Murine acquired immunodeficiency syndrome (MAIDS):

an animal model to study the AIDS pathogenesis

PAUL JOLICOEUR1
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montrea4 Quebec H2 W 1R7, Canada;
and Department of Microbiology and Immunology, Universit#{233}
de Montr#{233}al,
Montreal, Quebec H3C 3J7, Canada

ABSTRACT Murine AIDS (MAIDS) is a disease that cies and no other species has been found to be susceptible to
shows many similarities with human AIDS. Several im- HIV. Fortunately, several models of AIDS induced by
munological parameters of the disease have been analyzed animal retroviruses that exhibit some or many of the features
and genetic studies have mapped (or genes) of re- a gene of the human disease are available (8-10). Probably the best
sistance in the H-2 complex and that the genetic shown model is the simian acquired immunodeficiency syndrome
background of the mouse can significantly modify some (SAIDS) (8, 11-13). It is induced by some strains of lenti-
features of the disease. The etiologic agent of MAIDS is viruses, which have been isolated from various primates and
a defective murine leukemia virus that seems able to in- strongly resemble HIV. The clinical presentation of SAIDS
duce disease in the absence of virus replication. This is very similar, although not identical, to the human AIDS.
defective virus induces proliferation of its target cells and The feline AIDS (FAIDS), described recently, is also induced
the cell expansion was found to be oligoclonal, thus sug- by a lentivirus and appears to present some, but not all, of
gesting that the immunodeficiency observed in these mice the features of human AIDS (14). Severe immunodeficiency
is a paraneoplastic syndrome. The excellent response of syndromes have also been found to be induced by retro-
MAIDS mice to antineoplastic agents is consistent with viruses of the nonlentivirus group, such as the simian type D
this notion. This animal model has already been useful in retrovirus (15) or the defective feline (16) or murine (17, 18)
stimulating the emergence of novel questions and the for- leukemia viruses. Although these viruses have a structural
mulation of new hypotheses about human AIDS, namely genomic organization different from that of the lentiviruses,
about the role of defective HIV, the role of HIV replica- they induce immunodeficiency diseases that have many, but
tion in the progression of the disease, and the importance not all, characteristics of human AIDS. Transgenic mice har-
to identify the target cells of HIV in vivo. Although boring some or all HIV genes expressed in selected tissues
MAIDS and AIDS are not identical and are induced by may represent a fruitful avenue of experimentation (19, 20).
retroviruses of different classes, the availability of such a Also, it has been found that immunodeficient mice recon-
model in an easily accessible small animal species, whose stituted with human hematopoietic cells become infectable
genetics is very sophisticated, may be instrumental in with HIV (21): this model may eventually represent a good
understanding the pathogenesis of AIDS if some of the approach to study some aspects of human AIDS.
cellular and molecular affected pathways are common in In this article we review one of the animal models, the
both diseases. -Jolicoeur, P. Murine acquired im- murine AIDS (MAIDS), induced by a defective murine
munodeficiency syndrome (MAIDS): an animal model to leukemia virus (MuLV). Recent findings on the pathogenesis
study the AIDS pathogenesis. FASEB J. 5: 2398-2405; of MAIDS have provided novel hypotheses to study im-
1991. munodeficiency syndromes. Reviews on MAIDS have been
published previously (22, 23).
Key Words: AIDS imrnunodejiciency retrovirus rnurine leu-
kemia virus MAIDS
MAIDS

THE HUMAN ACQUIRED IMMUNODEFICIENCY syndrome (AIDS)2 The disease, now designated MAIDS (22, 24), was first
is a complex disease induced apparently by the human im- recognized by Duplan’s group in C57BL/6 mice that had
munodeficiency virus (HIV). Although much information been inoculated with cell-free extracts from X-irradiated in-
has been accumulated on HIV and its cycle, the molecular duced thymomas (25, 26). They noticed that in a large per-
and cellular mechanisms by which it induces such a severe centage of inoculated mice, the thymus was not involved and
immunodeficiency remain obscure. Several hypotheses have mice showed lymphadenopathy and splenomegaly. After suc-
been proposed, but experimental evidence to support them cessive passages in mice of cell-free extracts from these en-
is relatively thin and none has yet been accepted unani- larged spleens and lymph nodes, they obtained a crude virus
mously (1-4). Part of the problem resides, as with all human preparation that induced the disease (MAIDS) reproducibly
diseases, in the practical difficulties and ethical constraints in
doing research on human beings. To overcome this problem
and gain a full understanding of the pathogenesis of this ‘To whom correspondence should be sent, at: Laboratory of
retrovirus-induced immunodeficiency syndrome, studies of Molecular Biology, Clinical Research Institute of Montreal,
animal models of the disease are essential. 110 Pine Ave. W., Montreal, Quebec, Canada H2W 1R7.
