An observational study identifying highly tuberculosis-exposed, HIV-1-positive but persistently TB, tuberculin and IGRA negative persons with M. tuberculosis specific antibodies in Cape Town, South Africa

Elouise E Kroon; Craig J Kinnear; Marianna Orlova; Stephanie Fischinger; Sally Shin; Sihaam Boolay; Gerhard Walzl; Ashley Jacobs; Robert J Wilkinson; Galit Alter; Erwin Schurr; Eileen G Hoal; Marlo Möller

doi:10.1016/j.ebiom.2020.103053

An observational study identifying highly tuberculosis-exposed, HIV-1-positive but persistently TB, tuberculin and IGRA negative persons with M. tuberculosis specific antibodies in Cape Town, South Africa

EBioMedicine. 2020 Nov:61:103053. doi: 10.1016/j.ebiom.2020.103053. Epub 2020 Oct 7.

Authors

Affiliations

¹ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
² Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, 1001 boul Décarie, Site Glen Block E, Room EM3.3210, Montréal, QC H4A3J1, Canada; McGill International TB Centre, McGill University, Montréal, QC, Canada; Departments of Medicine and Human Genetics, McGill University, Montréal, QC, Canada.
³ Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA; University of Duisburg-Essen, Institute for HIV research, Essen, Germany.
⁴ Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA.
⁵ Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.
⁶ Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa; Department of Infectious Diseases, Imperial College London, W12 ONN, United Kingdom; The Francis Crick Institute, London, NW1 1AT, United Kingdom.
⁷ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: marlom@sun.ac.za.

Abstract

Background: Mycobacterium tuberculosis (Mtb) infection is inferred from positive results of T-cell immune conversion assays measuring Mtb-specific interferon gamma production or tuberculin skin test (TST) reactivity. Certain exposed individuals do not display T-cell immune conversion in these assays and do not develop TB. Here we report a hitherto unknown form of this phenotype: HIV-1-positive persistently TB, tuberculin and IGRA negative (HITTIN).

Methods: A community-based case-control design was used to systematically screen and identify adults living with HIV (HIV+), aged 35-60 years, who met stringent study criteria, and then longitudinally followed up for repeat IGRA and TST testing. Participants had no history of TB despite living in TB hyper-endemic environments in Cape Town, South Africa with a provincial incidence of 681/100,000. Mtb-specific antibodies were measured using ELISA and Luminex.

Findings: We identified 48/286 (17%) individuals who tested persistently negative for Mtb-specific T-cell immunoreactivity (three negative Quantiferon results and one TST = 0mm) over 206±154 days on average. Of these, 97·2% had documented CD4 counts<200 prior to antiretroviral therapy (ART). They had received ART for 7·0±3·0 years with a latest CD4 count of 505·8±191·4 cells/mm³. All HITTIN sent for further antibody testing (n=38) displayed Mtb-specific antibody titres.

Interpretation: Immune reconstituted HIV+ persons can be persistently non-immunoreactive to TST and interferon-γ T-cell responses to Mtb, yet develop species-specific antibody responses. Exposure is evidenced by Mtb-specific antibody titres. Our identification of HIV+ individuals displaying a persisting lack of response to TST and IGRA T-cell immune conversion paves the way for future studies to investigate this phenotype in the context of HIV-infection that so far have received only scant attention.

Keywords: Antibodies; Early clearance; Interferon gamma release assay; Resister; Tuberculin skin test.

MeSH terms

Adult
Antibodies, Bacterial / immunology*
Coinfection / epidemiology
Enzyme-Linked Immunosorbent Assay
Female
HIV Infections / epidemiology*
HIV Infections / immunology*
HIV Infections / virology
HIV-1 / immunology*
Humans
Immunoglobulin G / blood
Immunoglobulin G / immunology
Interferon-gamma / biosynthesis
Interferon-gamma Release Tests
Male
Middle Aged
Mycobacterium tuberculosis / immunology*
Public Health Surveillance
South Africa / epidemiology
Tuberculin Test / methods
Tuberculosis / diagnosis
Tuberculosis / epidemiology*
Tuberculosis / immunology*
Tuberculosis / microbiology

Substances

Antibodies, Bacterial
Immunoglobulin G
Interferon-gamma

Abstract

MeSH terms

Substances

Grants and funding