FIV-C36 (355), FIV-NCSU (409), and FIV-19K1 (341).
Clade designations have also been determined for lion (FIVple-A, -B, and -C) and puma (FIVpco-A and -B) lentiviruses, although these classifications were based on phylogenetic differentiation within pol, not env. Divergence among FIV strains is significant. In conserved regions of pol, FIVfca, FIVple, and FIVpco differ by as much as 30%, and differences in env and gag are even more pronounced (53, 59, 214, 376). FIVpco and FIVple intraspecies differences are also large; i.e., 10 to 20% divergence in pol occurs among isolates from the same species (53, 59, 376). In contrast, domestic cat FIVfca clades only differ in their nucleotide sequences by 5 to 10% across the entire genome (59, 351). FIV clades tend to be geographically oriented; for example, domestic cats in California are predominantly infected with the A clade, and infected pumas in the upper Midwest cluster significantly with respect to home ranges (41, 351). This pattern is not as strictly observed for lions. For example, lions of the Serengeti may be infected with A, B, or C clade viruses (53, 375). Partial genomic sequences are available for 11 nondomestic FIVs (376). Three nondomestic FIVs (FIVple, FIVpco, and Pallas cat-derived FIVoma) have been cultured and extensively sequenced (23, 24, 41, 53, 58, 214, 375).
SIV
Serology is the "gold standard" for studying the prevalence of SIVs in nonhuman primates (NHPs). In the past, most laboratories screened NHPs for anti-SIV antibodies by using commercial ELISA and Western blot kits (31, 68, 109, 123, 134, 258). ELISA screening tests are based on antigens consisting of viral lysates, recombinant proteins, or synthetic peptides corresponding to immunodominant epitopes of the two HIV type 1 (HIV-1) subtype B variants (strains LAI and MN) and HIV-2 group A (ROD strain). These "mixed" tests are therefore able to detect anti-HIV-1 and anti-HIV-2 antibodies. Cross-reactivity with other lentiviral lineages enables the use of these tests for screening nonhuman primate samples. For more sensitive detection of SIVs in NHPs, two strategies have been developed. The first uses a highly sensitive line assay (INNO-LIA HIV; Innogenetics, Ghent, Belgium) as a screening test. Using this strategy, more than 10 different new SIV types have been identified in NHPs (301). A second strategy uses synthetic peptides based on the gp41/36 and V3 peptides, allowing for increased sensitivity (gp41/36) and specificity (V3 peptides) (2, 346). This technique has also led to the discovery of several SIVs.
In the vast majority of cases, the infected NHP species represents the reservoir of that virus type, which is designated by a three-letter abbreviation of the host primate species name (with numerous exceptions). When related species of the same genus are infected, the name of the subspecies is included in the virus designation. Thus, the four species of African green monkeys (AGMs), i.e., vervet, grivet, tantalus, and sabaeus, are infected by SIVagm.Ver, SIVagm.Gri, SIVagm.Tan, and SIVagm.Sab, respectively (3, 120, 172, 190, 193, 258). For chimpanzee subspecies infected by SIVs, there is an exception to this rule; each SIVcpz isolate is named from the known or last known country of origin of the chimpanzee. Thus, the Pan troglodytes troglodytes subspecies is infected by SIVcpzGAB (Gabon), SIVcpzCAM (Cameroon), and SIVcpzUS (U.S. captivity), whereas Pan troglodytes schweinfurthii is infected by SIVcpzANT (Democratic Republic of Congo [DRC] via Antwerpen), SIVcpzTAN (Tanzania), and SIVcpzDRC1 (DRC) (75, 128, 268, 302, 303, 324, 405). Some authors have adopted the abbreviations SIVcpz.Ptt and SIVcpz.Pts to differentiate between the SIV strains infecting these two species of chimpanzees (165, 339).
For individual isolates of different SIV types, the current nomenclature rules include the country of origin in the name of the isolate; thus, SIVmnd-1GB1 and SIVrcmGAB1 are viruses isolated from a mandrill (MND) and a red-capped mangabey (RCM), respectively, from Gabon (134, 378), whereas SIVrcmNG409 originates from Nigeria (31). Some authors also include the year of sampling. Thus, SIVsmmSL92 is a sooty mangabey (SM) virus isolated from a sample collected in Sierra Leone in 1992 (67). This is a useful feature for tracing the origins of viruses, allowing for a better understanding of their evolution. In a recent paper, an attempt was made to rename SIVs using three-letter names. This method would introduce modifications to the current nomenclature, i.e., SIVsm would become SIVsmm, while SIVlhoest would become SIVlho (37).
Currently, there are 41 fully sequenced SIV genomes representing 23 different species types. Partial genomic sequences are available for 11 additional SIVs, and serologic evidence of SIV infection has been obtained for seven primate species for which no sequence information has been obtained (see Table 2). Ten infectious molecular SIV clones have been derived from different nonhuman primate species (rhesus macaques [Rh macaques], SMs, and AGMs).
In conclusion, serologic surveillance is the most useful tool for detection of infection in individuals and in new species, whereas genetic analysis allows classification of viruses and viral subtypes (Tables 1 and 2). FIVs and SIVs occur naturally in many feline and primate species and are characterized genetically as species specific. While intra- and interspecies heterogeneity may be high, FIVs and SIVs almost uniformly cluster by species and by family.