2Abbreviations: AIDS, acquired immunodeficiency syndrome;
HIV, human immunodeficiency virus; SAIDS, simian acquired im-
munodeficiency syndrome; FAIDS, feline AIDS; MuLV, murine
ANIMAL MODELS OF AIDS
leukemia virus; LPS, lipopolysaccharide; IL 2, interleukin 2; TNF,
Although HIV can infect and replicate in chimpanzees (5) tumor necrosis factor; SFFV, spleen focus-forming virus; AZT,
and rabbits (6, 7), it does not induce disease in these two spe- azidothymidine.

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 in nearly 100% of C57BL/6 mice. Initially thought to be a Altered lymphokine levels
type B reticulum cell sarcoma, the disease exhibits several
characteristics similar to those found in human AIDS (22, The production of lymphokines or cytokines has also been
reported to be altered in these mice. The interleukin 2 (IL 2)
24). These include immunodeficiency, hypergammaglobu-
linemia (increased serum 1gM [24, 25], IgG3 [24], IgG2a production of spleen cells to autologous antigens or to mito-
[25], but not IgA [24, 25] or IgGI [25]), susceptibility to in- gens was found to be decreased (29). Mice with MAIDS
were found to constitutively produce high levels of IFN-y
fection (27), and late onset B cell aggressive lymphomas (28).
(39), IL 1, and tumor necrosis factor (TNF) RNA (40) in
their spleen, and IFN--y protein in serum (39), but were
Altered immune functions
unable to respond to infection by New Castle disease virus
The immunodeficiency observed is severe. All the T cell by induction of IFN-cr/f3 in their spleen (39). However, the
functions that have been measured were found to be abnor- development of MAIDS is unlikely to be related to the high
mal: the T cell blastogenic response to mitogens (24, 25) and serum levels of IFN-y, as treatment of mice with neutraliz-
to alloantigens (24), the cytotoxic T cell generation (24, 29), ing antibodies against IFN--y did not affect the progression
and the helper T cell function for antibody production in vitro of MAIDS (40). Expression of IL 3, IL 4, IL 5, and IL 6
(24). The impaired T cell proliferative response appears to RNA did not seem to be influenced by infection with the
be caused by an intrinsic defect of CD4 T cells (and not of MAIDS virus (40). Peritoneal macrophages of diseased mice
CD8 T cells) (29, 30), and does not seem to be related to were found to constitutively produce IL 1/3 and to release en-
an aberrant function of antigen-presenting cells (30), as pre- hanced levels of IL 6 and IL I3 after stimulation with
viously suggested (31). The B cell functions were also found lipopolysaccharide or Newcastle disease virus, whereas
to be abnormal: these include their response to lipopolysac- IFN-’y and TNF were decreased and IFN-/3 was unchanged
charide (LPS) (24, 25) and to anti-it, and their ability to pro- by the same stimuli (41).
duce a specific antibody response to antigens (T-dependent
and T-independent) (24).
Although affected by the disease, the presence of CD4 T GENETICS OF MAIDS
(32, 33) and B (34) lymphoid cells, but not CD8 T cells,
seems to be required for development of MAIDS, as mice Not all strains of mice are equally susceptible to MAIDS. A
depleted of these specific cell populations fail to develop fea- survey of different mouse strains to test their susceptibility to
tures of MAIDS (33, 34) and MAIDS does not develop in MAIDS has shown that some (such as C57BL/6, C57BL/10,
nude mice (32). and l/St) were highly susceptible while others (such as A/J,
BALB/c, and FVB) were totally resistant to the disease (35).
