Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients

Abstract

Active TB in HIV-1-infected subjects is associated with increased HIV-1-related immunodeficiency and mortality. We assessed plasma viral load in HIV-1-infected patients with pulmonary TB (HIV/TB) and non-TB symptomatic HIV-1-infected patients (HIV). HIV-1 load was higher in HIV/TB compared with HIV at higher CD4 counts (> 500/microl) (P < 0.01), but not at lower CD4 counts (< 500/microl). We also evaluated the status of HIV-1 gene expression in peripheral blood mononuclear cells (PBMC) and serum from HIV/TB and CD4-matched healthy HIV-infected patients (HIV/C) by reverse transcriptase-polymerase chain reaction over a range of CD4 (> 900/microl to < 200/microl). HIV-1 RNA in serum and PBMC correlated to one another, and both were markedly higher in HIV/TB compared with HIV/C with higher CD4 counts. Also, during a longitudinal study of anti-tuberculous chemoprophylaxis in HIV-1-infected patients, 10 subjects who developed TB had serologies before, at the time, and after the diagnosis of TB. These HIV/TB patients had an increase in viral load (average 2.5-fold) at the time of diagnosis of TB (P < 0.05). Overall, these data indicate that the transcriptional activity of HIV-1 is enhanced in HIV-1-infected patients with active TB, especially during early HIV-1 disease. As TB often is an early HIV-1 opportunistic infection, it may particularly favour early viral replication and dissemination, and therefore contribute to progression of HIV-1 disease.

Fig. 1

Viral loads in HIV/TB and HIV. HIV-1 load was assessed in plasma obtained from HIV/TB and symptomatic, non-TB patients (HIV). (a) Viral load is plotted against CD4 counts in HIV/TB (•, n = 43) and HIV (○, n = 31). (b) Mean viral load is compared between HIV/TB (▪) and HIV (□), in three separate CD4 categories: > 500/μl (n = 16 and 7 for HIV/TB and HIV, respectively), 200–500/μl (n = 17 and 12 for HIV/TB and HIV, respectively), and <200/μl (n = 10 and 12 for HIV/TB and HIV, respectively). *P < 0·01 between HIV/TB and HIV.

Fig. 2

HIV-1 RNA in peripheral blood mononuclear cells (PBMC) and serum of HIV/TB and HIV/C. HIV-1 RNA was assessed in three pairs of HIV/TB and HIV/C representing different CD4 categories (shown on left). (a) Duplicate PBMC samples were assessed (by reverse transcriptase-polymerase chain reaction) for HIV-1 unspliced (gag/pol) and multiple spliced (tat/rev) mRNA, and for expression of the housekeeping gene, β-actin. (b) Sera from the same patients were assessed for HIV-1 load.

Fig. 3

Cytokine gene expression in peripheral blood mononuclear cells (PBMC) of HIV/TB and HIV/C. RNA (1 μg) from PBMC of HIV/TB (n = 5) and HIV/C (n = 4) were assessed for expression of cytokines (tumour necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF0, and IL-2) genes by reverse transcriptase-polymerase chain reaction. An aliquot of RNA was also assessed for expression of the housekeeping gene, GAPDH, to assure equal processing between samples.

Fig. 4

Serial HIV-1 RNA in the serum of HIV-1-infected patients with baseline viral loads <50 000 who developed TB. On the abscissa the time points when blood was drawn from the patient and the date when the patient was diagnosed with TB (TB) are identified. TB* are those subjects who subsequently died.