Animal models for AIDS

Immunology Today. Vol. 1I, No. 9 !990

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HIV ANDTHEIMMUNESYSTEM The discovery that a retrovirus (HIV) is involved in the development of AIDS spurred the search for animal models of the c:isease and encouraged the development of therapy aimed at eliminating the causative agent. The following contributions to the HIV and the immune system series review progress in these two areas. The first paper describes the wide range of animal models available to researchers, the importance of these models to the understanding cf the natural history of HIV infection, and their role in the development of effective chemotherapeutic agents and vaccines. In the second paper, recent developments in HIV treatment are described, emphasizing the mechanism of a~ie~l of the agents, their influence on immune function and their clinical usefulness.

Animal models will play a central role in AIDS research in the coming years. Important models for human immunodeficiency virus (Hl~-indu.'~ diseasein humans include HIV-infec:ed great apes, simian immunodeficiency virus-infected Asian monkeys and infe~ons of ungulatesand cats with HIV-relatedlen~iviruses. ~e nature of the diseasesinduced by these virusesare described here by Norman Letvin, emphasizing aspects with particular "~levance to human HIV infections.

Animalmodelsfor AIDS Norman L. Letvin

The definition of animal ~odels for H!V infection of humans will be crucial for furthering our understanding

with HIV-1 in the chimpanzee (Pan troglodytes) ~-4 and a limited number of gibbons (Hylobates spp.) have also been infected with the virus 5. Although virus can often be isolated from peripheral blood tymphocytes (PBLs) of inocuiated animals, and although these animals develop high titer virus-specific antibody responses after infection, neither the HIV-l-infected chimpanzee nor gibbon has

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be important in the developmem of efficacious drug therapies for AIDS and will be necessary for tesuna vaccines for protection against HIV infection. While HIV isolates have been shown to infect a variety of nonhuman species under experimental conditions, the virus-host interactions in those infections appear to be significantly different from those seen in HIV-infeded humans. Thus, HIV-infected labL'atory animals have proved inadequate as models for studies of the pathogenesis of AIDS. However, HIV is a lentivirus and is, therefore, closely related to a varie~, of other pathogenic viruses that infect ungulates, ca~ and nor, human pr;mates. Err ~rging data ~re now ,ndicating that the study of these other lentiviruses and the diseases that they induce will be of enormous value in elucidating the pathogenesis of AIDS and assessing strategies for the treatment of, and vaccine protection against, HIV infections.

H~-infected nonhumanspecies Pnmatemodels The ideal animal model for AIDS would be one in which HIV-1 infects and induces an AiDS-like disease in an inexpensive, readily available laboratory animal (Table 1). Great apes have been shown to be susceptible to experimental H!V-1 infection. Extensive work has been done

Harvard Medical School, New England Regional Primate Research Center, One PineHillDrive,Southborough,MA 01772, USA. 322

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species status of the animals, their lack of ready availability and their cost make plans for the extensive use of great apes in AIDS research unrealistic. A number of isolates of HIV-2, the AIDS-inducing virus endemic in human populations in West Africa, have also been studied in nonhuman primate species. Under experimental conditions, HIV-2 can infect a number of African and Asian monkeys 6.7. However, no disease has developed in these infected animals. Although these HIV-2infected nonhuman primates are not useful models for studying the pathogenesis of AIDS, they will be important in testing potential vaccines for protection against infection with AIDS viruses. dangered

Nonprimatemodels Interest has recently focused on nonprimate models for HIV infection. The rabbit has been shown to be susceptible to a low-level, persistent infection with HIV-1 (Refs 8,9). Although an AIDS-like disease has not been demonstrated in these animals after infection, recent studies indicate that HIV-l-infected rabbits cannot generate normal antigen-specific immunological responses 10. The eventual role that the HIV-l-rabbit model may play in AIDS research is still unclear. Mice with severe combined immunodeficiency (SCID), reconstituted with either human PBLs or human fetal thymus and liver or lymph nodes, have been shown to be capable of harboring HIV infections 11.~2.This observation ~

