E D I T O R I A L C O M M E N TA R Y
Human Herpesvirus 8 Seropositivity in Rural Uganda:
Maturation of Sero-epidemiological Studies
Sam M. Mbulaiteye and James J. Goedert
Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
(See the article by Butler et al., on pages 625–34.)
Human herpesvirus 8 (HHV8, also
called Kaposi sarcoma [KS]–associated
herpesvirus) is a necessary but in-
sufficient cause of KS . KS is a major
public health problem in Africa, where it
was endemic before the human immu-
nodeficiency virus (HIV) infection epi-
demic , accounting for up to 18% of
cancers in adults in some regions, in-
cluding parts of Uganda, the Congo, and
Rwanda . The disease was known to
occur in children , intuitively sug-
gesting that HHV8 could be transmitted
during childhood. Currently, KS is the
most common cancer in men and the
second most common cancer in women
and children in Uganda, highlighting the
dramatic impact of the HIV infection
epidemic on KS incidence . The
discovery of HHV8 in 1994  and
subsequent development of antibody
assays with reasonable sensitivity and
specificity paved the way for sero-
epidemiological studies to characterize
the distribution of HHV8, the risk fac-
tors for infection, and the risk for KS
after HHV8 infection. The geographic
distribution of HHV8
generally parallels that of KS [6, 7]. In
sub-Saharan Africa, HHV8 seropositiv-
ity is higher (50%–80% in adults) in the
eastern and central regions and lower
(10%–40% in adults) in western and
southern regions . HHV8 infection
seroprevalence increases with age in
children  and is associated with hav-
ing an HHV8-seropositive mother or
family member . HHV8 can be
transmitted by transfusion, but the risk
is relatively small (2%–3% per trans-
fusion), compared with the risk of
community-acquired HHV8 (3% per
year) [10, 11]. HHV8 DNA is detected
frequently and at high levels in saliva of
consistent with the theory that saliva is
the dominant conduit of HHV8 spread
. Among adults, some studies ,
but not all , have shown a modest
association of HHV8 seropositivity with
age. The association of HHV8 seroposi-
tivity with sexual risk factors has been
The article by Butler et al  in this
issue of the Journal is the largest pop-
ulation-based study to evaluate epide-
infection among children and adults in
a country where KS is a major public
health problem. Thus far, our knowledge
of HHV8 sero-epidemiology in Africa
has been derived from studies that suf-
fered from many limitations, including
relatively small size and especially the
reliance on selected populations, such as
children attending hospital clinics ,
commercial sex workers[18, 20], patients
attending sexually transmitted disease
clinics, or selected occupational groups
[17, 19]. These limitations may explain,
in part, some of the conflicting associa-
tions and/or lingering doubts that even
consistent findings can be generalized.
Butler et al  avoided many of the
limitations of prior studies. They studied
1383 children (age. 18 months–13 years)
and 1477 adults enrolled from their
homes in a rural parish in Uganda. They
nomic and behavioral risk factors, in-
cluding saliva sharing practices, which
have not been evaluated before, using
questionnaires. In addition, they tested
for serologic evidence of other infections
(cytomegalovirus [CMV], herpes sim-
plex virus-1 [HSV1], hepatitis B virus
[HBV]), and HIV) that have established
modes of transmission. They detected
HHV8 antibodies using an in-house
K8.1 immunoassay with which they have
accumulated substantial experience in
other studies conducted in Uganda .
Among the children, they found that
creased with age, doubling from 15.5%
Received 21 October 2010; accepted 19 November 2010.
The content is the responsibility of the authors alone and
does not necessarily reflect the views or the policies of the
United States Department of Health and Human Services or
Potential conflicts of interest: none reported.
Reprints or correspondence: James J. Goedert, MD, 6120
Executive Blvd, Executive Plaza South, Rm 7068, MSC 7248,
Rockville, MD 20852 (email@example.com).
The Journal of Infectious Diseases
Published by Oxford University Press on behalf of the
Infectious Diseases Society of America 2011.
d JID 2011:203 (1 March)
to 31.6% among those aged 2–9 years.
HHV8 seropositivity was increased when
both parents were HHV8 seropositive,
when at least 1 other child in the house
was HHV8 seropositive and when HSV1
antibodies were detected. HHV8 sero-
positivity was not related to the sex of
the child (27.3% in boys vs 26.6% in
girls), nor to HBV, CMV, and EBV se-
ropositivity. Of note, HHV8 seroposi-
tivity was not associated with exposure
to premasticated food from the mother.