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SEROPREVALENCE OF FIV AND SIV
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Feline Species with FIV
The seroprevalence of FIVs varies dramatically by species and geographic locale. For example, Serengeti African lions are nearly 100% seropositive (53, 375), as are pumas in Wyoming that are over 4 years of age (41). Pumas in Montana have maintained an approximate seroprevalence rate of 20% over time (40), similar to seroprevalence rates detected in Florida panthers and in cougars from Washington State (116, 252). In contrast, significant numbers of free-ranging Asiatic lions or those found in Etosha Pan (Namibia) were all seronegative (53, 356, 375). Asian lions held in captivity at the Lincoln Park Zoo in Chicago were noted to be 75% FIV seropositive, demonstrating that lions of Asian origin are not intrinsically resistant to infection (218). Interestingly, a similar geographic dispersal of seropositivity was noted for Asian versus African leopards (Panthera pardus), i.e., free-ranging African populations demonstrate seropositivity of >25%, whereas Asian-born animals are seronegative (286, 376). Greater than 50% of Pallas cats tested harbored anti-FIV antibodies (376); this is the only species of Asian origin as yet to be defined by a unique FIV strain. Six of 12 adult ocelots on Barro Colorado Island, Panama, were seropositive, which is a higher prevalence than those reported in other serosurveys (53, 281, 376; Franklin et al., unpublished data). While a recent report did not detect anti-FIV antibodies in a large cohort of bobcats from Northern California (317), close to 40% prevalence has been noted in a Southern California population. This divergence in prevalence may result from isolation of certain populations when wildlife corridors are disrupted, leading to geographically limited habitats and increased conspecific interactions (similar to island populations) (376). Interestingly, 22 of 51 spotted hyenas (Crocuta crocuta) from the Serengeti harbored anti-FIV antibodies (158, 376), confirming the findings of an earlier serosurvey of a separate population (158). FIV-like pol sequences were amplified from hyena PBMC, confirming infection with an FIV-related agent (158, 376). Serum antibodies have been detected in 8 of 17 striped hyenas (Hyeana hyeana); however, infection of these animals has not been confirmed by viral isolation or PCR amplification (376).
Captive nondomestic felid seroprevalence rates range from 3 to 75%, depending on the species (110, 201). The seroprevalence of domestic cat FIV varies between 1 and 15%, with significantly higher incidences occurring in certain demographics, such as feral animals, those presenting as clinically ill, or intact males allowed to roam outdoors (59, 101, 216, 226, 234, 241, 305, 360, 376, 403). Two reports describing the prevalence of infection in feral domestic cats in England (59) and Vietnam (184) demonstrated that FIVfca can be diagnosed in >25% of certain populations.
Serosurveys have not detected FIV antibodies in cheetahs (261), wildcats (87, 220), five species of South American felids (119), leopard cats (184, 255), civets (184), or sandcats (288), whereas evaluations of wildcats from France (122) and Saudi Arabia (288) demonstrated low levels (<10%) of FIV seropositivity.
In summary, a wide range of feline species demonstrate antibodies which recognize FIV antigens, and nine of these species (lion, cheetah, leopard, Pallas cat, jaguarundi, ocelot, domestic cat, puma, and bobcat) have been shown to harbor species-specific FIVs by evaluation of partial viral genomic sequences. African lion, puma, African leopard, and Pallas cat populations demonstrate very high rates of seropositivity. Other species, including the domestic cat, cheetah, and South American neotropical free-ranging populations, tend to demonstrate seroprevalence rates of 10% or less. Asian species other than the Pallas cat are apparently not infected with an endemic FIV, although when exposed to other species harboring FIVs, particularly during captivity, these animals may become infected, as evidenced by seroconversion (Table 1).
Primate Species with SIV
SIV infections are described below for the major phylogenetic primate radiations, namely, anthromorphic primates (great apes), cercopithecines (guenons), Papionini, and Colobinae (Table 2). A description of the relatedness of these families is discussed later.
Studies of SIV seroprevalence in great apes have revealed SIV in only two subspecies of chimpanzees, i.e., Pan troglodytes troglodytes and P. t. schweinfurthii (75, 128, 268, 302, 303, 323-325, 405). The current view is that HIV-1 originates from SIVcpz.Ptt, which naturally infects the common chimpanzee (P. t. troglodytes), whose range is in West-Central Africa. Studies of hundreds of captive wild-born common chimps from Gabon, Cameroon, and Democratic Republic of Congo resulted in the isolation of five SIVcpz strains (named SIVcpzGAB-1, SIVcpzGAB-2, SIVcpzCAM-3, SIVcpzCAM-5, and SIVcpzCAM) (39, 75, 268, 303). Another case of SIVcpz infection has been identified in a captive chimpanzee in the United States (SIVcpzUS) (128). Therefore, the prevalence of SIVcpz was considered to be very low, although given that primarily juveniles were tested in these surveys, these rates may be underestimates. However, an extensive seroepidemiological study recently conducted in Cameroon, using a noninvasive sampling approach (205), reported a higher seroprevalence (10%). This finding is consistent with the emergence of three HIV-1 groups (M, N, and O) in this region (91, 150, 345, 381). Indeed, by sequencing of these new SIVcpz strains, the circulation of group M- and N-like SIVcpz strains in Southern Cameroon was demonstrated (205).
Until recently, only one isolate had been characterized from eastern chimpanzees (P. t. schweinfurthii), namely, SIVcpzANT (302, 382). Three more cases of SIVcpz infection were recently identified in chimps from a single familial group from National Kibale Park (Uganda) and Gombe National Park (Tanzania) (323-325), indicating that geographical foci of SIVcpz infections can be defined within the area of endemicity (325). Recently, an SIVcpz sequence from an eastern chimp originating from the Kisangani region of Democratic Republic of Congo was shown to cluster together with the other SIVcpz.Pts strains (405).