1990, Elsevier Soence Publishers Ltd, UK 0167--4919/90/$02.00

Immuno,'ogyToday. Voi. 1I. No. 9 1990

generated a tremendous amount of optimism when it was first reported, raising the possibility of using the HIVinfected, 'humanized' SCID mouse as an inexpensive, easily accessible small animal model for/',IDS. More recent work, however, has indicated that functional CD8 ÷ human lymphocytes do not persist in SCID mice reconstituted with human PBLs~3. Moreover, HIV-I in 'humanized' SCID mice appears to spread rapidly and ablate T cells rather than replicate in a chronic, low-grade fashion ~3. Thus, like the HlV-l-infecLed rabbit, the value .~f this murine model in AIDS research remains to be demonstrated. Lentiviruses of ungulates The human AIDS viruses are members of the retrovirus subfamily Lentiviridae and are, therefore, related in their morphology and nucleotide sequence to a variety of pathogenic lentiviruses of nonprimate species. The best studied of these viruses are those that infect and induce disease in ungulate species: maedi-visna virus (MVV) o~ sheep, caprine arthritis-encephalitis virus (CAEV), equine infectious anemia virus (EIAV), and a newly recognized lentivirus of cattle, bovine imrnunodeficlenc/virus (BIV)TM. Like the human AIDS viruses, these ungulate lentiviruses appear in electron microscope studies as enveloped particles with dense cylindrical cores. Like HIV, the ungulate viruses contain gag, pol and env genes, as well as small open reading frames between pol and env and at the 3' terminus that code for regulatory proteins. The chronic diseases induced in the ungulates by those lentiviru; are analogous in many ways to HIV-induced disease i humans. The common features of the diseases and the virus-host interactions include prolonged periods of clinical latency, the development of only a weak neutralizing antibody response with resulting persistent viremia, a tendency for the virus to undergo extensive genetic mutation and antigenic drift, significant neuropatho!ogy, and lytic viral infection of selected bone-marrow-derived cells (Table 2). Maedi-visnaand caprinearthritisencephahtisviruses M W causes chronic, progressive, interstitial pneumonia and severe demyelinating encephalomyelitis in sheep after an incubation period of months to years ls.~6 Although the disease is severely debilitating, there is no clin!cal evidence that the condition is associated with immunosuppression. However, certain aspects of MWinduced disease have potentially important parallels to AIDS. The progressive leukoencephalopathy seen with M W has features in common with the encephalopathies associated with HIV infections, and the pathogenesis of these encephalopathies may be similar. M W also appears to undergo considerable antigenic drift in persistently infected sheep. Viral mutants emerging in vivo elude neutralization by serum taken from infected animals earlier in the course of the disease The pathogenic lentivirus of goats, CAEV, is antigenically related to, but distinct from, MVV. The virus causes a progressive leukoencephalomyelitis in goats aged 2-4 months that results in paralysis and deatM 6. Some of these early infections do not result in any apparent neurological abnormalities in juveniles, but may result in synovitis, periarthritis and maedi-like chronic progressive pneumonia in adult animals. It has been reported that persistent infections occ,~r with CAEV because no neu-

.ii/VserieTabl~ 1. HIV infeGionsin nonhumanspecies Species

Isolate

Clinical manifestations

Limitationsas AIDSmodel

Chimpanzee, Gibbon

HIV-I

None

Scarcityof animals. expense,absenceof disease

Old World monkeys

HIV-2

None

Sporadicinfectabili~/, absenceof disease

Rabbit

HIV-1

Abnormalimmune responsiveness

Low levelinfection, absenceof disease

'Humanized' SCIDmouse

HIV-1

Rapid T-lymphocyte Abnormalhuman ablation lymphocyterepopLiaton in mou-ehost

tralizing antibody response to the virus is produced by the g oat; 7. Equineinfectiousanemia virus The lentivirus of horses, EIAV, causes a chronic, persistent infection that is characterized in its early stages by repeated, acute episodes of fever, weight loss and anemia, with intervening periods of clinical quiescence 18. Animals that survive these early, acute episodes of the disease may eventually manifest no clinical signs of illness, yet they typically remain viremic for life. The natural mode of transmission of EIAV is by bloodsucking insects, such as stable flies and mosquitoes, but transmission may also occur through contact with contaminated hypodermic needles. Like other lentiviruses, EIAV undergoes considerable genetic mutation and antigenic drift in persistently infected animals; this phenomenon is probably important for the maintenance of persistent viremia. Antibodies to EIAV have been shown to fix complement and neutralize virus. However, emerging mutant viruses that can elude neutralization by preexisting antibody are found in viv019.20. Bovineimmunodeficiencyvirus Considerably less is known about the bovine immunodeficiency virus thaq about the other ungulate lentiviruses. In limited studies, BiV has been shown to induce lymphocvtosis and lymphadenopathy in experimentally inoculated calves21.22. Interestingly, recent studies have shown that BIV readily infects rabbits and induces a disease in rabbits with some parallels to AIDS (M.A Gonda, pers. commun.). Table 2. Commonfeaturesof lentivirus-inducedpathology Prolongedclinicallatency Weak neutralizingantibodyresponses Persistentviremia Continuousvirusmutationand antigenicdrift Neuropathology Infectionof bone-marrow-derivedcells 323

