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

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.

Hypoxia-inducible factor 1α (HIF1α) Suppresses Virus Replication in Human Cytomegalovirus Infection by Limiting Kynurenine Synthesis

“…Immunosuppressed HCMV-infected transplant recipients have elevated KYN serum levels (18). Additionally, people with HCMV and human immunodeficiency virus type 1 (HIV-1) co-infection have enhanced KYN serum levels relative to those with HIV and herpes simplex virus type 1 (HSV-1) co-infection (19). While our observations demonstrate that HCMV-infection increases Figure 5B) (22).…”

“…Peaks 1 and 4 remain unidentified. Since the levels of KYN in human serum were previously found to be associated with HCMV infection (18,19), we decided to focus on the role of KYN in virus replication.…”

Enrichment of gut-derived Fusobacterium is associated with suboptimal immune recovery in HIV-infected individuals

“…However, reduced Lactobacillales was not correlated with increased plasma IDO activity in our study (data not shown). The lack of correlation could potentially be explained by the presence of other IDO mediators including IFN-α levels, which we recently showed to remain elevated despite years of suppressive ART in our setting 52 . The association between reduced Lactobacillales and CD4 T-cell counts was also weaker when compared to Fusobacterium in our cohort and was lost when both bacterial taxa were included in a multiple linear regression model.…”

Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: An observational cohort study.

“…The Kyn:Trp ratio, measured in blood, is a valuable clinical benchmark of IDO-1 activation, and reflects the state of immune activation or tolerance in cancer immunity, autoimmunity, infection and other disorders. Changes in Kyn:Trp ratio have been associated with viral infections, such as HIV and HIV-human herpes virus co-infection [ 14 ], seasonal influenza [ 15 ], Dengue virus [ 16 ], and HBV [ 17 ].…”