Despite extensive testing, naturally occurring lentiviruses have not been detected in West African chimpanzees (P. t. verus) or the P. t. vellorosus subspecies, although one P. t. vellorosus chimpanzee contracted SIV from a P. t. troglodytes chimpanzee in captivity (75, 314, 362). Seroepidemiological studies failed to produce evidence of SIV infection in the two other African ape species, gorillas (Gorilla gorilla) (233, 346) and bonobos (Pan paniscus) (387). Given that both of these species are frugivorous, they do not experience interspecies aggression and predation, suggesting that this behavior might be protective against lentiviral infection.
In conclusion, epidemiological data revealed that the prevalence rates of SIVcpz infection in wild chimpanzees are significantly lower than those reported for other species of nonhuman primates and that other great ape species are not infected with lentiviruses.
Guenons with SIV
Due to their number, genetic diversity, and large distribution in sub-Saharan Africa, guenons (tribe Cercopitecini) are the largest reservoir species for SIV. Studies of hundreds of wild-born AGMs (genus Chlorocebus) belonging to different subspecies revealed prevalence rates of SIVagm infection of 40 to 50% (163, 233, 280). These prevalence levels are similar for all four AGM subspecies, i.e., vervet (Chlorocebus pygerythrus), grivet (Chlorocebus aethiops), tantalus (Chlorocebus tantalus), and sabaeus (Chlorocebus sabaeus), and are independent of geographic origin (258). Interestingly, seroepidemiological studies showed that AGMs from Caribbean Islands, which were extensively imported from Africa in the 17th and 18th centuries (92), are not infected with SIV (85, 163). This lack of exposure has been attributed to the capture and movement of these animals as unexposed juveniles; an alternative, less probable explanation is that SIVagm was not yet present in the AGM population 3 centuries ago.
Eight of 14 (57%) l'Hoest monkeys (Cercopithecus lhoesti) originating from the Haut-Congo and Kiwu regions of the DRC were infected with SIVlhoest (27). Prevalence rates of SIV infection in Syke's monkeys (Cercopithecus albogularis) have been reported to be between 28 and 59% for wild-caught or colony-born Syke's monkeys (109, 169, 368). Nine of 14 (64%) blue monkeys (Cercopithecus mitis) tested positive for SIV, and SIVblu has been characterized genetically (154). The prevalence of SIVdeb, which naturally infects de Brazza's monkeys (Cercopithecus neglectus), is relatively high (39%) (2). No prevalence study exists thus far for the SIVs infecting different species of mona monkeys (Cercopithecus mona); however, viruses have been isolated from naturally infected monas (C. mona mona) from Nigeria and Cameroon (21, 76) and from a Dent's monkey (C. mona denti) from Democratic Republic of Congo (88). Of 302 tested mustached monkeys (Cercopithecus cephus), 56 (19%) had cross-reactions with HIV antigens (76). In Cameroon, the prevalence of SIVgsn, the virus that naturally infects greater spot-nosed monkeys (Cercopithecus nictitans), was established at 16% (27/165) (80). However, when a significant number of samples were tested using specific SIVgsn and SIVmus peptides, prevalence rates of 5% and 4%, respectively, were reported (2).
Papionini Tribe Members with SIV
Several studies produced compelling evidence that SMs are infected at high prevalence rates in the wild (25 to 55%) and also suggested that the major route of transmission in this species is sexual (14, 67, 326). Initially, a study of SIVsmm prevalence in feral SMs in Sierra Leone reported a 25% (4/16) prevalence of SIVsmm infection. Three of the four seropositive animals were adults, once again demonstrating an age-related increase in SIV seroprevalence (67). Pet SMs in Sierra Leone and Liberia have a 4 to 8% seroprevalence, probably as a consequence of being separated from feral populations while juvenile (14, 67, 243).
Testing of nine RCMs (Cercocebus torquatus) in Gabon revealed a SIVrcm infection in one (134). A more recent report established a higher SIVrcm prevalence level of 22% (4/18) (346). For a related species, the agile mangabey (Cercocebus agilis), two independent studies produced conflicting results. We characterized two SIVagi strains as being closely related to SIVrcm and concluded that SIVagi may have resulted from cross-species transmission (267). Other authors failed to identify any SIVagi strain following testing of 92 agile mangabeys (2).
Other mangabey species have not been reported to carry species-specific SIVs. A limited number of samples from white-crowned mangabeys (Cercocebus lunulatus) were repeatedly negative for SIV by PCR, despite serological cross-reactivity with both HIV-1 and HIV-2 antigens (C. Apetrei, unpublished data). Sera from three dozen gray-cheeked mangabeys (Lophocebus albigena) did not reveal any seropositivity. No data are available concerning SIV prevalence in Eastern mangabeys, Tana river mangabeys (Cercocebus galeritus), Sanje mangabeys (Cercocebus sanjei), or the newly described highland mangabey (Lophocebus kipunji) (196).
The prevalence of SIVmnd-1 infection in wild MNDs (Mandrillus sphinx) originating from the Lope Reserve in Gabon was 76% (16/21) (353). Age-related differences in prevalence levels have been reported for SIVmnd-1-infected MNDs (353). Moreover, earlier studies reported lower prevalence rates in juvenile MNDs of 9 to 17% (135, 233, 377). A recent study found a high SIVmnd-2 prevalence in MNDs (52%) from Cameroon (2).