Disturbance of hematopoietic cell populations Some strains were also found to be moderately susceptible to
After virus inoculation,an increased proportion of spleen MAIDS, the disease developing after a longer latent period
cells are in S or G2/M (24). This cell expansion
phase ob- or in a smaller proportion of animals. We have recently ex-
served in the lymphoid organs is thought to primarily reflect tended these results with additional mouse strains, reaching
B cell proliferation/differentiation (35, 36). The distribution essentially the same conclusions (42). In addition, we found
and proportion of several populations of hematopoietic cells that the degree of lymphadenopathy developing in some sus-
are affected, and the spleen and lymph node architecture is ceptible mouse strains varied enormously and did not appear
destroyed (35, 37). The observed changes are distinct as the to correlate with the extent of immunodeficiency. These
disease progresses. The absolute number of Thy 1.2 cells in- results indicate that the development of MAIDS is under the
creases early in the disease and returns to normal values later
control of one or more than one specific gene (or genes), and
(25). In addition, a major redistribution of the four CD4 T that some manifestations of the disease, such as lymphad-
cells subsets recognized by two monoclonal antibodies enopathy, can be modulated by the genetic background of
(SM3G11 and 5M6C10) was observed (29, 34). One of these the mouse.
CD4 T cell subsets was found to expand significantly in To determine the type of resistance to MAIDS and to map
MAIDS mice, which suggests activation by an unknown the gene (or genes) involved, a classical genetic study was
stimulus (29, 38). The absolute number of B cells, especially performed with mice susceptible (C57BL/6, H2b) or resis-
the Ig-secreting B cells, increases throughout the disease and tant (A/J, H2a) to MAIDS (43). Resistance to MAIDS was
hypergammaglobulinemia develops (24, 25, 36). In the more found to be a dominant trait, segregating with gene (or
advanced stage of the disease, the number of Ig-secreting genes) in the H-2 complex. It will be of interest to determine
cells and serum Ig levels begin to fall (36). As the proportion whether the gene (or genes) of resistance in other mouse
and absolute number of non-T, non-B cells increase drasti- strains are allelic to the one (or ones) described in A/J strain
cally throughout the disease (25), the proportion of T and B or whether they map outside the H-2 complex.
cells, especially those of small size, is reduced (24, 25, 36,
38). Studies of the spleen cells with more specific reagents
showed that in the early stage of the disease, an increased IDENTIFICATION OF THE ETIOLOGIC AGENT
number of dull kappa, dull ly-S (B-220), dull ThB, IgG, OF MAIDS: A DEFECTIVE VIRUS
and Mac-1 cells, and a much lower number of normal size
bright kappa cells are found (35, 36). The more advanced The crude Duplan virus extract inducing MAIDS (26) con-
stage of MAIDS is characterized by a greatly reduced num- tained many different MuLV strains that have been partly
ber of normal size kappa, ly-S (B220), and ThB cells, and characterized over the years (44-48). Unfortunately, none of
by a marked increase of IgG and Mac-1 cells (35, 36). A these MuLV isolates induced MAIDS when reinoculated
similar picture was observed in the lymph nodes: the Ia and into susceptible mice, indicating that the etiologic agent of
the Mac-1 cells increased during the course of the disease, the disease had not been identified. The presence of several
whereas Thy-P cells (mostly the CD8 cells) decreased. After variants, some not pathogenic or poorly pathogenic, is fre-
virus inoculation, the kappa cells first increased and then quently found in infiltrated tissues of retrovirus-induced dis-
progressively decreased (33). eases in animals. Such a phenomenon is likely to be found

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 in the human retrovirus-induced disease, and in fact has free stocks of the defective MAIDS virus (53). These stocks
already been documented (3). As in animals, some HIV var- were efficient in inducing MAIDS (53). They appeared to do
iants may not be pathogenic. so in the absence of virus replication in vivo, as helper MuLV
RNA sequences (8 kb) were not detected in infiltrated tis-
Molecular cloning of the pathogenic viral genome sues, and infectious helper MuLVs of various classes were
not detected either. The only helper MuLV detected in these
Using molecular hybridization techniques, we (17) and mice was a virus replicating on mink cells which had all the
others (18) recently identified a defective viral DNA in cells characteristics of a xenotropic MuLV. This class of viruses is
infected with the crude virus preparation, and showed that known to replicate on cells of various species but not on
it was associated with pathogenicity of the extract. Molecular mouse cells (54).
