Abstract
BackgroundCo-infections with human herpesvirus (HHV) have been associated with residual chronic inflammation in antiretroviral (ART)-treated human immunodeficiency virus (HIV)-infected individuals. However, the role of HHV in modulating the tryptophan-kynurenine pathway and clinical outcomes in HIV-infected individuals is poorly understood. Thus, we investigated the seroprevalence of four common HHVs among treated HIV-infected participants and their impact on kynurenine/tryptophan (K/T) ratio and long-term CD4 T-cell recovery in HIV/HHV co-infected participants.MethodIn this cross-sectional study, HIV-infected participants receiving suppressive ART for a minimum of 12 months were recruited from the University Malaya Medical Centre (UMMC), Malaysia. Stored plasma was analyzed for CMV, VZV, HSV-1 and HSV-2 IgG antibody levels, immune activation markers (interleukin-6, interferon-γ, neopterin and sCD14), kynurenine and tryptophan concentrations. The influence of the number of HHV co-infection and K/T ratio on CD4 T-cell recovery was assessed using multivariate Poisson regression.ResultsA total of 232 HIV-infected participants were recruited and all participants were seropositive for at least one HHV; 96.1% with CMV, 86.6% with VZV, 70.7% with HSV-1 and 53.9% with HSV-2. K/T ratio had a significant positive correlation with CMV (rho = 0.205, p = 0.002), VZV (rho = 0.173, p = 0.009) and a tendency with HSV-2 (rho = 0.120, p = 0.070), with CMV antibody titer demonstrating the strongest modulating effect on K/T ratio among the four HHVs assessed in SOM analysis. In multivariate analysis, higher K/T ratio (p = 0.03) and increasing number of HHV co-infections (p<0.001) were independently associated with poorer CD4 T-cell recovery following 12 months of ART initiation.ConclusionMultiple HHV co-infections are common among ART-treated HIV-infected participants in the developing country setting and associated with persistent immune activation and poorer CD4 T-cell recovery.
Highlights
Infection with human immunodeficiency virus (HIV) is still associated with a high degree of morbidity and mortality in developing countries partly due to the limited access to antiretroviral therapy (ART) [1]
K/T ratio had a significant positive correlation with CMV, varicella zoster virus (VZV) and a tendency with human simplex virus 2 (HSV-2), with CMV antibody titer demonstrating the strongest modulating effect on K/T ratio among the four Human herpes viruses (HHVs) assessed in self-organizing map (SOM) analysis
We investigated whether an increasing number of HHV co-infection in a participant had an impact on K/T ratio and the other immune activation markers (Fig 1)
Summary
Infection with human immunodeficiency virus (HIV) is still associated with a high degree of morbidity and mortality in developing countries partly due to the limited access to antiretroviral therapy (ART) [1]. Co-infections with CMV, HSV, human herpesvirus 8 (HHV8), and VZV, have all been associated with residual chronic inflammation in HIV-infected participants receiving suppressive ART [7,12,13,14,15]. CMV has been shown to be directly associated with serious non-AIDS events [8], cardiovascular morbidity [16], stroke [17], poorer neurocognitive performance [18] and frailty [19] in HIV while HSV and VZV infections have been associated with an increased risk of stroke in the HIV [20] and general population [21]. Co-infections with human herpesvirus (HHV) have been associated with residual chronic inflammation in antiretroviral (ART)-treated human immunodeficiency virus (HIV)-infected individuals. We investigated the seroprevalence of four common HHVs among treated HIV-infected participants and their impact on kynurenine/tryptophan (K/T) ratio and long-term CD4 T-cell recovery in HIV/HHV co-infected participants.
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