2: 29-34 (1992)
Viral Cofactors in Acquired
Immune Deficiency Syndrome
Department of Virology. Royal Free Hampstead NHS Trust, London NW3, UK
Symptomatic immunodeficiency does not usually occur
until several years after infection with human immunodeficiency virus (HIV), although the length o this time
interval is subject to considerable individual variation. This
can be explained to some extent by the life cycle of HIV
within an infected cell: reverse transcription of viral RNA is
followed by integration of the proviral DNA into the host
cell genome, in which form the virus may remain latent
for prolonged periods. Subsequent activation of the virus
results in lysis of the infected CD4 lymphocyte and release
of infectious virions. Symptoms of AIDS might also be
caused by the dissemination of HIV to cell populations
other than CD4 lymphocytes.
In an infected individual markers of HIV disease progression, such as loss of CD4 lymphocytes and the presence of HIV viraemia suggest that the disease processes
commence at the time of HIV seroconversion. The rate at
which these processes occur may determine the interval at
which AIDS develops, and potentially could be modulated
by the effects of a cofactor virus defined as one which
hastens the onset of acquired immune deficiency syndrome
(AIDS).A viral cofactor may not be essential for the development of AIDS, since AIDS is probably the inevitable
consequence of HIV infection, although for some individuals, the time taken to develop AIDS may exceed their
natural life span.
The acquisition of HIV itself may be enhanced by other
viral infections, such as genital ulceration due to herpes
simplex virus. Once AIDS has supervened, other viruses
may play an opportunist role in the development of lifethreatening infections or neoplasms. The scope of this
review is limited to consideration of the progression from
asymptomatic HIV infection to AIDS, and the role that
other viruses, acting as cofactors in conjunction with HIV,
may play in this process. In practical terms, identification
of viral cofactors is extremely important, since abrogation
of their effects, even if it extends the disease-free interval
by I to 2 years, may offer a worthwhile benefit to the
patient, equivalent to any currently available antiretroviral therapy. Laboratory studies have suggested
many potential mechanisms by which heterologous
viruses may accelerate HIV disease, which are discussed
ISSN I052-92 76/92/010029-06 $05.OO
0 1992 by John Wiley & Sons,Ltd.
INTERACTIONS AT THE MOLECULAR
Transcription of the HIV proviral DNA is under the control
of regulatory elements located in the long terminal repeat
(LTR). Both viral and cellular proteins interact with
sequences in this region to modulate expression of the
genome. These include the HIV trans-acting protein (tat),
and several cellular transcriptional factors such as NFKB,
SP-I and LBP-I.
The ability of various heterologous viral proteins to
transactivate the HIV LTR has been studied by many groups
using cells cotransfected with plasmids containing the HIVI LTR linked to the reporter gene chloramphenicol acetyl
transferase (CAT),and plasmids containing the viral gene of
interest. Alternatively, cell lines chronically infected with
the heterologous virus have been transfected with the HIV
LTR-CAT construct. Herpes simplex virus (HSV), cytomegalovirus (CMV), human herpesvirus-6 (HHVd),
Epstein-Barr virus (EBV), papovaviruses, hepatitis B virus
(HBV), human T cell leukaemia virus (HTLV) type I and
adenoviruses’-’ have all been reported to transactivate the
HIV LTR under these conditions. Interest has focused on
identifying the particular viral proteins involved, and the
HIV sequences with which they interact. Transactivation
by heterologous viruses appears to be independent of the
interaction between HIV tat and its response element, tar.
The HBV x gene and HTLV-1 tax gene products have been
identified as transactivators of the HIV LTR, and the
immediate early (IE) gene products of the herpesviruses
have been shown to mediate this effect, but there is some
disagreement as to precisely which herpesvirus genes are
responsible. The fact that nonproductive herpesvirus infection may be sufficient to stimulate HIV gene expression is
The precise mechanism of transactivation is unclear; it
may result directly from binding of the viral protein to the
HIV LTR, or indirectly from the interaction of the viral
protein with cellular transcription factors (see Figure I).
