Discrepancy betweenMtb-specific IFN-γ and IgG responses in HIV-positive people with low CD4 counts
Authors: Mthembu Maphe , Bowman Kathryn A , Davies Leela RL , Khuzwayo Sharon , Mazibuko Lusanda , Bassett Thierry , Ramjit Dirhona , Mhlane Zoey , Karim Farina , Alter Galit , Ndung’u Thumbi , Wong Emily B 
Published: October 2022

SummaryBackgroundTuberculosis (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) andMtb-specific IgG antibodies in otherwise healthy HIV-negative and HIV-positive adults.MethodsOne-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 multipleMtbantigens were measured using the QuantiFERON-TB Gold Plus (QFT) and customized Luminex assays, respectively. The relationships between QFT status and anti-MtbIgG levels and HIV-status, sex, age and CD4 count were analyzed.FindingsOlder 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 (2ndquartile), <0.0001 (3rdquartile)).Mtb-specific IFN-γ levels were lowest, andMtb-specific IgGs were highest in HIV-positive individuals with the lowest CD4 counts.InterpretationThese results suggest that the QFT assay underestimates LTBI among immunosuppressed people with HIV andMtb-specific IgG may be a useful alternative biomarker forMtbinfection. Further evaluation of howMtb-specific antibodies can be leveraged to improve LTBI diagnosis is warranted, particularly in HIV-endemic areas.FundingThe 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 contextEvidence before this studyMtb-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 ofMtbinfection 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 toMtbbut consistently test negative for evidence ofMtbinfection by IGRA and tuberculin skin test (TST). These individuals have been observed to have a unique profile ofMtb-specific antibodies when compared to the classical IGRA positive LTBI group, suggesting thatMtb-specific antibodies may identify additional people with a history ofMtbinfection 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 studyHere, we concurrently assessedMtb-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 betweenMtb-specific IFN-γ andMtb-specific IgG levels, particularly in HIV-positive individuals with low CD4 cell counts. Notably people with the lowest CD4 counts had the highest levels ofMtb-specific IgG levels in the plasma, and the lowest levels of QTF positivity.Implications of all evidence availableIGRAs may underestimateMtbinfection 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 toMtband may have promise as an alternative biomarker of TB immunoreactivity that does not depend on T cell function.