Premasticated food also was not associ-
ated with CMV, EBV, HBV, or HSV1,
which are presumed to be transmitted
through contact with saliva. HHV8 se-
ropositivity was increased by 2-fold
(95% confidence interval, .99–4.3) with
sharing of food and/or sauce plates in
the household, which was reported by
91% of the children. Food sharing was
also associated with a 3-fold higher
prevalence of HBV core antibody (95%
confidence interval, 1.2–7.5), but not
with CMV, EBV, HBV, or HSV1 sero-
Among the adults, HHV8 seropositiv-
ity was higher in men than in women
(43% vs 38%; P 5 .04), and it increased
slightly with age, in men and women
combined, from 42.0% at age 40–49 years
to 49.3% after age 50 years. HHV8 sero-
positivity was unrelated to the number of
lifetime sexual partners, history of genital
ulcer disease or discharge, or HIV sero-
positivity. Sexual exposures were associ-
ated with HIV infection, providing face
validity for the questionnaire data.
The study provides the clearest data
thus far that HHV8 in Uganda, and
perhaps in much of Africa, is trans-
mitted through nonsexual social inter-
actions, especially in childhood. The
clarity can be attributed to their careful
population-based epidemiological de-
sign, large sample size, detailed interview
data, and measurement of biomarkers
for related exposures. The study also
provides data that low-grade, nonsexual
HHV8 transmission probably occurs
during adulthood. It is theoretically
possible, although unlikely, that the
rather small increase in seroprevalence
of HHV8 infection with age among
adults is attributable to age-related delay
in antibody seroconversion following
primary infection at a much younger
age. Adult seroprevalence of HHV8 in-
fection was different by gender, possibly
reflecting different behavioral risk fac-
tors that are associated with exposure to
HHV8 in men compared with women.
The findings in the current study also
a cross-sectional sero-epidemiological
study to demonstrate HHV8 trans-
mission. The hypothesis that HHV8
transmission occurs through saliva still
has not been confirmed, despite the in-
tuition that exposure would be high with
premasticated food. This null result may
be explained in part to limited statistical
power, because only 8.8% of the moth-
ers reported this practice. However,
misclassification of the frequency, load,
and timing of salivary exposure to in-
fectious HHV8 is likely. HHV8 is de-
tected frequently in saliva of children
(17%; median viral load,10,100 copies
/mL; interquartile range [IQR], 320–
29,333 copies/mL), their mothers (10 %;
median viral load, 7200 copies/mL; IQR,
220–32,000 copies/mL), and in HIV-
uninfected adults without KS (22%) in
Uganda [12, 13]. Shedding of virus in
saliva also varies over time , with
some individuals shedding virus more
consistently and others shedding virus
infrequently. Accurate classification of
study will not be possible. A better ap-
proach would be a prospective cohort in
a community with a high prevalence of
HHV8 infection, then comparing case
children who do against control children
who do not acquire HHV8 infection.
The exposure measure would be receipt
of premasticated food but, more in-
formatively, the load of HHV8 shed in
frequent, longitudinally collected saliva
from mothers and siblings of the case
and control children. Determining the
relatedness of HHV8 sequences between
children, mothers, siblings, and perhaps
other close contacts would help confirm
the source of HHV8 that is transmitted.
Colluzi at al proposed that HHV8
transmission is influenced by use of sa-
liva to soothe blood-sucking arthropod
bites , another hypothesis that could
be confirmed or refuted.
Host vulnerability by genetic variants
or immune alteration may also affect
the likelihood of HHV8 transmission.
A statistical genetics analysis pointed to
the possibility of a major recessive gene
effect on HHV8 seropositivity , and
polymorphisms may affect HHV8 shed-
ding . In addition, shedding or vul-
nerability may be increased, even at low
levels of exposure, by helminthic para-
sites [6, 25].
Finally, to reduce the heavy burden of
KS in Africa, especially in the context of
the HIV infection epidemic, strategies
will be needed to prevent HHV8 trans-
mission. Such prevention strategies will
only be effective if the mechanisms of
HHV8 transmission are well character-
ized. Progress has been made, but much
more, multidisciplinary, carefully de-
signed and executed research is needed.
The work was supported by the Intramural
Research Program, National Cancer Institute,
National Institutes of Health, Department of
Health and Human Services.
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