Binding sites for several cellular transcription factors have
been identified on the HIV LTR. Recent studies have
suggested that the relative abilities of HIV tat, and two
CMV IE genes to transactivate the HIV LTR are highly
dependent upon the cell system
importance of cellular transcription factors. Interaction
Accepted 29 June 1991
Figure 1.Transactivationof the HIV long terminal repeat (LTR).Possible
mechanismsof interaction between extracellular o intracellularcofactor
virus, and the HIV LTR, resulting in stimulation of HIV gene expression.
with the binding site for the cellular transcription factor,
NFKBmay be a common pathway in transactivation of the
HIV LTR by HHV-6, HSV and HBV.’&’’
Molecular interaction between HIV and cofactor viruses
may be a two way process. Upregulation of a cofactor
virus by HIV may be a mechanism by which opportunistic
viral infections develop, independently of a decline in
immune surveillance. This reciprocal enhancement of viral
expression has been demonstrated in vitro for CMV’3*’4
and the papovavirus JC,I5 but not for HSV.I6 For such
direct molecular interactions to occur in vivo, it is necessary
that both viruses are present within the same cell. This
may occur coincidentally for some viruses, especially the
lymphotropic viruses such as HHV-6 and HTLVs, but
specific mechanisms may facilitate dual infection (see
below). However, the extent to which coinfection occurs
in vivo is unclear.
The results of cotransfection experiments should be
interpreted with caution, however, since this artificial system may not predict the result of coinfection in vih-o or
in viva. Both CMV and HSV increase the expression of HIV
in dually infected cells,” and CMV enhances lysis” of T
lymphoblasts infected with HIV. Conflicting results have
been reported for HHV-6 since different groups have
found an increase3 or decrease” in HIV replication in
dually infected cells.
INTERACTIONS AT THE CELLULAR LEVEL
Upregulation of HIV gene expression by cellular transcription factors may also be brought about by external stimuli
such as mitogens or cytokines. Stimulation of HIV infected
peripheral blood mononuclear cells (PBMC)by inactivated
HTLV-1 has been shown to increase HIV expression,” and
HIV expression in a chronically infected T-cell line” can be
increased by the cytokine tumour necrosis factor alpha
(TNF-a).Production o cytokines can be stimulated by viral
infections, so providing an alternative mechanism by
which viruses upregulate HIV (see Figure I), and this has
been investigated in u i h . Soluble mediators, identified as
TNF-a, produced by PBMC following challenge with
inactivated viral antigens, are capable of upregulating
HIV expression in chronically infected T-cell lines.” Cells
stimulated with CMV, EBV or HIV produced cytokines
which upregulated HIV; in contrast, challenge with HSV-I,
HSV-2, varicella-zoster virus, HHV-6, vaccinia or HBV was
ineffective in this
In addition to these interactions, mediated via the stimulation of HIV gene expression, the presence of cofactor
viruses may facilitate the progression of HIV disease by
other specific and nonspecific mechanisms. One specific
mechanism might be the enhancement of cellular tropism,
so allowing HIV to penetrate cells which do not express
CD4, for example within the central nervous system,
where it may cause local pathology. Cofactor-enhanced
uptake of HIV may also increase the opportunity for direct
molecular interaction between the two viruses by increasing the frequency of dually infected cells. Infection and
transformation of cord-blood B lymphocytes by EBV has
been shown to render these cells susceptible to HIV infect i ~ n . ’ ~is known that antibody-coated HIV is able to gain
entry into cells via the receptor for the Fc component of
IgG on the cell ~urface.’~ herpesviruses CMV and HSV
induce the expression of these receptors on the surface of
infected cells, which could then be exploited by HIV (see
Figure 2a). This possibility has been demonstrated in vitro:
it has been shown that antibody-coated HIV can be taken
up into CMV-infected fibroblasts, cells which lack CD4
expression, and which are not normally permissive for
HIV uptake may also be facilitated by infection with a
cofactor virus through the induction of transcription of the
cellular gene encoding the HIV receptor, the CD4 molecule
(see Figure 2b). Expression of the CD4 molecule has been
shown to occur in mature CD8+CD4- lymphocytes
following HHV-6 infection, so rendering the cells susceptible to infection with HIV.” In contrast, cells infected with
CMV or HSV in this system did not behave in the same way.
Phenotypic mixing of HIV with other viruses may result
in the formation of pseudotypes with altered target cell
tropism. Incorporation of additional viral proteins into the
HIV envelope could allow HIV to exploit a wider range of
host cell receptors (see Figure 2c). Pseudotypes have been
reported to occur in T-cell lines coinfected with HTLV-1
and HIV,” with progeny virus able to penetrate into various cells lacking CD4, and also in T-cell lines coinfected
with HIV and HSV.29
Nonspecific mechanisms of interaction might include
the recruitment and activation of HIV-infected cells of the
monocyte-macrophage lineage in response to an active
infection with a cofactor virus, so increasing dissemination
of HIV. Differentiation from monocyte to macrophage, as
part of the immune response, may be a prerequisite for
activation of latent HIV within these cells.
