Soluble biomarkers of HIV-1-related systemic immune activation are associated with high plasma levels of growth factors implicated in the pathogenesis of Kaposi sarcoma in adults

Abstract

Background: Human Herpesvirus-8 (HHV-8) is the etiologic agent of Kaposi's sarcoma (KS), a multicentric angio-proliferative cancer commonly associated with Human Immunodeficiency Virus (HIV) infection. KS pathogenesis is a multifactorial condition hinged on immune dysfunction yet the mechanisms underlying the risk of developing KS in HHV-8 seropositive adults remains unclear. Here we explored whether soluble markers of HIV-1-related systemic immune activation (SIA) and angiogenesis (VEGF and FGF acidic) are involved in the pathogenesis of KS in adults with HHV8.

Methodology: Blood samples from 99 HIV-1 infected and 60 HIV-1 uninfected adults were collected in Yaoundé, Cameroon. CD3+/CD4+ T cell counts and HIV-1 plasma viral load were determined using the Pima Analyzer and the RT-PCR technique, respectively. Plasma levels of SIA biomarkers (sCD163, sCD25/IL-2Rα, and sCD40/TNFRSF5) and biomarkers of progression to KS (VEGF and FGF acidic) were measured using the Luminex assay. Seropositivity (IgG) for HHV-8 was determined using the ELISA method.

Results: Overall, 20.2% (20/99) of HIV-1 infected and 20% (12/60) of HIV-1 uninfected participants were seropositive for HHV8. Levels of sCD163, sCD25/IL-2Rα, sCD40/TNFRSF5, and FGF acidic were higher in the HIV-1 and HHV8 co-infection groups compared to the HIV-1 and HHV8 uninfected groups (all P <0.05). In addition, Higher plasma levels of VEGF correlated with sCD163 (r_s = 0.58, P =0.0067) and sCD40/TNFRSF5 (r_s = 0.59, P = 0.0064), while FGF acidic levels correlated with sCD40/TNFRSF5 (r_s = 0.51, P = 0.022) in co-infected. In HIV-1 mono-infected donors, VEGF and FGF acidic levels correlated with sCD163 (r_s =0.25, P = 0.03 and r_s = 0.30, P = 0.006 respectively), sCD25/IL-2Rα (r_s = 0.5, P <0.0001 and r_s = 0.55, P <0.0001 respectively) and sCD40/TNFRSF5 (r_s = 0.7, P <0.0001 and r_s = 0.59, P <0.0001 respectively) and even in patients that were virally suppressed sCD25/IL-2Rα (r_s = 0.39, P = 0.012 and r_s = 0.53, P = 0.0004 respectively) and sCD40/TNFRSF5 (r_s = 0.81, P <0.0001 and r_s = 0.44, P = 0.0045 respectively).

Conclusion: Our findings suggest that although the development of KS in PLWH is multifactorial, HIV-associated SIA might be among the key drivers in coinfections with HHV8 and is independent of the patients' viremic status.

Keywords: FGF acidic; HIV-1; IgG anti HHV8; VEGF; systemic immune activation.

Figure 1

National algorithm for HIV Rapid Test in Cameroon, RDT1, highly sensitive (Alere Determine HIV-1/2, Matsudo, Japan); and RDT2, highly specific (Oraquick HIV-1/2, Orasure Technologies, Inc).

Figure 2

Plasma levels of solubles biomarkers of systemic immune activation stratified by HIV-1 status in adults. Plasma levels in sCD163, sCD25/IL-2R alpha, and sCD40/TNFRSF5 were compared between HIV+&HHV8- (N=79) and HIV-&HHV8- (N=48) adults using Mann- Whitney Rank Sum Test.

Figure 3

Plasma levels of solubles biomarkers of systemic immune activation and growth factors stratefied by Viral load in adults.

Figure 4

Plasma levels of solubles biomarkers of systemic immune activation and growth factors in HIV-1 and HHV8 in adults. Plasma levels of sCD163, sCD25/IL-2R alpha, sCD40/TNFSF5, FGF-acidic and VEGF were compared between HIV+&HHV8+ (N = 20) and HIV-&HHV8- (N = 48) adults using Mann-Whitney Rank Sum test.