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

Yap SH 1 , Abdullah NK 1 , McStea M 1 , Takayama K 2 , Chong ML 1 , Crisci E 3 Show all authors , Larsson M 3 , Azwa I 1 , Kamarulzaman A 1 , Leong KH 4 , Woo YL 1 , Rajasuriar R 1

Affiliations 

  • 1 Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia
  • 2 Department of Pharmaceutics, Hoshi University, Tokyo, Japan
  • 3 Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  • 4 Department of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia
PLoS One, 2017;12(10):e0186000.
PMID: 29016635 DOI: 10.1371/journal.pone.0186000

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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