To date, there is no proof that baboons (genus Papio) are naturally infected with SIVs. Several studies reported relatively frequent serological reactivities in both ELISA and Western blotting with baboon sera (34, 208, 346). However, no species-specific virus could be recovered from different baboon species. Two baboon species (Papio anubis and Papio hamadryas) have been shown to carry SIVagm from sympatric green monkeys (191).
Colobinae Members with SIV
Seven of 25 (28%) wild-born black and white colobus (Colobus guereza) monkeys from Cameroon were infected with SIVcol (79). Three species of West African colobines have been evaluated for the presence of SIV seroreactivity; 46% (6/13) of animals tested seropositive. Two isolates were characterized from this population, namely, SIVolc from the olive colobus (Procolobus verus) and SIVwrc from the Western red colobus (Piliocolobus badius) (77). To date, there is no study reporting the presence of SIV in Asian species of colobus.
Seroepidemiological surveys of Cercopithecus hamlyni, Allenopithecus nigroviridis, Lophocebus albigena, Cercopithecus pogonias, and Cercopithecus lowei have detected seroantibodies reactive against SIV, but no genetic evaluations have been performed (155, 233, 301).
Comparison of FIV and SIV Distributions
A comparative analysis of feline and simian lentiviral distributions provides interesting parallels. It appears that, like the recent emergence of HIV in humans, domestic cat and chimpanzee lentiviral infections are relatively new diseases, with more limited distribution and lower seroprevalence than infections noted in lions, pumas, AGMs, and SMs. Interestingly, SIV infection has been confined to African species, whereas FIV infection has a worldwide distribution, although the Mongolian Pallas cat is the only Asian species with a unique and endemic strain of FIV (Tables 1 and 2). The reasons underlying this observation are unknown but could include factors such as different migration patterns and home range territories for feline versus primate species, different levels of interspecies aggression, an earlier emergence of FIV than of SIV, or different population dynamics and speciation patterns in the two families. Because the dynamics of lentiviral evolution occurs on a shorter timeline than that of species evolution, these infections may be useful for tracking species dispersion, radiations, and population declines or expansions (40). In populations with high seroprevalence rates, these viruses may drive species evolution, as suggested to occur in regions with high HIV seroprevalence (P. J. Goulder, Abstr. Keystone Symp., Keystone, Colo., abstr. 11, 2006).
Phylogenetic Clusters of FIVs
FIV isolates are highly divergent within and among strains but are monophyletic. Partial FIV genome sequences have been identified from 12 different species, which correlate with 10 distinct genotypes. While strains are highly divergent (up to 25% heterogeneity in pol), monophyly within species and clustering within felid families have been demonstrated conclusively (58, 281, 376). Large portions of puma FIVpco genomes have been analyzed comparatively and found to form largely phylogeographic patterns of evolution. However, comparative phylogenetic studies of most other nondomestic cat FIVs have been limited to relatively short sequence comparisons for pol, often with small numbers of animals. This has limited the ability to form deep nodes conclusively relating divisions between FIV subfamilies (40, 41, 53, 58, 376). Thus, while FIVs cluster distinctly from all other lentiviruses, with the closest associations being bovine and equine lentiviruses (281), the exact relationship and origin of primordial FIVs have not been determined. In the most comprehensive phylogenetic study performed to date, nucleotide and amino acid sequence phylogenetic trees were constructed using sequences amplified from seven nondomestic feline species, the spotted hyena, and domestic cats (376). These analyses found that species lineages tended to be most closely related and roughly followed a pattern of phylogeography, particularly when amino acid sequences were compared (Fig. 2).
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FIG. 2. FIVs appear to cluster phylogeographically rather than ancestrally. FIV sequences were analyzed phylogenetically from eight feline species (376) representing five of eight feline lineages (195). Comparison of FIV relationships with ancestral lineages does not demonstrate consistent relationships, as represented by lines drawn between FIVs and their corresponding familial groups. However, FIVs are roughly divided between New and Old World species, with relatively high bootstrap associations, suggesting that recent geography is more highly related to FIV strain relationships than are lineage radiations.
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Phylogenetic Clusters of SIVs
Partial or full-length nucleic acid sequences are available for 34 SIV types, whereas for 23 types there is at least one complete genome sequence. Phylogenetic analyses of the available strains have shown a high level of variation in SIVs and a starburst phylogenetic pattern suggesting evolution from a single ancestor (Fig. 3). The approximate equidistances among the major SIV lineages do not always match the relationships among their hosts. Asian species of Old World monkeys (colobines and macaques), as well as some African species (such as baboons), do not carry species-specific SIVs, which also suggests that the last common ancestor of the catarrhines (Old World monkeys and apes) was not infected by SIV 25 million years ago (29, 143). This suggests that the emergence of SIV followed infection after radiation by these species, possibly from a nonprimate source (334).
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FIG. 3. Comparison between SIV phylogeny (a) and primate phylogeny (b). (a) Neighbor-joining tree constructed from available SIV sequences; (b) primate phylogeny is shown by a schematic using relationships cited in the text. While general alignment of hosts and viruses can be observed, cross-species transmissions and viral recombination events make this correlation less than absolute. Asterisks indicate significant bootstrap values.
