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Discrepancy between Mtb-specific IFN-γ and IgG responses in HIV-positive people with low CD4 counts

Background Tuberculosis (TB) is a leading infectious cause of death worldwide and treating latent TB infection (LTBI) with TB preventative therapy is a global priority. This study aimed to measure interferon gamma (IFN-γ) release assay (IGRA) positivity (the current reference standard for LTBI diagnosis) and Mtb-specific IgG antibodies in otherwise healthy HIV-negative and HIV-positive adults. Methods One-hundred and eighteen adults (65 HIV-negative and 53 antiretroviral-naïve HIV-positive), from a peri-urban setting in KwaZulu-Natal, South Africa were enrolled. IFN-γ release following stimulation with ESAT-6/CFP-10 peptides and plasma IgG antibodies specific for multiple Mtb antigens were measured using the QuantiFERON-TB Gold Plus (QFT) and customized Luminex assays, respectively. The relationships between QFT status and anti-Mtb IgG levels and HIV-status, sex, age and CD4 count were analyzed. Findings Older age, male sex and higher CD4 count were independently associated with QFT positivity (p = 0.045, 0.05 and 0.002 respectively). There was no difference in QFT status between HIV-positive and HIV-negative groups (58% and 65% respectively, p = 0.06), but within CD4 count quartiles, people with HIV had higher QFT positivity than people without HIV (p = 0.008 (2nd quartile), <0.0001 (3rd quartile)). Mtb-specific IFN-γ levels were lowest, and Mtb-specific IgGs were highest in HIV-positive individuals with the lowest CD4 counts. Interpretation These results suggest that the QFT assay underestimates LTBI among immunosuppressed people with HIV and Mtb-specific IgG may be a useful alternative biomarker for Mtb infection. Further evaluation of how Mtb-specific antibodies can be leveraged to improve LTBI diagnosis is warranted, particularly in HIV-endemic areas. Funding The study was funded by the NIH/NIAID [K08AI118538] (EBW) and, in part, by the Africa Health Research Institute through the Wellcome [Strategic Core award: 201433/Z/16/A]. The study was also supported in part by the Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council with funds received from the South African Department of Science and Innovation as part of a bilateral research collaboration agreement with the Government of India. Other support came from the South African Research Chairs Initiative and the Victor Daitz Foundation (TN) and the Burroughs Wellcome Fund Investigators in Pathogenesis of Infectious Disease [1022002] (EBW). This research was also funded in part by the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) through a grant [DEL-15-006] by the Wellcome Trust and the UK Foreign, Commonwealth & Development Office, with support from the Developing Excellence in Leadership, Training and Science in Africa (DELTAS Africa) programme (TN, MM). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Copyrights © 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/) Research in context Evidence before this study Mtb-specific IFN-γ production as measured by IGRA is the current gold standard for determining latent TB infection. However, since these tests measure immunoreactivity to Mtb peptides, they are indirect measures of Mtb infection and their performance characteristics are impacted by co-infections and comorbidities that influence immune responses, including HIV. Recently, a human phenotype has been defined in people who are highly exposed to Mtb but consistently test negative for evidence of Mtb infection by IGRA and tuberculin skin test (TST). These individuals have been observed to have a unique profile of Mtb-specific antibodies when compared to the classical IGRA positive LTBI group, suggesting that Mtb-specific antibodies may identify additional people with a history of Mtb infection or exposure when compared to IGRA alone. Comparison of IGRA and Mtb-specific antibodies in people living with HIV has not previously been performed. Added value of this study Here, we concurrently assessed Mtb-specific IFN-γ production and IgG in a cohort of 118 well-defined HIV-negative and antiretroviral naïve HIV-positive individuals from KwaZulu-Natal, South Africa, a highly TB endemic area. We found a discrepancy between Mtb-specific IFN-γ and Mtb-specific IgG levels, particularly in HIV-positive individuals with low CD4 cell counts. Notably people with the lowest CD4 counts had the highest levels of Mtb-specific IgG levels in the plasma, and the lowest levels of QTF positivity. Implications of all evidence available IGRAs may underestimate Mtb infection status, especially in people with HIV infection or who have T cell depletion or dysfunction. Mtb-specific IgG antibodies indicate development of a B cell response to Mtb and may have promise as an alternative biomarker of TB immunoreactivity that does not depend on T cell function.