cloning of this viral DNA species and its transfection in
mouse fibroblasts in culture (17) allowed the rescue of this in-
fectious defective virus with a nonpathogenic helper MuLV. Relative virus titers of helper and defective viruses
This cloned defective virus complex was pathogenic (17), in- It appears that MAIDS can develop in the absence of virus
dicating that it represents the viral species responsible for in- replication. In fact, considering that the titer of helper
ducing MAIDS, thus fulfilling Koch’s postulates. Sequencing MuLVs are in general much higher (by 100- to 1000-fold)
of this 4.8 kbp defective viral genome revealed a unique than those of defective viruses, it may be what happens
structure: the gag gene, normally found in helper MuLV, naturally even when helper MuLVs are present in the stocks.
was conserved but the p01 and env genes were largely deleted Because its titer is much higher, helper MuLV would infect
(17). The single long open reading frame found was in the many more cells in the primary infection than the defective
gag gene and could encode a putative p#{216}gag protein. The helper virus complex. These cells, initially infected by the
gag gene has sustained many point mutations and small in- helper MuLV, would release a large amount of viruses that
sertions/deletions in the pl2 domain of the gag sequences. will reinfect additional cells. These cells, including the puta-
tive target cells of the MAIDS virus infected by the helper
The defective genome encodes Pr6Ogag protein alone, would quickly outnumber those coinfected by the
In fibroblast cells infected in vitro with this defective MAIDS defective virus and by the helper MuLV, and in fact would
virus, the Pr6Ogag protein was found to be made, thus in- become resistant (by interference) to further infection by the
dicating that the virus codes for this protein (18, 49). As the defective virus. One can imagine that in some stocks, where
helper p5gag precursor, to which it resembles most, the the titer of the helper MuLV and of the defective MuLV are
p#{216}gagis myristylated, phosphorylated, and attached to the about the same, this interference would be less important
cell membrane (49). However, in contrast to the helper and virus replication would seem to play some role in the in-
p5gag, it is not produced outside the cells unless these are duction of the disease. This would be especially true if the
reinfected with helper MuLV, and it remains largely un- target cells for the virus are numerous and if infection of a
cleaved (49). It also seems to behave as a dominant negative larger number of these cells leads necessarily to a higher level
mutant, interfering with complete cleavage of the helper of immunodeficiency in a shorter time.
Pr65gag protein (49).
As the Pr60gag protein represents the major gene product
Antiviral drugs and MAIDS
of the defective MAIDS virus and may even be its only gene
product, it is likely to be involved in its pathogenicity. Recent Recent results with anti-viral drugs are consistent with the
results in our laboratory with variants of the defective virus, fact that the defective MAIDS virus can induce disease in
which have sustained deletions or point mutations, suggest the absence of virus replication. Indeed, azidothymidine
that the gag sequences are essential for pathogenicity of the (AZT) and 9-(2-phosphonylmetoxyethyl) adenine were found
virus (M. Huang, Z. Hanna, and P. Jolicoeur, unpublished to inhibit the development of MAIDS only if given immedi-
results). One of the roles of p#{216}gag may be that of an ately after virus inoculation. If given later, both drugs were
oncoprotein (see below). found ineffective in stopping the progression of MAIDS (55)
(J. Billelo, personal communication).