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Phylogenetic analysis of the available SIV strains is complicated due to sequence diversity and recombination between divergent lineages resulting in different patterns of clustering when different genomic regions are analyzed. Originally, the different clusters were reported as lineages. Classically, the following six such lineages have been described: SIVcpz/HIV-1, SIVsmm/HIV-2, SIVagm, SIVlhoest, SIVsyk, and SIVcol (29, 79, 338). Recent studies have shown that the definition of "pure" versus "recombinant" lineages is primarily a matter of chronology and have suggested that each of the "classical" lineages might in fact be recombinant (322). With the recent discovery of new SIVs, some of the classical lineages were indeed shown to be formed by recombinant strains, with the most notable being the SIVcpz/HIV-1 lineage. The remaining "nonrecombinant" strains cluster into six lineages.
These six phylogenetic lineages are approximately equidistant, with genetic distances of up to 40% in Pol proteins. All six lineages have two or more strains. The l'Hoest lineage is unique in being formed by SIVs circulating in distantly related species. The relationship between these SIV lineages and newly characterized SIVs is complex, such that the characterization of recombinants is limited to the identification of the most obvious mosaic genomes. Table 3 and Fig. 3 demonstrate SIV clusters based on genomic identity. These phylogenetic clusters are partially superimposable on primate phylogenetic trees.
SIV Diversity Relative to Viral Genomic Structure
Using gene and ORF structures as a second method for determining relatedness, three groupings of SIVs can be identified (Fig. 1). All primate lentiviruses harbor five regulatory genes (vif, rev, tat, vpr, and nef) that generally fall in the same regions of the SIV/HIV genome. tat and rev each consists of two exons. The presence of two other regulatory genes (vpx and vpu) is variable and thus defines three patterns of genomic organization, as follows. (i) SIVsyk, SIVasc, SIVdeb, SIVblu, SIVtal, SIVagm, SIVmnd-1, SIVlhoest, SIVsun, and SIVcol contain only five accessory genes (tat, rev, nef, vif, and vpr) (27, 28, 37, 79, 86, 166, 169, 172, 223). (ii) HIV-1, SIVcpz, SIVgsn, SIVmus, SIVmon, and SIVden genomes also include a supplementary gene, vpu (76, 88, 182, 395). (iii) HIV-2, SIVsmm, SIVmac, SIVrcm, SIVmnd-2, and SIVdrl form the third genomic group, which is characterized by the presence of the vpx gene (31, 61, 151, 173, 181, 353). Thus far, vpx appears to be specific for SIVs infecting the Papionini group of monkeys and was acquired following a nonhomologous recombination which resulted in a duplication of the vpr gene (336). SIVblu, SIVolc (77), SIVwrc (77), SIVasc (392), SIVbkm (364), SIVery (P. A. Marx, personal communication), and SIVagi (Apetrei, unpublished results) have not been sequenced completely, so it is not possible to characterize these viruses by gene organization at this time.
In conclusion, SIVs that infect apes contain vpu, whereas Papionini-infecting SIVs contain vpx (11, 15). Three of eight guenon species have been shown to harbor vpu-containing viruses (C. mona, C. mitis, and C. cephus groups). Chlorocebus, C. lhoesti supergroup, and Miopithecus SIVs have an eight-gene organization, whereas Allenopithecus and Erythrocebus have no specific SIVs. This points to the Cercopithecini as the origin of SIVs or at least as the major reservoir of the viruses. Since vpu first appeared in SIVs from cercopithecines, these also appear to be a significant reservoir for viruses in the SIVcpz/HIV-1 lineage (20).
Feline and Primate Speciation and Relationship to Virus Phylogeny
FIV and feline species radiation.
A recent study elegantly demonstrated feline species origins based on an assortment of host genetic markers (195). This analysis distributed the 37 living species into eight major lineages that have radiated over the past 11 million years. A comparison of the feline tree with available FIV phylogeny demonstrates a closer association of recent home territory locations than of species relatedness with respect to FIV similarities (Fig. 2). While significant numbers of partial sequences have been evaluated only from lions, pumas, and domestic cats, limiting the conclusions that can be drawn, it appears that proximate recent geography may be more closely linked to FIV phylogeny than feline ancestry (195, 376). This analysis is complicated by the fact that members of only four of the eight lineages still inhabit the regions of their original establishment; the other lineages (three of which [domestic cat, puma, and panther] contain multiple FIV-positive species) have undergone significant migrations since species radiations occurred (195). Further studies using FIV-versus-host genomic analysis will be useful in determining when these viruses may have appeared relative to species radiations and the relationship between ancestral migrations and FIV evolution.
SIV and primate species radiation.
The Old World monkeys (family Cercopithecidae) are divided into two subfamilies (Cercopithecinae and Colobinae), which also separated 11 million years ago (Fig. 3) (149). Colobus monkeys are a large subfamily common in both Africa and Asia. SIVs have been described only from African colobines. The Cercopithecinae subfamily is further divided into two tribes, the Papionini and Cercopithecini. The Papionini tribe includes the two mangabey genera (Chlorocebus and Lophocebus), baboons (Papio), mandrills and drills (Mandrillus), and gelada (Theropithecus) as well as the Asian genus, Macaca (156). Only African Papionini members have been shown to be natural hosts of SIVs. Finally, there are over 25 guenon species. These include three arboreal genera, Allenopithecus, Miopithecus, and Cercopithecus, and three terrestrial genera, Erythrocebus, Chlorocebus, and the Cercopithecus lhoesti supergroup. Cercopithecini are terrestrial only when circumstances do not favor arboreal survival. Recent studies have defined a clade of terrestrial monkeys exclusive of all other guenons (369-371), indicating that the evolutionary transition between arboreality and terrestriality has occurred only once among the extant lineages (369-371).
