Background
People with HIV (PWH) have impaired Mycobacterium tuberculosis (Mtb)-specific T cell responses, making induction of effective immunity challenging. Whether TB preventive therapy (TPT) modifies Mtb-specific T cell profile in PWH is unknown. We interrogated Mtb antigen-specific T cell responses in PWH with latent TB infection (LTBI) pre- and post-TPT within the ACTG A5279 clinical trial, a phase III trial of PWH comparing 4 weeks of daily isoniazid/rifapentine (INH/RPT) to 9 months of daily INH.
Methods
Cryopreserved PBMCs were obtained pre-TPT (week 0) and post-TPT (week 48) from A5279 participants with LTBI (TST+ or IGRA+) on stable antiretroviral therapy, HIV viral load <200 copies/mL, and CD4 count >100 cells/mm3 at study entry. PBMCs were thawed and stimulated overnight with CMV pp65 peptide pool, Mtb ESAT-6/CFP-10 peptide pool, and whole cell Mtb lysate (WCTBL). Cells incubated in media alone served as a negative control. PBMCs were stained for markers of T cell lineage (CD3, CD4, CD8), activation, and differentiation (PD1, CD45RA, HLA-DR, Ki-67, TIM3, CD38, CD153, CD95). Intracellular cytokine staining for TNF-α, IFN-γ, and IL-2 was performed to assess function. Samples were then analyzed via flow cytometry. Primary analyses investigated changes (Δ) in Mtb-specific T cell phenotype and cytokine responses from pre-TPT to post-TPT. We also explored these changes by TPT treatment arms.
Results
Samples in 27 participants from 4 countries were included. Overall, Mtb-specific CD4 and CD8 T cell phenotype, differentiation, and functional attributes were similar pre- and post-TPT. The frequency of WCTBL-specific TNF-α+ CD8 T cells increased post-TPT, compared with pre-TPT (n=27, median Δ +0.17%, p=.006). Compared to pre-TPT, the percentage of activated (CD38–HLA-DR+) WCTBL- and ESAT-6/CFP-10-specific CD8 T cells decreased post-TPT (n=16, Δ -3.8%, p=.044; n=9; Δ -8.1%, p=.039, respectively). The percentage of CD153+ ESAT-6/CFP-10-specific CD8 T cells also decreased post-TPT (n=9, Δ -5.9%, p=.012). Pre- and post-TPT comparisons between INH/RPT and INH treatment arms showed no consistent differences.
Conclusions
TPT had little effect on Mtb-specific CD4 and CD8 T cell phenotypic and functional profiles, although modest changes were observed in CD8 T cell activation and TNF-α production post-TPT. Our results suggest that TPT does not substantially modify TB-specific T cell responses in PWH and LTBI, thus supporting a need for novel TB vaccine strategies to boost TB immunity regardless of TPT.