ROLE OF VIRUS REPLICATION IN THE
INDUCTION OF MAIDS
CLONAL PROLIFERATION OF THE INFECTED
Some diseases induced by defective retroviruses can develop
TARGET CELLS
in the absence of virus replication. This has been found to
be the case for the erythroleukemia induced by the defective
The induction of MAIDS with helper-free stocks of defective
spleen focus-forming virus (SFFV) (50) and for the T cell
virus has allowed us to study the fate of the infected target
(51) or pre-B cell (52) lymphomas induced by the Abelson
cells. Using in situ hybridization and Southern blot analysis,
virus. In one of the crude stocks of the Duplan virus (the LP-
we found that the infected cells were more numerous in dis-
BM5 stock) that contains the defective virus with various
eased infiltrated tissues late in the disease than early after in-
helper MuLVs, it has been postulated that a replicating
oculation, thus suggesting an expansion of this cell popula-
ecotropic MuLV pseudotype of an MCF (mink cell focus-
tion in the absence of virus replication, i.e., through cell
forming virus) MuLV was essential for development of the
division (53). Recent data on differential expression of helper
disease (27, 35). This work, done largely before identifica-
and defective MuLV in enlarged tissues tends to confirm
tion of the defective MuLV and with uncloned viruses, could
these results (40). In fact, using the newly integrated
not be confirmed with cloned MuLVs (35).
proviruses as a marker for clonality, we could determine that
this cell expansion was clonal or oligoclonal. This clonal ex-
Helper-free stocks of the MAIDS virus
pansion occurred in infiltrated tissues from animals inocu-
To look further at the role of helper MuLV and of viral repli- lated with either helper-free or helper-competent stocks of
cation in the development of MAIDS, we constructed helper- the MAIDS defective virus (53).

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 Variable numbers of infected cells in enlarged organs
In mice inoculated with the cloned MAIDS-defective virus
(clone Du5H), we found that enlarged lymph nodes con-
tained a variable proportion of infected cells (sometimes as
little as 5%) (53). In this case most cells contributing to the
mass of these enlarged lymph nodes were not infected and
possibly represent reacting cells that had migrated into these
nodes. In addition, in most mice the clonal expansion
seemed to occur independently in each node, as the emerg-
ing clones of infected cells were distinct in each node. In
some animals, however, we found that one clone of infected
cells was the same in all enlarged organs of the animal, in-
dicating that it has migrated (or metastasized) and suggest-
ing that it may have been more malignant. Most likely, this
metastatic property is related to additional genetic events oc-
curring in these cells, possibly the activation of some on-
cogenes. We recently found that this metastatic potential is
very much influenced by the genetic background of the
mouse and by the defective virus strains used (M. Huang,
C. Simard, and P. Jolicoeur, unpublished results).
It therefore appears that the primary event in the develop-
ment of this disease is the proliferation of the infected target
cells, and that the defective MAIDS virus present in these
cells behaves as an oncogenic MuLV. We suggested that the
immunodeficiency syndrome seen in these mice develops as
the consequence of proliferation of these infected target cells
as a paraneoplastic syndrome (23, 53).

TREATMENT OF MAIDS WITH ANTINEOPLASTIC

AGENTS
Figure 1. Effect of drug therapy on the concanavalin A response of
If MAIDS develops as the consequence of the proliferation spleen T cells in control and MAIDS mice. Stimulation of spleen
of some infected target cells, ablation of these infected cells T lymphocytes with mitogen was performed by measuring incorpo-
with antineoplastic drugs should prevent the development ration of [3H]thymidine essentially as described before (17, 53).
and/or progression of MAIDS. To test this hypothesis, we Drugs were given 6 h (group A) or 48 days (group B) after virus
treated mice inoculated with the MAIDS virus with drugs or saline inoculation. In group B6, the open circles represent the
known to be effective against leukemia or lymphoma in mice. result from the two mice macroscopically diseased. CY, cyclo-
phosphamide; AZ, 5-aza-2deoxycytidine; AR, cytosine arabino-
Some of these drugs (especially cyclophosphamide) were
side. Data are adapted from Simard and Jolicoeur (37).