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Fi9.1. ~a)Pho'comzo'ographof a porbon of a lymphnodeof a 51V~.~c-infectedrhesusmonkeyin which follicularhyperplasiaand contractedinterfollicularregionsof the ~.ph node are apparent(h~atoxylin and eosin, x 71). (b) Photomicrographof a portion of cerebralcortex of a SIV~ac-infectedrhesusmonkey demonstratinga mul~nudeatedgrant cell and ~nvascular infiltrate of macrophages(hematoxylinand eosin, x 284). (c) Electronmicrographof a portion of a macrophagefrom a oernr~tar ~nfiltratein ~e brazn,showLngSIV,~acparticleswithin membrane-boundvacuoles.

Felira immunodefidenojvirus The best available small animal model described to date for AIDS may well be the Feline immunodeficiency virus (FIV)-infectec] cat. FIV. a T lymphotrophic lentivirus, was first isolated from cats with an immunodeficiency syndrome 23-24. While FIV-inoculated pathogen-free cats have developed only a transient fever and persistent lymphadenopathy, cats co-infected with the distinct ret:ovirus, feline leukemia virus, develop more severe disease and opportunistic infections2~. FIV-infected cats have also been shown to develop encephalomyelitis and a vacuolar myelopathy26.

Simian immunodefidencyviruses Soon after the initial isolation of HIV-1, a number of HIV-related viruses of nonhuman primates were identified. These simian immunodeficiency viruses (SIV) include: SlVmac. first isolated from a rhesus monkey with a !ymphom~27; SIVa~, first isolated from a healthy African Green monkey2e; ~lVs~, first isolated from a healthy sooty mangabey29; SIV~nd, first isolated from ~ healthy mandrill 3°, and SiVcpz, isolated from healthy chimpanzees in Gabon 31. It can be presumed that further SIV isolates from other nonhuman primate species will be described. These isolates all share striking nucleotide homology with HIV-1 and HIV-2 as well as a similar tropism for CD4-bearing lymphocytes and monocyte--macrophages. The nucleotide sequences of SIVmacand SIV~n ~re so similar that it is assumed that the macaque isolate arose in the recent past from the mangabey virus 32. These two SIV isolates also show striking sequence similarities to the West African human AIDS virus isolates of HIV-2. These similarities in nucleotide sequence provide the most compelling evidence to date that the simian and human immunodeficiency viruses have arisen in recent evolutionan/history from a common ancestor 33. The mangabey, African green monkey, mandrill and

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chimpanzee isolates all sha;e certain epioemiologic features. They h3ve all been isolated from African nonhuman primate species. Furthermore, none has yet been shown to induce disease in their presumed natural hosts. However, SlVma c and the closely related SIVsm, after experimental infection of a variety of Asian macaque species, induce a disease with remarkable similarities to human AIDS (Fig. 1)34,3s. SlVoinduced disease in macaques One to three weeks after inoculation with these SIV isolates, macaques frequently develop a transient rash on the face, trunk and groin that is similar in chnical and histological appearance to that described in humans early after infection with HIV-1 (Ref. 36). Six weeks to one year after experimental inoculation with SIV, some monkeys develop transient axillary and inguinal lymphadenopathy 37. When this has been noted clinically, CD4 ÷ PBL counts have been substantially decreased, usually to less than 1 000 mm -3. Biopsy specimens of the lymph nodes examined histologically appear remarkably similar to those of HIV-infected humans with AIDS-related complex. The B-cell-containing follicles are active and expanded. The T-cell-rich paracortex of these nodes is reduced, and the usual 2:1 ratio of CD4:CD8 cells is altered, with the CD8 subset of lymphocytes present in greater than normal numhers, equ~_!ing or exceeding the number of CD4 + lymphocytes. Macaque monkeys infected with SIV develop immune abnormalities similar to those of HIV-l-infected humans34. The absolute number of CD4 ÷ cells in their blood falls to one-half that of normal monkeys as early as two weeks after experimental infection, whereas the number of circulating CD8 ÷ cells remains unchanged. Thus, the ratio of CD4 to CD8 cells decreases in e~.perimentally infe~ed monkeys. The blastogenic response of their PBLsto the plant lectin concanavalin A and in mixed