Epidemiological studies have not satisfactorily confirmed
or refuted the clinical relevance of the experimental results
VIRAL COFACTORS IN AIDS
containing HIV genome
Figure 2. Possible mechanisms by which HIV host cell range may be expanded. (a) Cofactor virus infection may induce expression of
receptors for Fc com onent of IgG (FcR)on cell surface, so enabling uptake of antibody-coated HIV. (b) Cofactor virus infection may
induce expression orthe CD4 molecule, the receptor for HIV gp120 on the cell surface, which may then mediate uptake of HIV. (c)
Phenotypic mixing of cofactor virus and HIV may result in an HIV pseudotype expressing cofactor viral proteins.HIV may then exploit
cofactor virus-receptor interactions.
described above, and it is useful to spend a few moments
considering why this might be so. The prolonged period
to development of AIDS demands that patients must be
followed for many years from the time of HIV seroconversion; merely documenting an association between a
particular measure of viral infection and the severity of
HIV disease in a cross-sectional study cannot be taken as
proof o a causative role. Even when groups are followed
prospectively, results may be inconclusive. Other host
factors, including a e?' genetic background?' and continuing drug abuse!'
have been identified as important
variables in determining the time to onset of AIDS, and
failure to account for these may confound the analysis of a
cofactor effect. Other factors, relating to patient lifestyle,
underlying diseases, and route and quantity of HIV inoculum may also affect the progression of AIDS. This latter
factor is especially important where HIV and a putative
cofactor share routes o transmission, since the presence of
a cofactor may simply reflect an increased exposure to
HIV itself. This may to some extent preclude extrapolation
from studies undertaken in particular risk groups or
geographical areas to the HIV-infected population in general. Few studies have been undertaken in heterosexuals,
yet it is this group that is likely to occupy our attention in
The herpesvimses are ubiquitous amongst the general
population, and HIV infection therefore frequently occurs
against a background of herpesvirus infection. Their role
as cofactors in AIDS, particularly the lymphotropic herpesviruses CMV and HHV-6, has been investigated in various
HIV risk groups. Infection with these viruses has generally
been diagnosed on the basis of serological studies.
HHV-6 has been isolated from T and B lymphocytes, and
infection is common amongst the general population,
being acquired during the first few years of life. Antibodies
to HHV-6 are generally detected by immunofluorescence,
which is a subjective technique, and prevalence rates are to
some extent arbitrarily determined by the cut-off titre
chosen. The possible influence of HHV-6 on progression to
AIDS has been analysed in a group of homosexual men
with lymphadenopathy, whose dates of HIV seroconversion were not known, 66% of whom were reported to
be seropositive for HHV-6.33Over a period of 5 years, 30%
of patients developed AIDS; no association was found
between HHV-6 and disease progression. However, it is
not clear whether the serological criterion chosen is a true
reflection of HHV-6 infection, since prevalence rates higher
than this have been reported to occur in the general population. Epidemiological studies to elucidate the role o
HHV-6 are likely to be difficult because of its very high
lation of blood donors and blood or blood product recipients whose dates of HIV seroconversion were unknown.37
The proportion of HIV-infected homosexuals who have
elevated IgA antibody titres to EBV virus capsid antigen
increases with the stage of HIV di~ease,~’ this may
be a consequence, rather than a cause, of progressive HIV
There is some circumstantial evidence that suppression
of herpesviruses might have a beneficial effect in HIV
infected patients. In a small placebo-controlled trial,
therapy with high dose acyclovir has been shown to improve some markers of HIV disease rogression in patients
with asymptomatic HIV infection.4
CMV is found in 50-60% of adults from developed
countries, but is even more prevalent amongst certain
groups because of their high-risk sexual behaviour. For this
reason, the cofactor effect of CMV cannot be studied in
HIV-infected homosexuals since CMV infection is virtually universal in this group. Furthermore, because both
viruses are transmitted via the same route, an absence of
CMV may merely reflect a lower HIV inoculum.
Human T-cell leukaemia viruses
We have reported the adverse effect of CMV serostatus
The HTLVs are infrequently found within the general
on the progression of HIV disease on a cohort of HIV
population in the western world, but are endemic in Japan
infected haemophiliacs, a population with a CMV preand the Caribbean. These viruses are tropic for T cells, and
valence of 54%. CMV is not transmitted by clotting factor
share certain routes o transmission with HIV, and are thus
concentrates, and is therefore not a marker of increased
exposure to HIV in this group.34Further follow-up (for a
found in certain risk groups for HIV, such as i.v. drug
abusers (IVDA). Their role as potential cofactors for AIDS
median o 8.3 years) confirms that CMV-positive patients
has been investigated in IVDA and in homosexuals in
are significantly more likely to have progressed to AIDS,
the Caribbean. Serological methods are generally unable
compared with CMV-negative patients, after controlling
to distinguish between infections with HTLV-I or 2, so
for age. This study attempted to address the difficulties
epidemiological studies have considered both viruses
outlined in the introduction to this section. Other groups
who have not reached the same conclusions, have been less
rigorous in their approach.