quite effective in preventing the appearance of MAIDS if
given soon after virus inoculation or in stopping its progres-
sion if given later (48 days after virus inoculation) (37). The
treatment not only abolished the lymph node and spleen en- severe immunodeficiency syndrome. The first suggests that
largement, but the spleen architecture was restored and the the pgag which would be present on the surface of in-
T cell function, as measured by the response to the mitogen fected B cells, would stimulate polyclonal activation of helper
concanavalin A, remained or came back to normal (Fig. 1). T cells, leading the production of lymphokines that would
As expected, the number of infected cells measured by levels themselves provide secondary stimuli to activate various
of the defective provirus DNA or RNA was much reduced other cells (other T cells, B cells, and macrophages) (40). In
by the treatment. Obviously these drugs, and especially cy- this model, it is hypothesized that p#{216}gag presumed to act
clophosphamide, were also effective in preventing the pro- as an antigen, is different enough from other antigens so that
liferation of other noninfected cells whose contribution to the its presence would eventually lead to destruction of the entire
development and/or progression of the disease is yet un- immune system instead of inducing a more usual immune
known but is likely to be significant. response. This model does not take into account nor explain
This result with cyclophosphamide is paradoxical as this the primary proliferation of infected target cells, a phenome-
drug is also quite immunosuppressive. It suggests that the non likely to be important in the pathogenesis of the disease,
immunosuppressive effect of the infected target cells is as it occurs very soon after virus inoculation.
stronger than that of cyclophosphamide. These results are The second model we have proposed has been described
consistent with our hypothesis that the immunodeficiency previously in detail (23, 53). It suggests that the immuno-
seen in this disease is initially caused by proliferation of the deficiency arises as a paraneoplastic syndrome, as the con-
infected target cells (23, 53). sequence of the proliferation of the infected target cells yet
to be identified. Infection of these cells could lead to an in-
creased production of a factor (lymphokine, cytokine)
MAIDS PATHOGENESIS detrimental to the immune system, or less likely, to a
decreased production of a factor essential to keep intact the
A few hypotheses have been proposed to explain the mecha- immune system. Alternativelythe infectedtargetcells,possi-
nisms by which the defective MAIDS virus induces this bly through the pog, could themselves interact directly

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 or indirectly with other cells of the immune system and lead progression of the disease is still unclear. It is possible that
to the immunodeficiency seen. In this model, much empha- HIV may replicate better as the severity of the immuno-
sis is put on the infected target cells and their proliferation. deficiency increases, thus serving as a marker (63). The ab-
They are assumed to belong to a specific cell lineage and to sence of correlation between plasma HIV p24 antigen levels
have been modified specifically by pgag so that they have and plasma HIV titer or the clinical stage of the disease (63,
acquired new characteristics (such as proliferating ability 64) is intriguing, and suggests that release of infectious HIV
and gene activation or inhibition). may not be linked to the production of some HIV proteins
The two models, although different, are not necessarily (63). In addition, the relatively high number of infected cells
contradictory, especially if the proliferating infected target detected in the late stage of AIDS does not explain a major
cells we have detected belong to the B cell lineage. They may feature of the disease, which is the emergence of T cell
even be complementary. However, both models fail to ex- anergy early in the disease, long before T cell depletion (1,
plain the detailed cellular and molecular mechanisms of the 4) and when the plasma titer of the virus (63, 64) and the
emergence of this severe immunodeficiency syndrome, how number of infected cells (64, 66) are still very low in the
it relates to, and how it is distinct from other animal or peripheral blood circulation. Moreover, other manifestations
human immunodeficiency syndromes. of AIDS (such as lymphadeopathy and polyclonal B cell acti-
vation) may not be explained by the loss of CD4 cells (4,
22). Together, these observations suggest that other infected
MAIDS AS A MODEL FOR HUMAN AIDS cells infiltrating various organs outside the peripheral blood
circulation may contribute significantly to progression of the
We have previously discussed the difficulty in ascertaining immunodeficiency. Virtually nothing is known about the
the validity of animal models for AIDS (23). As pointed out variations of their numbers during progression of the disease.