Immunology loday, Vol. I 1, No. 9 1990

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[ ~ymphocyte reactions does not decrease significantly. However, the T-cell-dependent proliferation of their B cells after stimulation with pokeweed mitoger, is dramatically and persistently diminished after infection. After experimental infection with SIV, many of the macaque monkeys have died with weight loss, opportunistic infections and primary SlV encepkalitis. Some have developed profound wasting, losing up to 60% of their body weight. Disseminated adenovirus and cytomegalovirus infections, disseminated Mycobacterium avium intracellulare infections, and Pneumocystis carinii pneumonias and intestinal crypto~,poridiosis have been seen. Some SIV-infected monkeys have developed a lymphoma-like lymphoproliferative syndrome. Some have also died with a lentiviral encephalitis in which peqvascu lar infiltrate~ of SlY-containing macrophages have beer, present throughout their brains 38. Although most of the, eported disease in these animals occurs within months te years after infection, a fatal disease has been induced in macaques within a few days of infection with the idiosyncratic pbj14 isolate ot SlVsm. This isolate ~nduces a rapidly fatal syndrome characte,ized by bloody diarrhoea and abdominal lymphadenopathy 39. The SlV-macaque model has already proved valuable in assessing novel approaches to the treatment of AIDS. The demonstration that rhesus monkeys infected with SlV~¢ show significant virological and clinical improvement as a result of treatment with recombinant soluble CD4 pro~,ided an irr,petus to pursue clinical trials of this molecule in HIV-infected humans 4°. Preliminary studies in a number of laboratories have indicated that immunization of macaques with inactivated whole virus in adjuvant can provide at least a degree of protection against subsequent challenge with hve SIV4~,42. These studies have provided the first evidence that a protective immune response can be induced against a lentiviral infection. Considerable resources and effort are being ded.cated to developing this AIDS model. Recent developments in the SlVmacaque system, including the generation of pathogenic SlV clones43 in a number of laboratories and the definition of SIV-specific cell-mediated immunity in the monkey 44,4s, suggest that this model will prove of pivotal importance in AIDS research in the coming years. Conclusion As the regulation of HIV replication and the natura' ilistory of HIV infections in humans become better understood, animal models of HlV-induced disease will take on greater importance in the study of AIDS (Table 3). In fact, many of the central questions in AIDS research in the coming years can only be addressed in lentivirus-infected animals. The events leading to CD4 + lymphocyte depletion in AIDS can be elucidated through studies of the SlY-infected macaque monkey. The pathogenesis of central nervous system disease in AIDS can be clarified in the SIV-macaque and FlV-cat models. Screening large numbers of potential anti-viral therapeutic agents can only be done in small animal models of HIV-I infection. The definition of the protective immune response to HIV and the delineation of the wmmunogenic determinants of the virus crucial for that protection will be accomplished first in the SlY- and HlV-2-infected monkeys. Final testing of potential HIV-I vaccines will be done in chimpanzees b.~tore human trials are entertained. Work already accomplished in these animal systems has indicated the

Table 3. Nonhumanlent~virusesand the ,..,.,~a.,_~ ~-" '-~" t~:atthey ~nduce Virus

Spec,es

Dsease

Maedi-visnavirus (MVV)

Sheep

Pneumonia,enceDha[omyeiitis

Caprine arthritis-encephalitis Goats virus (CAEV)

Arthritis, encephalomyelitis, pneumonia

Equineinfectiousaqemiawrus Horses (EIAV)

Fever,weight!oss,anemia

Bovine immunodeficiencyvirus Cattle (BIV)

Lymphadenopathy, lymphocytosis

Felineimmuncdefoencyv,rus Cats (FIV)

Lympha~enopathy, encephalomyelitis- with coincidentalFeLVinfection, fatal opportunisticinfections

SimiaP immunodeficiency ~'ru£e~.(SV)

AIbS-IPediseaseinducedby someisolatesin Asianmonkeys

No,qhuman pr,~ates

power of these models for exploring the pathogenesis and treatment of AIDS. I wish to thank Debbe~Bro~.-',~a,Jfor preparing this manuscript and Norval W. King for providing photomicrographs. References

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