Abstract
HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co-infection. CD4+ T-cell subsets producing interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4+ IFN-γ and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-γ-secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection.
Highlights
HIV co-infection is the greatest risk factor for progression of latent tuberculosis infection (LTBI) to active tuberculosis (TB) [1] and is associated with increased risk of de novo infection and reinfection [2]
We previously showed that HIV infection was associated with a reduced frequency of Mycobacterium tuberculosis (MTB)-specific IFN-γ and IL-2 dual-secreting CD4+ cells in patients with LTBI, most of whom had normal or near normal CD4 counts due to immune restoration with HAART [24]
Our data accords with mounting evidence that MTB-specific T-cells secreting IL-2 with or without IFN-γ have a protective role to play in immune containment and suggests that the dual-secreting cells may be of greatest significance in this capacity
Summary
HIV co-infection is the greatest risk factor for progression of latent tuberculosis infection (LTBI) to active tuberculosis (TB) [1] and is associated with increased risk of de novo infection and reinfection [2]. Data from SIV or HIV-TB co-infection indicate an increase in the risk of disease reactivation prior to the onset of severe immunosuppression [3, 4] This risk is not eliminated with HIV therapy remaining at least twice that of the general population [5]. HIV co-infection impacts the clinical phenotype of TB resulting in reduced cavitation, more severe disease, increased bacillary dissemination and poorer outcomes in terms of morbidity and mortality. This early, specific and lasting effect on MTB-specific immunity makes HIV and LTBI coinfection a good model in which to dissect out defective, protective and dysfunctional MTBspecific immune responses. MTB-specific cell subsets that are preferentially impaired or depleted by HIV infection are candidates for correlation of immune containment and protective immunity
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