Two studies in IVDA in the USA report an association
A small study of HIV-infected haemophiliacs failed to
between HTLV seropositivity and severity of HIV disease.
find an association between CMV status and the developLee ef al. report4’ that 15%of HIV infected IVDA are also
ment of symptoms of HIV infecti0n.3~However, this
infected with HTLV. Dually infected subjects were significategory included patients with generalised lymphadencantly more likely to have fever or weight loss, compared
opathy, a condition which does not carry prognostic sigwith those infected with HIV alone. However, the nonnificance. Two other longitudinal studies have also failed to
specific nature of these symptoms, the possible shared
find a relationship between CMV serostatus and prof
route o transmission, the lack o knowledge of the length
gression to AIDS; one in HIV-infected haemophiliac~,~~ of HIV seropositivity and the variation in prevalence of
and another in a diverse population of blood donors and
both viruses in different age groups prevent us from drawrecipients of blood or blood pr0ducts.3~
The dates of HIV
ing many conclusions from this study. Page ef al. report4’ a
seroconversion were unknown for most of these indiprospective study of HIV-infected IVDA, 21% of whom
viduals, and few of their patients developed a measurable
were also infected with HTLV. After a follow-up of about 2
end-point during the study period. Differences in the study
years, mortality from AIDS was significantly higher in
design prevent comparisons being made between these
dually infected patients (35% vs 12%) after controlling for
age and injecting frequency. These results are certainly
A study of a small number of infants perinatally exposed
suggestive of a cofactor role for HTLV 112 in AIDS, but a
to HIV suggests that infants infected with CMV and HIV
more detailed study in patients with known dates of HIV
have a worse prognosis, as reflected in AIDS mortality, than
seroconversion is required.
those infected with HIV alone.38Interaction between CMV
A study of a small number of HIV-infected homosexuals
and HIV may occur in the mother, with transmission of a
in Trinidad reveals that dually infected individuals are more
higher HIV inoculum to her offspring, or within the infant.
likely to have HIV disease, but this re ort suffers from the
However, the possibility cannot be excluded that mothers
limitations of a cross-sectional study.4 P
who have more advanced HIV disease for whatever reason
HTLVs might prove to be important cofactors in these
are more likely to reactivate and transmit CMV, and so give
populations, but are unlikely to have any major impact
birth to infants who have a worse prognosis because they
in patients in the western world because o the rarity o
have received a larger inoculum of HIV.
infection with these viruses.
Hepatitis B virus
Evidence in support o a role for EBV in HIV disease prof
gression is lacking. Lang and colleagues report no association between EBV seropositivity (as measured by IgC
antibodies against virus capsid antigen) and progression to
AIDS over a study period o up to 32 months in a popu-
HBV is transmitted by the same routes as HIV, and this
virus is therefore prevalent amongst certain unvaccinated
HIV risk groups. Solomon ef al. report a study of HIVinfected homosexuals followed for a period o 2.5 years.44
The presence of serological markers for HBV was not
VIRAL COFACTORS IN AIDS
related to progression to AIDS in this group, although the
date of HIV seroconversion was not known for these
The topic of viral cofactors in AIDS is highly controversial.
Other variables, such as age and genetic background, may
modulate the size of any cofactor effect in a given study
population, as will the prevalence of the virus in that population. As yet no consensus has emerged on the effects of
any virus on progression to AIDS. Evidence in favour of, or
against, a particular virus acting as a cofactor can be found
in the experiments outlined above. The discrepant laboratory results may be partly explained by differences in the
experimental cell system chosen, since it is becoming
increasingly clear that molecular interactions are to some
extent dependent upon host cell mediators.
Identification of viral cofactors is undertaken with the
aim of prolonging the interval between HIV infection and
AIDS by suppressing their effects with antiviral agents.
This could conceivably be achieved with active or passive
immunoprophylaxis, or with antiviral agents. Vaccines are
likely to be useful tools in preventing cofactor infection
only as part of a general vaccination policy, since these
infections are often acquired in early life. However, vaccines
may potentially modulate the effects of prior infection, for
example by suppressing active infection. Antiviral agents,
such as high dose acyclovir, may be useful in lessening the
effect ofacofactor, by inhibiting viral replication.The taskof
establishing the precise mechanisms o interaction between
cofactor viruses and HIV thus takes on extra importance,
so that the molecular targets for antiviral agents can be
identified. For example, the development of agents which
interfere with transcriptional factors might be effective in
suppressing the effects of latent cofactor infections.
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