HIV/Human herpesvirus co-infections: Impact on tryptophan-kynurenine pathway and immune reconstitution

PLoS One. 2017 Oct 9;12(10):e0186000. doi: 10.1371/journal.pone.0186000. eCollection 2017.

Abstract

Background: Co-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.

Method: In 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.

Results: A 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.

Conclusion: Multiple 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.

MeSH terms

  • Adult
  • Antibodies, Viral / blood
  • Antiretroviral Therapy, Highly Active
  • CD4-Positive T-Lymphocytes / immunology
  • Coinfection / blood
  • Coinfection / epidemiology*
  • Coinfection / immunology
  • Coinfection / virology
  • Female
  • HIV Infections / blood
  • HIV Infections / epidemiology*
  • HIV Infections / immunology
  • HIV Infections / virology
  • Herpes Simplex / blood
  • Herpes Simplex / epidemiology*
  • Herpes Simplex / immunology
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / isolation & purification
  • Herpesvirus 1, Human / pathogenicity
  • Humans
  • Immune Reconstitution Inflammatory Syndrome / blood
  • Immune Reconstitution Inflammatory Syndrome / immunology
  • Immune Reconstitution Inflammatory Syndrome / metabolism
  • Immune Reconstitution Inflammatory Syndrome / virology
  • Inflammation / blood
  • Inflammation / epidemiology*
  • Inflammation / immunology
  • Inflammation / virology
  • Kynurenine / metabolism
  • Male
  • Metabolic Networks and Pathways
  • Seroepidemiologic Studies
  • Tryptophan / metabolism

Substances

  • Antibodies, Viral
  • Kynurenine
  • Tryptophan