This primate classification can be partially correlated with SIV phylogenetic classification (Fig. 1 and 3). Arboreal guenons are infected with viruses sharing biological properties and structural features and forming a single cluster. Conversely, each of the terrestrial genera is infected with specific viral lineages, with the exception of Erythrocebus, which carries a cross-species-transmitted SIVagm (38). Papionini monkeys are infected with related viruses, although a larger proportion of recombinant viruses can be observed in these monkeys (181, 353).
Humans are infected by two different lentiviral types, HIV-1 and HIV-2, belonging to two lineages harboring two different genomic types with different simian origins (see below). In phylogenetic trees, HIV-1 and HIV-2 are dispersed among related SIVs and show no species-specific pattern. Thus, from a phylogenetic point of view, the differentiation between HIVs and SIVs is irrelevant, which is the basis for the argument supporting the simian origin of HIV (333, 335, 337).
SIV phylogenetic lineages continue to become more difficult to superimpose on primate phylogeny as new strains are defined. It may ultimately be more effective to consider the three types of primate lentiviruses based on their genomic organization (i.e., accessory gene structure) (Fig. 1) versus their phylogenetic relationships with other viruses (Fig. 3).
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RECOMBINATION BETWEEN VIRUS SPECIES
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FIV and SIV Recombinants
Recombination events have been documented to occur during both FIV and SIV infections. This has been recorded during cross-species transmission as well as between different viral subtypes within the same species. Several reports have demonstrated that recombination between FIVfca env variable regions is relatively frequent during natural infection and may give rise to new clade designations. Individuals infected with multiple clade types of FIV (i.e., domestic cat [59, 212] and puma [58]) have been described, implying that infected individuals are not immune to reinfection with different strains of species-specific virus. In one large cohort of African lions, over 40% of FIVple-seropositive individuals were coinfected with two or more distinct and highly divergent FIV clades. In the latter study, evidence of recombination between coinfecting viruses was detected (375).
The most critical recombination of SIVs appears to be that involving SIVgsn and SIVrcm and resulting in the origin of the chimpanzee SIVcpz (20, 339). Subsequent cross-species transmission from chimpanzees to humans created the HIV/AIDS pandemic (75, 128, 182, 188, 302, 303, 323, 325, 326, 381, 405). Other SIVs originating from recombination events include SIVagm.Sab (containing SIVrcm-like fragments) (20, 190) and SIVmnd-2/SIVdrl (mosaic between SIVrcm and SIVmnd-1) (73, 181, 353).
SIVcpz Arose following Recombination between SIVrcm and SIVgsn
Although chimpanzees have been shown to be a reservoir for SIV (327), available data fail to demonstrate that SIVcpz coevolved with its host (314, 327, 362). Therefore, it has been postulated that chimpanzees acquired SIVcpz after their divergence into different subspecies about 1.5 million years ago (339).
Genomic analysis offers strong support that SIVcpz is a recombinant virus. In the 5' region of the genome, SIVcpz's closest relative is SIVrcm (31), whereas in the 3' half of its genome, it aligns most closely with SIVgsn (80). SIVgsn was the first monkey virus identified to contain a vpu gene, an accessory gene also found in SIVcpz (80, 182). Initially, SIVrcm and SIVgsn were believed to be recombinant viruses resulting from SIVcpz and unidentified SIV lineages (31, 80); however, recent characterizations of SIVs from other primates (mustached monkeys and mona monkeys) provide evidence of other SIV types similar to SIVgsn (21, 76, 88). Therefore, it appears that the SIVgsn lineage predates SIVcpz, which arose via interstrain recombination events (discussed more completely below).
Thus, in both feline and simian lentiviral infections, virus substrain recombination appears to be a relatively common occurrence and, at least in the case of SIV, may represent an important intrinsic mechanism for the development of strains which may infect new species. The potential for recombination to occur with a relatively high frequency in lentiviral infections provides a mechanism other than rapidly accumulating point mutations for the viruses to adapt to evade host defense mechanisms.
FIV
FIV seroprevalence rates for domestic cats, lions, and pumas increase as animals reach sexual maturity, suggesting that horizontal transmission is by far the most prevalent mode of transmission (32, 41, 58, 234, 376). The correlation between seropositivity and sexual maturity suggests that mating behavior is associated with exposure, either during the mating act itself or during conspecific interactions occurring around the time of mating. Long-term direct contact appears to be required for efficient transfer of FIV among domestic cats (83). Experimentally, domestic cat FIV can be transmitted via the oronasal, rectal, vaginal, intravenous, intraperitoneal, and subcutaneous routes (32, 56). Domestic cat FIV intrauterine or milk transmission has been documented experimentally, with a frequency that varies with the viral strain (6, 7, 284, 320). Obviously, such conditions are much more difficult to observe or simulate in nondomestic cat lentiviral infections. However, closely related virus sequences have been isolated from mother-cub lion and puma pairs, suggesting that infection can occur via maternal contact (41, 58). The frequency of this observation compared to age-related seroconversion suggests that vertical or maternal lentiviral transmission is the exception rather than the rule.
SIV
Seroepidemiologic surveys of AGMs, SMs, and MNDs revealed higher prevalence levels for adult monkeys than for juveniles, indicating a horizontal route of transmission. A retrospective analysis conducted at Pasteur Institute of Dakar on sera collected between 1967 and 2000 demonstrated that the SIVagm prevalence in adult AGMs was 80%, which is fourfold higher than that in juveniles aged 1 to 3 years (99). This is consistent with an earlier study on vervet monkeys in Awash National Park in Ethiopia, East Africa, in which all animals identified as juveniles by dentition were SIV seronegative (308).