before (22), many characteristics of MAIDS are similar
enough to those found in human AIDS to believe that this Anti-HIV drugs and the role of cell reinfection
model would be useful to understand at least some mani-
Therefore, drugs able to block early events of the virus cycle,
festations of AIDS. So far, the MAIDS model has fulfilled its
such as the antireverse transcriptase drugs, should be helpful
role (the precise role of animal models) in stimulating the
in testing the role of cell reinfection by HIV in the progres-
emergence of novel questions and the formulation of new
sion of AIDS. If progression of the disease depends on con-
hypotheses about human AIDS, namely, about the role of
tinuous cell reinfection by HIV, these drugs should be highly
defective HIV, the role of virus replication, and the impor-
tance to define the target cells of HIV in vivo. beneficial to the HIV-infected individuals. Zidovudine
(AZT), although not specific, is very efficient in blocking the
Defective HIV? HIV reverse transcriptase (67), and in fact seems efficient in
the AIDS dementia complex (68) where evidence for HIV
The fact that two of the retroviruses of the non-lentivirus replication is relatively good (69). Moreover, this drug
group, inducing feline (16) and murine (17, 18) AIDS were prolongs survival in persons with AIDS and delays progres-
found to be defective, suggested that defective HIV may be sion of the immunodeficiency syndrome (70), although its
present in infected individuals and may play a role in effect on the immune dysfunction appears less dramatic than
progression of the disease (17, 56). In fact, the presence of on the neurological disease. The moderate beneficial effect of
several classes of defective HIV genomes in patients with AZT on the progression of AIDS may not be attributed en-
AIDS have now been documented (57). This also seems to tirely to its antiviral effects but may be due to its antiprolifer-
be the case in primates infected with Sly. However, the role, ative effects, as AZT has a strong cytotoxic effect on prolifer-
if any (58), of these defective HIV in the induction or/and ating cells (67). A better test of this hypothesis will probably
progression of the disease (the topics of a recent National In- be available when more specific antireverse transcriptase
stitute of Allergy and Infectious Diseases workshop entitled drugs, such as the TIBO derivatives (71), will be used clini-
“The role of defective virus genomes in AIDS pathogenesis”) cally. The relatively poor response of the immunodeficiency
remains to be determined. to the AZT treatment suggests that these new, more specific
drugs may not achieve a better response. This issue is a
Role of HIV replication rather important one as most of the anti-HIV drugs being
developed now aim at blocking its reverse transcriptase or its
As mentioned previously, MAIDS can progress in the ab-
protease. If HIV does not need to reinfect new cells continu-
sence of virus replication (53), raising the possibility that in
ously to achieve progression of the disease, and if the deter-
other retrovirus-induced immunodeficiency syndromes, in- minant of pathogenicity and/or the critical viral protein (or
cluding human AIDS, progression of the disease may not de-
proteins) involved in inducing disease does (or do) not lie in
pend on virus replication (i.e., on the continuous reinfection
the gag gene, then these antireverse transcriptase or anti-
of new cells but rather on the production of some or all HIV
protease drugs are not going to be beneficial to treat or pre-
gene products in a specific cell population). Although it was vent development of the immunodeficiency syndrome, al-
initially thought that HIV did not replicate at very high
though they are likely to remain useful in treating or
levels in infected individuals, because of the low number of
preventing the AIDS dementia complex.
productively infected cells detected in the blood and in the
lymph nodes (59), it now appears that in some organs, such
HIV targetcellpopulation
as the brain (60, 61) and the upper respiratory lymphoid tis-
sues (62), a relatively high number of infected cells can some- Our studies with helper-free stocks of the MAIDS defective
times be detected. Moreover, recent results have shown that virus have established that one of the primary events of the
as the immunodeficiency progresses, the titer of infectious disease is the infection and clonal proliferation of a specific
viruses (63, 64) and the number of productively infected (64) cell population (53). Because viruses did not appear to rein-
or infected CD4 (65, 66) cells increases significantly in the fect in our experimental setting, infection of a single cell type
blood. Whether this increase contributes to or merely reflects seems to be necessary and sufficient to induce disease. In

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 another experimental context where a replicating helper efficiently. Future experiments should aim at further deter-
MuLV would be present, many other cell types would be- mining similarities and differences between this mouse dis-
come infected, but none of these infected cells is likely to con- ease and human AIDS.
tribute significantly to the development and progression of The work done in our laboratory was supported by grants from
the disease. As retroviruses have the ability to infect several the Medical Research Council of Canada (MRC) and from the
cells types in vivo, this is also most likely the case in HIV- National Cancer Institute of Canada (NCIC) to P. J. We are
infected individuals. If so, not all cells of different lineages in- grateful to Marie Bernier for typing this manuscript.
fected with HIV are likely to contribute to the disease unless
the only important inducing event in AIDS is the accumula-
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