Decreasing CD4 count number due to HIV replication is usually associated with activation of CMV- and EBV-specific CD4 T-cells as part of chronic immune activation, which may subsequently stimulate humoral responses and produce higher IgG titres in time. The observed weak, though significant associations between serum IgG levels of different HHVs suggest that risk factors of reactivation leading to higher IgG titres partially overlap. limited for sub-Saharan Africa. These are important to provide an indication of potential burden of HHV-related disease, in particular in human immunodeficiency computer virus (HIV)-infected individuals who are known to be at increased risk GTF2F2 of these conditions in the Western world. In this cross-sectional study among 405 HIV-infected and antiretroviral therapy na?ve individuals in rural South Africa the seroprevalence of HHVs was: herpes simplex virus type 1 (HSV-1) (98%), herpes simplex virus type 2 (HSV-2) TTNPB (87%), varicella zoster computer virus (VZV) (89%), and 100% for both Epstein-Barr computer virus (EBV) and cytomegalovirus (CMV). Impartial factors associated with VZV seropositivity were low educational status and having children. Lack of in-house access to drinking water was independently associated with positive HSV-1 serostatus, whereas Shangaan ethnicity was associated with HSV-2 seropositivity. Increasing age was associated with higher IgG titres to both EBV and CMV, whereas CD4 cell count was negatively associated with EBV and CMV IgG titres. Moreover, IgG titres of HSV-1 and 2, VZV and CMV, and CMV and EBV were positively correlated. The high HHV seroprevalence emphasises the importance of awareness of these viral infections in HIV-infected individuals in South Africa. Introduction Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) are human herpesviruses (HHV) that are prevalent worldwide. HHV Infections can lead to a variety of clinical conditions that range in severity from cold sores and genital ulcers (HSV), and chickenpox (VZV) to potentially sight-threatening (e.g. CMV uveitis and HSV keratitis) or even life-threatening diseases such as HSV encephalitis and EBV-associated malignancies [1]C[3]. Primary HHV infections, commonly acquired at young age, lead to a life-long latent infection with intermittent reactivation resulting in periodic asymptomatic or recrudescent disease. The host immune system is pivotal to resolve lytic infections and to inhibit HHV reactivation from latency. Consequently, reactivation of HHV is much more frequent among immunocompromised individuals including those infected with TTNPB human immunodeficiency virus (HIV) [4], [5]. Also, HIV-infected individuals have an increased risk of developing more severe HHV-related disease [4], [5]. Even after the introduction of antiretroviral therapy (ART), HIV-infected individuals remain at risk of developing severe HHV-related diseases as ART-induced recuperation of adaptive immunity may result in vigorous anti-HHV cellular immune responses. In the case of residual ocular CMV infection, restored CMV immunity may lead to sight-threatening immune recovery uveitis [6]. HHV infections clinically interact with HIV, contribute substantially to hospitalization, morbidity and mortality and some HHVs (e.g. HSV-2) may even facilitate HIV transmission [4], [7], [8]. This is of particular importance in sub-Saharan Africa where HIV prevalence rates are at their highest. Despite the roll-out of ART programmes in this region, ART coverage is still low [9]. Many HIV-infected patients seek healthcare with considerably more advanced immunodeficiency and may present with clinically different HHV-related diseases compared to individuals TTNPB in resource-rich countries. In contrast to developed countries, where HHV seroprevalence and occurrence of associated diseases are well-documented, there is only scarce information available on the seroprevalence and risk factors of HHV infections in sub-Saharan Africa. This information is important to provide an indication of the burden of HHV infections which is particularly relevant for HIV-infected individuals who are known to be at increased risk for development of HHV-induced disease due to reactivation. Material and Methods Study setting and population Study participants were recruited between September 2012 and January 2013 at primary healthcare (PHC) facilities across the Mopani District (Limpopo Province, South Africa), where the two main ethnic groups are Sotho (46%) and Shangaan (44%) [10]. Participating PHC facilities were selected by ratio of population-size of each of five sub-districts with a minimum of two PHC facilities/sub-district. Within each sub-district, PHC facilities were selected based on the number of patients on the wellness, pre-ART programme, geographic location and size of the catchment area. Individuals who had an indication to draw blood for determination of CD4 count (CD4 T-cells/mm3 blood) were eligible for this study. Criteria to participate were adult age (i.e. 18 years and older) and no prior ART exposure..