Abstract
HIV-1 co-infection is a leading cause of susceptibility to tuberculosis (TB), with the risk of TB being increased at all stages of HIV-1 infection. Antiretroviral treatment (ART) is the most effective way to reduce the risk of TB in HIV-1 co-infected people. Studying protective, ART-induced, immune restoration in HIV-1 infected individuals sensitised by Mycobacterium tuberculosis (Mtb) can thus help identify mechanisms of protection against TB. In order to understand ART-mediated prevention of TB in HIV-1 infected adults, we investigated the expression of 30 genes in whole blood from HIV-1 infected patients during the first 6 months of ART-induced immune reconstitution. The 30 selected genes were previously described to be differentially expressed between sorted Mtb specific central and effector memory CD4 T cells. HIV-1 infected persons sensitised by Mtb were recruited in Khayelitsha, South Africa, when initiating ART. RNA was extracted from whole blood at initiation and 1, 3 and 6 months of ART. qRT-PCR was used to determine gene expression and three reference ‘housekeeping’ genes were used to calculate the fold change in the expression of each gene relative to day 0 of ART. Results were assessed longitudinally. We observed a decrease in the expression of a number of genes at 6 months of ART, reflecting a decrease in immune activation. However, following correction for multiple comparisons and increasing CD4 counts, only the decrease in CD27 gene expression remained statistically significant. While not statistically significant, a number of genes also showed increased expression at various timepoints, illustrating the broad regeneration of the T cell pool in HIV-1 infected adults on ART. Our findings generate hypotheses underlying ART- induced protective immune reconstitution and may pave the way for future studies to evaluate ART mediated prevention of TB in HIV-1 infected persons.
Highlights
Tuberculosis (TB) is the leading bacterial cause of death worldwide [1] and HIV infected persons are 20–30 times more likely to develop TB than HIV uninfected persons, who have a 5–10% chance of developing active TB in their lifetime [2]
The subunit vaccine H1 boosts CD4+KLRG1-IL-2-secreting TCM [5]; the recombinant BCG DeltaureC::hly vaccine mediated protection is based on the expansion of central memory CD4 T cells that are CXCR5+CCR7+ and express low levels of the transcription factors T-bet and Bcl-6 [6] the sustained protection induced by the H56/CAF01 subunit vaccine was mediated by the less differentiated lung parenchyma homing CD4 T cells that express low levels of KLRG1 and secrete high amounts of IL-2 and IL-17A [7]
Blood stored in Tempus tubes for RNA extraction was available from n = 48 HIV infected persons (36 females, 12 males, median age 35 years, IQR 29–38) at all follow up timepoints, all of whom were sensitised by Mycobacterium tuberculosis (Mtb) as determined by interferon gamma release assays Quantiferon Gold Intube (QFT) and Enzyme-Linked ImmunoSpot assay (ELISpot) (Table 1 and Fig 2)
Summary
Tuberculosis (TB) is the leading bacterial cause of death worldwide [1] and HIV infected persons are 20–30 times more likely to develop TB than HIV uninfected persons, who have a 5–10% chance of developing active TB in their lifetime [2]. A previous longitudinal follow-up of 19 HIV infected adults with Mycobacterium tuberculosis (Mtb) sensitisation over 48 weeks of ART showed that the strongest correlate of increased ART mediated immunity was the expansion of the less differentiated central memory CD4 T cell pool [4]. Chiacchio et al found that antiretroviral and anti-tuberculosis therapies significantly increased the frequency of Mtb specific CD4 T cells in HIV-TB co-infected patients with an increase in the central memory compartment [9]. Overall, these findings support the role of central memory CD4 T cells as potential correlates of protection in TB. We evaluated the change in gene expression during the first 6 months of ART and hypothesised that the transcription of central memory T cell associated genes would increase over time in HIV infected persons during the first 6 months of ART
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
