We found moderate but significant regional variation of HHV8 seropositivity, which has not been noted in Uganda before. We also found significant association of HHV8 seropositivity with male gender, older age, and lower level of attained education and significant statistical interaction of HHV8 seropositivity with age-group and gender. Our findings suggest that factors correlated with small-area geography, gender, age, and formal education may influence risk for HHV8 infection.
The geographical pattern of HHV8 seropositivity resembled the pattern of standardized KS morbidity in Uganda before the AIDS epidemic () [9
]. Ecological comparisons of HHV8 and KS regional distributions are risky because HHV8 seropositivity and KS data are derived from non-contemporaneous time-periods and KS data are probably not accurate. Both conditions, however, were coincidentally highest in West Nile and western regions of Uganda and lower elsewhere. Notable differences were also apparent. HHV8 seropositivity varied 1.5-fold from the lowest to highest prevalence region, whereas standardized KS incidence varied 3–6-fold from low to highest region [9
]. This HHV8-KS disparity suggests that geographical co-factors may influence risk for HHV8 seropositivity separately from risk for KS, given HHV8 infection. In contrast to KS, whose incidence has dramatically increased in Uganda during the AIDS epidemic, based on data from Kampala region [16
], HHV8 seropositivity was unrelated to HIV seropositivity in our study. Similar findings have been reported in some [17
], but not all studies [19
]. The pattern of HHV8 seropositivity does not resemble the HIV pattern in Uganda, i.e., HIV seropositivity is high in Kampala and low in the West Nile region [10
], which suggests that our HHV8 seropositivity patterns are more comparable to pre-AIDS era KS patterns.
Figure 2 Map of Uganda showing the standardized morbidity ratio (SMR) for Kaposi sarcoma for 17 regions in Uganda during 1964 to 1968 based on published data in reference  (left panel) and HHV8 seropositivity for 9 regions based on HHV8 serological testing (more ...)
Geographical co-factors, including soil types [4
], exposure to plants [5
], and behaviors, such as transferring HHV8 in saliva to denuded surfaces when saliva is used to soothe itchy insect bite wounds [6
] have been postulated, but most remain untested in individual-level studies [23
]. Our finding of higher HHV8 seropositivity in West Nile region reinforces the notion that geographical co-factors may influence risk for HHV8 infection and/or KS. Interestingly, the small-area variation we observed is reminiscent of the modest but significant positive association we found between HHV8 seropositivity and low village elevation in Tanzania [24
]. The West Nile region differs from other regions in Uganda in lying at the center of the Congo-Nile river basin, where climate is favorable for colonization and dispersion of diverse vectors for helminth parasites, such as snails for schistosomal parasites and simulium flies for filarial worms [25
]. This ecologic niche, coupled with traditional economic activity, such as fishing, subsistence farming, and gathering firewood, places humans in direct regular contact with numerous parasites. Given that chronic exposure to helminth parasites is associated with immune perturbations[26
], we speculate that this small-area variation in HHV8 seropositivity and KS, similar to HHV8 variation in Tanzania [24
], may be a surrogate for biological effects of parasites that influence HHV8 spread and/or progression to KS. Interestingly, intestinal heminths have been associated with KS [27
] and schistosomal infection with HHV8 seropositivity [29
], lending some support to the hypothesis that parasites may influence HHV8 and/or KS risk.
Our finding of age-related increase of HHV8 seropositivity agrees with some [24
], but not all studies [18
]. This finding is interpreted as an epidemiological clue to ongoing low-grade HHV8 transmission, possibly, via sexual contact, although this is controversial in Africa [31
]. HHV8 infection is thought to spread mostly via person-to-person contact with saliva during childhood [32
]. Our finding of higher HHV8 seropositivity in older women than men in Uganda contrasts with findings in Tanzania [24
]. The Tanzanian study was designed to investigate intra-familial HHV8 patterns and HHV8 seropositivity was higher in older men than women and women with seropositive husbands were more likely to be seropositive, suggesting sexual transmission was possible. Perhaps, women are infected by children who are shedding HHV8 virions in their saliva [32
], to whom they are exposed culturally through sharing of mothering responsibilities. Alternatively, older women may be more prone than older men to lytic HHV8 infection [8
], which could also explain our findings. The HHV8 seropositivity disparity in by gender, while significant, is substantially less in magnitude than the disparity of endemic and of epidemic KS by gender (M:F 10:1 and 3:1, respectively) [16
]. HHV8- KS disparities by gender and geography suggest that co-factors may influence risk for HHV8 infection and for KS separately or through different mechanisms.
Our study has some limitations. HHV8 serology is imperfect [34
], so HHV8 seropositivity could have been misclassified. Misclassification of HHV8 seropositivity, however, would be random and would bias the results towards the null. The strengths of our study include being a large nationally-representative population-based sample with detailed demographical data from all regions in Uganda. This allowed us to explore small-area geographical HHV8 patterns. Our study demonstrated a model for international collaboration and feasibility of technology transfer to Africa for large-scale HHV8 serology testing.
To summarize, HHV8 seropositivity showed significant variation by geography, age, gender, and was inversely related to level of attained formal education. Our findings point to an interplay of factors correlated with geography, gender, and age in HHV8 infection and KS risk.