Antiretroviral Treatment-Induced Decrease in Immune Activation Contributes to Reduced Susceptibility to Tuberculosis in HIV-1/Mtb Co-infected Persons

Abstract

Antiretroviral treatment (ART) reduces the risk of developing active tuberculosis (TB) in HIV-1 co-infected persons. In order to understand host immune responses during ART in the context of Mycobacterium tuberculosis (Mtb) sensitization, we performed RNAseq analysis of whole blood-derived RNA from individuals with latent TB infection coinfected with HIV-1, during the first 6 months of ART. A significant fall in RNA sequence abundance of the Hallmark IFN-alpha, IFN-gamma, IL-6/JAK/STAT3 signaling, and inflammatory response pathway genes indicated reduced immune activation and inflammation at 6 months of ART compared to day 0. Further exploratory evaluation of 65 soluble analytes in plasma confirmed the significant decrease of inflammatory markers after 6 months of ART. Next, we evaluated 30 soluble analytes in QuantiFERON Gold in-tube (QFT) samples from the Ag stimulated and Nil tubes, during the first 6 months of ART in 30 patients. There was a significant decrease in IL-1alpha and IL-1beta (Ag-Nil) concentrations as well as MCP-1 (Nil), supporting decreased immune activation and inflammation. At the same time, IP-10 (Ag-nil) concentrations significantly increased, together with chemokine receptor-expressing CD4 T cell numbers. Our data indicate that ART-induced decrease in immune activation combined with improved antigen responsiveness may contribute to reduced susceptibility to tuberculosis in HIV-1/Mtb co-infected persons.

Host Immunity toMycobacterium tuberculosisInfection is Similar in Simian Immunodeficiency Virus (SIV)-infected, Antiretroviral Therapy-treated and SIV-naïve Juvenile Macaques

“…One limitation of our study was that we did not have an ART-naïve group of SIV-infected juveniles with which to directly compare the effect of ART on TB pathogenesis in SIV-infected juvenile macaques. There is ample evidence in humans (69, 70, 78) that supports our hypothesis that ART may have restored anti-Mtb immunity and control of TB in SIV-infected juvenile macaques. ART previously was shown to reduce the risk of SIV-induced reactivation of latent TB infection (LTBI) in adult macaques (71), and ART may be an important tool to reduce TB reactivation in HIV+ people with LTBI (84).…”

“…One limitation of our study was that we did not have an ART-naïve group of SIV-infected juveniles with which to directly compare the effect of ART on TB pathogenesis in SIV-infected juvenile macaques. There is ample evidence in humans (69,70,78) that supports our hypothesis that ART may have restored anti-Mtb immunity and control of TB in SIV-infected juvenile macaques.…”

“…Interestingly, in this study, there was no difference between the two groups of juvenile macaques in PD-1 or TIGIT expression on CD4+ and CD8+ T cells from either airways (Figure S1) or granulomas (Figure 10), aside from the decline in PD-1+ CD4+ T cells in airways following Mtb infection. Signaling pathways associated with inflammation and immune activation have been shown to decline during the first 6 months of ART in whole blood from HIV-1/Mtb coinfected individuals (78). Similarly, our data suggest that ART may have alleviated the chronic immune activation associated with uncontrolled viral replication.…”

The role of IL‐1β during human immunodeficiency virus type 1 infection

“…reported that the inflammatory cytokines IL‐1β, IL‐6, TNF‐α were elevated in the serum of HIV‐1 patients and there was a positive correlation between the level of these cytokines and the levels of viral RNA 186 . Although ART seems to be able to significantly decrease the serum levels of such cytokines in HIV‐1 patients, their levels are still significantly higher than the normal uninfected controls 186,187 . In line with these results, a recent study conducted by Masyuko et al., who enroled 286 HIV‐1 positive Kenyan adults with suppressive ART for several years, reported that HIV‐1 patients express higher serum levels of the inflammatory cytokines IL‐1β, IL‐6, TNF‐α than the uninfected controls, even when the virus is fully suppressed 188 .…”

“…186 Although ART seems to be able to significantly decrease the serum levels of such cytokines in HIV-1 patients, their levels are still significantly higher than the normal uninfected controls. 186,187 In line with these results, a recent study conducted by Masyuko et al, who enroled 286 HIV-1 positive Kenyan adults with suppressive ART for several years, reported that HIV-1 patients express higher serum levels of the inflammatory cytokines IL-1β, IL-6, TNF-α than the uninfected controls, even when the virus is fully suppressed. 188 On the contrary, other studies showed that treatment with ART has no effect on decreasing the expression of several proinflammatory cytokines including IL-1β.…”