ARTICLE Serum apoptosis markers in HIV-infected patients with human herpesvirus type 8 and herpes simplex virus type 2 co-infection O. Dakovic Rode & A. Markotic & M. Kujundzic Tiljak & S. Zidovec Lepej & J. Begovac Received: 23 May 2012 / Accepted: 4 July 2012 / Published online: 27 July 2012 # Springer-Verlag 2012 Abstract This study aimed to examine the influence of human herpesvirus type 8 (HHV-8) and herpes simplex virus type 2 (HSV-2) co-infections on apoptosis serum markers in human immunodeficiency virus (HIV)-infected patients. Sera from 110 HIV-infected and 59 HIV-uninfected individuals were analyzed for soluble Fas (sFas), sFas li- gand (sFasL), caspase-8, and Bcl-2. The findings of HIV- infected patients with no co-infection (n 0 37), HIV-infected patients with HHV-8 co-infection (n 0 22), HIV-infected patients with HSV-2 co-infection (n 0 51), and patients with HSV-2 co-infection and no HIV infection (n 0 20) were compared to controls (reference group) with no HIV, HSV- 2, and HHV-8 co-infections (n 0 39). Soluble Fas and sFasL concentrations were the highest in HIV and HHV-8 co- infected patients (medians, 912.7 pg/ml and 74.3 pg/mL, respectively). No difference in caspase-8 concentrations was found, whereas Bcl-2 concentrations were the highest in HIV and HHV-8 co-infected individuals. Older age was associated with higher sFas (p <0.001) and lower sFasL (p 0 0.04) concentrations. In a robust regression model adjusted for age, the log-transformed sFas concentrations were significantly lower in HIV-infected patients with no co-infections (β 0 -0.244; p <0.001) and higher in HIV and HHV-8 co-infected patients (β 0 0.216; p 0 0.012) compared to the reference group. Soluble FasL was significantly lower in HIV-infected patients with no co-infections (β 0 -0.284; p 0 0.005) and in HIV-infected patients with HSV-2 co-infection (β 0 -0.381; p <0.001) compared to the reference group. Solu- ble FasL was also higher in HIV and HHV-8 co-infected patients compared to controls (β 0 0.248; p 0 0.036). Our results suggest that HHV-8 and HSV-2 may have a significant effect on Fas–FasL-mediated apoptosis in HIV-1 patients. HHV- 8 upregulates while HSV-2 downregulates sFas and sFasL. Introduction Fas-mediated apoptosis is considered to be an important T- cell depletion mechanism in human immunodeficiency virus (HIV) infection that is supposed to be diminished by the downregulation of apoptosis [1–3]. Soluble Fas (sFas) inhibits apoptosis by blocking the binding of Fas with Fas ligand (FasL) or soluble FasL (sFasL). Fas is a cell membrane receptor which translates apopto- tic signals from FasL and induces a cascade of apoptotic cell death signals [4]. FasL has a primary role to induce the apoptosis of Fas receptor-expressed cells [5, 6]. FasL is expressed on the cell surface membrane or stored in intra- cellular microvesicles. Membrane FasL is reduced by metal- loprotease proteins cleavage, and soluble forms of FasL (sFasL) that block the apoptotic activity of membrane FasL are released. Soluble and membrane FasL have different functions. Depending on the microenvironment conditions, sFasL can have pro- or anti-apoptotic activity. The anti- apoptotic sFasL function is based on Fas binding competi- tion with membrane FasL. Soluble FasL conjugated with Fas is ineffective and not capable of inducing apoptosis [6]. In addition, FasL triggers inflammation and sFasL is a potent chemoattractant for human neutrophils [7]. O. Dakovic Rode (*) : A. Markotic : S. Zidovec Lepej : J. Begovac University Hospital for Infectious Diseases “Dr. Fran Mihaljevic”, Mirogojska 8, 10000 Zagreb, Croatia e-mail: orode@bfm.hr O. Dakovic Rode e-mail: oktavija.rode@gmail.com M. Kujundzic Tiljak : J. Begovac University of Zagreb, School of Medicine, Zagreb, Croatia M. Kujundzic Tiljak Andrija Štampar School of Public Health, Zagreb, Croatia Eur J Clin Microbiol Infect Dis (2012) 31:3303–3308 DOI 10.1007/s10096-012-1696-5