However, in a semifree colony of MNDs at the International Medical Research Center of Franceville, no sexual transmission was found after 16 years of follow-up (74, 113, 135, 353). Two of the founders (one female and one male) had been infected with two different viral types, i.e., SIVmnd-1 and SIVmnd-2, respectively (353). SIVmnd-1 had been transmitted to four offspring (males and females) of the SIVmnd-1-infected female founder. SIVmnd-2 had been transmitted from the infected male founder to four other males following aggressive contacts for dominance (266, 353). Interestingly, two of the dominant males became SIVmnd-2 infected, with no evidence of sexual transmission of this virus being observed. In wild MNDs from the Lope Reserve in Central Gabon, cases of SIVmnd-1 infection could be diagnosed in both sexes (353).
Several cases of horizontal transmission occurring by biting have been described for captive monkeys, including AGMs (99, 308), SMs (315), and chimpanzees belonging to two different subspecies (75). SIVsmm has been reported to be transmitted among macaques by biting (232).
SIV vertical transmission seems less frequent than horizontal transmission, and if it does occur, the point of transmission (in utero, perinatally, or via breast milk) has not been identified. In a recent prospective study, experimental mother-to-offspring transmission by breast-feeding was not observed in MNDs (I. Pandrea, unpublished results), while another study did not demonstrate vertical transmission in AGMs (289). Some recent phylogenetic studies also suggested vertical transmission as a potential mechanism of SIVsmm transmission (14, 326).
Epidemiologic patterns of seroconversion in wild felid and primate populations endemically infected with lentiviruses suggest that these agents are most efficiently transmitted during adult contacts. Considering that it is well established that HIV is spread by sexual contact via primarily mucosal exposure, it is likely that naturally occurring viruses are spread via this route as well. While mother-to-offspring transmissions have been reported for felids and primates, they are relatively rare compared to horizontal transmissions.
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CROSS-SPECIES LENTIVIRAL TRANSMISSION
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Cases of FIV and SIV infections crossing species barriers have been documented; however, these events appear to be rare, despite ample opportunities for cross-species transmission to occur.
Naturally Occurring Cross-Species Transmission of FIVs
Cross-species transmission of FIVs has been documented primarily for captive nondomestic cats, suggesting that artificially close contact contributed to the opportunity for cross-species transmission. For example, a captive puma in an Argentinian zoo was infected with a domestic cat FIVfca isolate (58), and a captive-born snow leopard and tiger were both infected with a FIVple (lion lentivirus) isolate (376). Interestingly, the latter report represents the only documented infection of either of these species with FIV, suggesting that while these species are not infected in the wild, they are clearly susceptible to FIV infection. One additional report demonstrated that a wild Asian leopard cat became infected with a domestic cat FIV isolate (270). Although these reports document the potential for cross-species transmission of FIV to occur, the overwhelming pattern of infection is for each species to have its own strain or strains of FIV, which map nearly exclusively to that species.
Naturally Occurring Cross-Species Transmission of SIVs
Clear evidence of the cross-species transmission potential of SIVagm has been observed in the wild, where this virus has been isolated from a yellow baboon (Papio cynocephalus) (191), a chacma baboon (Papio ursinus) (388), and a patas monkey (Erythrocebus patas) (38). In Kenya, SIVagm.Ver was transmitted to a white-crowned mangabey (Cercocebus lunulatus) in captivity housed at the same primate center (368). Systematic prevalence studies have not been carried out yet to determine if SIVagm is established as a virus endemic to these species or if the isolation of these strains is the result of unique, accidental transmissions. No long-term follow-up is available for these cases to conclude that SIVagm is pathogenic in African NHP species following cross-species transmission. It is noteworthy that none of these species were reported to date to carry a specific SIV, which may explain their higher susceptibilities to cross-species-transmitted infection and, as described above for FIV, document the susceptibilities of these species to lentiviral infection.
Origins of HIV-1 and HIV-2
Following the discovery in 1986 of HIV-2 (71), a virus which was shown to be closely related to SIVsmm (72), it was rapidly established that this human AIDS virus had a simian origin (66, 129). The discovery of SIVcpz in the area of HIV-1 epidemic emergence pointed to a simian source for HIV-1 as well (128, 303). In 1998, HIV-1 group N was discovered in a Cameroonian patient with AIDS (345). This virus clearly clusters with SIVcpz from Cameroon in parts of the genome, which reinforced the hypothesis that SIVcpz was the ancestor of HIV-1 (259, 321, 345). Altogether, these seminal studies have solved the origins of HIV-1 and HIV-2. However, the mechanism(s) of HIV-1 and HIV-2 emergence in the human population as pathogenic agents is still under debate. Based on results showing the simian origin of HIV, AIDS was postulated to be a zoonosis (reviewed in reference 155). This hypothesis was based on data showing cross-species transmission (128), such as (i) similarities in viral genome organization, (ii) phylogenetic relatedness, (iii) prevalence in the natural host, (iv) geographic coincidence, and (v) plausible routes of transmission. Both SIVsmm/HIV-2 and SIVcpz/HIV-1 fulfill these criteria (66, 128, 155); however, it seems more likely that the emergence of AIDS constitutes a rare occurrence of cross-species transmission versus a readily transmissible zoonosis (12).
