95
7.2 Epidemiology of KSHV
7.2.1 Prevalence and Genetic Diversity
The prevalence of KSHV infection varies globally. The infection rates in Western
Europe and America are low, whereas the rates in Africa are higher [ 38 ]. The
Mediterranean region (e.g., Italy and Spain) is an exception in that it shows a rela-
tively high prevalence of KSHV infection [ 39 , 40 ]. KSHV is also prevalent in the
Xinjiang province of China, where high rates are found in the Uyghur and Kazakh
ethnic groups [ 3 , 4 ]. The seroepidemiological approach is the major method to
determine the prevalence of KSHV infection. Seropositivity not only reflects past
exposure to KSHV but also the presence of an ongoing viral infection. However,
in most cases, KSHV infection is not associated with any symptoms, and the anti-
body titers in these individuals are lower than those in individuals with KSHV-
related diseases. Thus, the reported seropositivity may be underestimated. To
determine seroprevalence, testing of LANA (the major latently expressed antigen)
and at least one lytic antigen (e.g., K8.1, ORF65) is recommended for variable
seroreactivity [ 38 ].
Unlike the rates of KSHV infection, which may be difficult to determine accu-rately in epidemiological studies, the incidence of KSHV infection-related diseases
such as KS is clear. The incidence of KS is around 1 in 100,000 in the general popu-
lation, whereas it is approximately 1 in 20 in HIV-infected individuals, increasing to
almost 1 in 3 in HIV-infected gay men prior to the introduction of highly active
antiretroviral treatment (HAART) [ 7 , 41 ]. The overall incidence of KS in the United
States is as follows (age-standardized incidence in males per 100,000): non- Hispanic
whites, 0.8; white Hispanics, 1.4; and blacks, 2.4. In Italy, the incidence ranges from
0.2 to 2.0. The incidence of KS in Africa is much higher and can be above 22 in
endemic or HIV pandemic regions [ 38 ]. KS is one of the most common cancers in
many subequatorial African countries. Almost all KS patients are seropositive for
KSHV infection [ 42 ]. The geographic variation in KS incidence corresponds to the
imbalanced worldwide seropositivity of KSHV infection. Therefore, the association
of KS with KSHV infection strongly supports that KSHV is the etiologic agent of
KS. Moreover, KSHV genomic DNA and viral antigens can be detected in all cases
of KS [ 43 ].
Although KSHV is a DNA virus with a highly conserved genome, remarkablesequence variability can be found in the regions surrounding the terminal repeats,
which are the ORFs of K1 and K15 [ 44 , 45 ]. The genetic diversity in the K1 and
K15 regions is used as a marker of strain diversity, which can help track the spread
of KSHV and study the evolution of KSHV, as well as the relationship with its
human host. The K1 gene encodes a transmembrane protein. Its N-terminal domain
is highly variable, and the hypervariable regions are named by V1 and V2 [ 46 ]. The
sequence variability may be related to the host immune pressure or the recognition
of highly polymorphic cell surface proteins [ 47 ]. KSHV isolates can be classified
into four major subtypes, A, B, C, and D, according to the K1 sequence variation.
7 KSHV Epidemiology and Molecular Biology