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. 2016 Nov 21;11(11):e0166954.
doi: 10.1371/journal.pone.0166954. eCollection 2016.

Immune Activation at Sites of HIV/TB Co-Infection Contributes to the Pathogenesis of HIV-1 Disease

Qinglai Meng  1 , Ismail Sayin  1 , David H Canaday  1   2 , Harriet Mayanja-Kizza  3   1 , Joy Baseke  4 , Zahra Toossi  1   2
Affiliations

Immune Activation at Sites of HIV/TB Co-Infection Contributes to the Pathogenesis of HIV-1 Disease

Qinglai Meng et al. PLoS One. .

Abstract

Systemic immune activation is critical to the pathogenesis of HIV-1 disease, and is accentuated in HIV/TB co-infected patients. The contribution of immune activation at sites of HIV/TB co-infection to viral activity, CD4 T cell count, and productive HIV-1 infection remain unclear. In this study, we measured markers of immune activation both in pleural fluid and plasma, and in T cells in pleural fluid mononuclear cell (PFMC) and peripheral blood mononuclear cell (PBMC) in HIV/TB co-infected subjects. The relationship between soluble and T cell activation markers with viral load in pleural fluid and blood CD4 T cell count were assessed. The T cell phenotype and activation status of HIV-1 p24 + T cells in PFMC and PBMC from HIV/TB patients were determined. We found that T cell and macrophage-specific and non-specific soluble markers of immune activation, sCD27, sCD163, IL1Ra, and sCD14, were higher in pleural fluid as compared to plasma from HIV/TB co-infected subjects, and higher as compared to pleural fluid from TB mono-infected subjects. Intestinal fatty acid-binding protein, a marker of intestinal tract damage, in plasma from HIV/TB co-infected patients was not different than that in HIV+ subjects. Expression of HLADR and CD38 double positive (HLADR/CD38) on CD4 T cells, and CD69+ on CD8 T cells correlated with pleural fluid viral load, and inversely with blood CD4 T cell count. Higher expression of HLADR/CD38 and CCR5 on CD4 T cells, and HLADR/CD38 and CD69 on CD8 T cells in PFMC were limited to effector memory populations. HIV-1 p24+ CD8 negative (includes CD4 + and double negative T cells) effector memory T cells in PFMC had higher expression of HLADR/CD38, Ki67, and CCR5 compared to HIV-1 p24- CD8 negative PFMC. Cumulatively, these data indicate that sites of HIV/TB co-infection are the source of intense immune activation.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Soluble Markers of immune activation at sites of HIV/TB co-infection.
Plasma (PL) and Pleural fluid (PF) from HIV/TB co-infected subjects were assessed for soluble activation markers and compared to PL from HIV-1 infected and PF from TB mono-infected subjects. (A) sCD14 levels in PL and PF, (B) sCD14 correlation between PF and PL, (C) sCD163 and (D) sCD27 levels in PL and PF. **, p < 0.01 and ***, p < 0.001
Fig 2
Fig 2. IFABP in HIV/TB subjects with pleural TB.
IFABP levels were measured in pleural fluid (PF) and plasma (PL) from HIV/TB co-infected patients, and in PL from CD4-matched HIV-1 infected (HIV) and HIV-1 un-infected healthy (HC) subjects.
Fig 3
Fig 3. Expression of markers of immune activation and proliferation on CD4 and CD8 T cells at sites of HIV/TB, and association with HIV viral load in pleural fluid and CD4 T cell counts.
Markers of immune activation and proliferation were assessed on PFMC T cells as compared to PBMC from HIV/TB co-infected subjects, and between PFMC from HIV/TB and TB mono-infected subjects. Analysis of CD4+ (A) and CD8+ (B)T cells are shown. Association of HLADR/CD38 on PFMC CD4 (C and E) and CD69 on PFMC CD8 (D and F) T cells with HIV viral load in pleural fluid (PF) (C and D) and blood CD4 T cell count (E and F). *, p< 0.05; **, p< 0.01 and ***, p< 0.001.
Fig 4
Fig 4. Expression of markers of immune activation on central and effector memory CD4 and CD8 T cells in PFMC.
Expression of activation markers (HLADR/CD38, CCR5, CD69) was assessed on central memory (Tcm) (A and C) and effector memory (Tem) (B and D) for CD4 (A and B) and CD8 (C and D) in PBMC and PFMC T cells from HIV/TB co-infected subjects. **, p < 0.01 and ***, p < 0.001
Fig 5
Fig 5. Activation and differentiation state of PFMC T cells with productive HIV-1infection.
T cells were gated by expression of intracellular HIV-1 p24 and differentiation and activation markers (CD45RO, CCR7, HLADR, CD38), proliferation marker (Ki67) and CCR5. (A) A representative analysis of PFMC p24+ (lower panel) and p24- (upper panel) CD8- T cells is shown. (B): Comparative analysis of frequency of naïve, central memory (TCM), effector memory (TEM) and terminally differentiated (TEMRA) HIV-1 p24 positive and negative CD8- T cells. (C): Analysis of HLADR/CD38, Ki67 and CCR5 on HIV-1 p24 positive (black bar) and negative CD8- T cells (white bar) (n = 8) are shown. Association of HIV-1 p24 +CD8—T cells with viral load in pleural fluid (D) and HLADR+/CD38+ dual positive CD4 T cells (E). *, p<0.05, **, p<0.01 and ***, p<0.001.
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