In spite of the frequent contact between humans and SIV-infected monkeys in Central and West Africa (301), extensive molecular epidemiologic studies have documented only 10 cross-species transmission events to humans during the last century (11, 15, 155, 333-335). Four of these events resulted in the following epidemic strains: HIV-1 group M, the major group of viruses of the AIDS pandemic (13, 187, 248, 304); group O, which is responsible for approximately 5% of HIV cases in Cameroon (17); and epidemic groups A and B of HIV-2 (81, 129). HIV-1 group N and HIV-2 groups C through G are nearly identical to SIVcpz and SIVsmm, respectively, and are extremely rare in humans, with only seven known HIV-1 group N-infected patients (18, 44, 321) and only single individuals infected by HIV-2 groups C to G (66, 129, 407). Group C to H (66, 82, 129, 407) nonepidemic strains are weakly pathogenic, replicate poorly in infected humans, and are found only within the range of SMs or in persons who emigrated from Western Africa (66, 129). It thus appears that cross-species transmission is not the only requirement for the emergence of HIV and that additional events, such as viral adaptation through serial passages or a lack of host defenses against specific viral strains, may contribute to successful lentiviral adaptation to new host species (12, 106, 242).
Origin of SIVcpz
As described previously, there is strong evidence that recombination between ancestral SIVs found in greater spot-nosed, mustached, and mona monkeys was the source of SIVcpz (21, 76). Four scenarios describing SIVcpz occurrence and emergence are as follows (339): (i) chimpanzees acquired ancestral viruses through hunting, resulting in exposure to more than one SIV type (254, 397), which then recombined in the new host; (ii) the two SIVs that generated SIVcpz were transmitted independently to different chimpanzees and then spread separately in the new host population until coinfection occurred, resulting in SIVcpz; (iii) an anscestral SIV established itself as a chimpanzee virus and, following superinfection with a new SIV, evolved into the SIVcpz present today; and (iv) the recombinant virus was generated in another monkey host species which has yet to be identified and was subsequently transmitted to chimpanzees.
Comparison of naturally occurring cross-species transmissions of either SIV or FIV demonstrates that successful infection is a rare event. In FIV infections, direct and "unnatural" contact, such as that occurring in captivity, seems to be a prerequisite for cross-species transmission events. While evidence points to cross-species transmission events leading to emerging lentiviral diseases in primates, including humans, the reasons for the success of these infections and the factors necessary for disease to result in pathogenicity have not been delineated clearly. Further studies of natural SIV or FIV infections may provide answers to these questions.
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PATHOGENICITY OF NATURALLY OCCURRING FIV AND SIV
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Pathogenicity of Nondomestic Cat FIV
It is difficult to determine whether FIV or SIV infection of free-ranging species causes significant changes in hematological parameters or other subclinical disease. The stress associated with sample collection can preclude meaningful interpretation of hematological tests, and field samples are often suboptimal for all but the most resilient assays. Epidemiological studies evaluating survival success and reproduction or coinfection/seroconversion rates among lentiviruses and other intercurrent diseases have not revealed statistically significant disadvantages associated with FIV seroconversion (40, 176). Studies of lentiviral pathogenicity in nondomestic felids have been hampered by the fact that for the two most highly studied populations, African lions and North American pumas, age-matched seronegative cohorts are not readily available for comparisons. While it appears that the trend is for naturally occurring infections to be apathogenic for native hosts, several reports implicating both FIV and SIV diseases have been published, typically from captive settings where animals have outlived their "normal" life span. For example, an aged FIVple-positive captive lion developed lymphoma (312), and three aged FIVple-infected lions in the Columbus zoo developed neurological disease reminiscent of HIV-induced encephalitis (51). There is also a trend for FIV-infected lions and pumas to experience CD4+ T-cell depletion, similar to that noted in domestic cats infected with virulent FIV (55, 319). However, functionally measurable negative impacts of infection, such as fecundity and intercurrent disease rates, have not been detected in seropositive lions (176) or pumas (40) in the wild. The trend for seropositive status to increase with age also suggests that lentiviral infection does not hamper survival rates.
FIV Infection of Domestic Cats Causes AIDS
FIV was discovered in 1987 in a cattery in California that had been experiencing high morbidity and mortality of unknown origin (299). Since the initial report, serosurveys of contemporary and banked cat serum samples have revealed that the virus has been present in the domestic cat population since at least 1968 (32), with the current prevalence in the United States ranging from 1 to 15% and approaching 50% in at least one population (59, 279, 379, 408). Feral cats, animals with outdoor access, and animals presented for undiagnosed illness are more likely to be infected than are indoor neutered house cats (32, 234, 265).
Strain variation correlates with the pathogenicity of virus for natural hosts in domestic cat FIV infections (300). Natural and experimental FIV infections in domestic cats result in classical immunodeficiency disease at 3 months to 10 years postinfection. Clinical findings include CD4+ T-cell depletion, weight loss, neurological disease, and opportunistic infections (32, 56). The range of the disease spectrum has been related to different strains of virus; predictably, tissue culture passage tends to result in strains with attenuated infectivity. Several naturally occurring cloned and uncloned isolates used in pathogenesis and vaccine studies are highly to moderately pathogenic, resulting in disease in as little as 4 to 8 weeks postinoculation (97, 98). Strain virulence is generally related to the env-defined clade classification; however, it is likely that other genomic features besides this region are influential in modulating disease outcome. For example, an FIV vif-null mutant was replication defective in vivo relative to wild-type FIV (231).
Pathogenicity of African Primate SIV Infection
For 20 years, it was believed that SIV infections are nonpathogenic<
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