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

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/mm 3 . 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 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. Funding Funding provided by National Institutes of Health [1R01AI124349-01]. Research in Context section Evidence before this study The majority of individuals who are exposed to Mycobacterium tuberculosis (Mtb) appear to have natural immunity against developing tuberculosis (TB). A subset of these individuals may clear or control Mtb without developing a classical T-cell immune response as measured by a tuberculin skin test (TST) or IGRA. While the gold standard for TB diagnosis is culturing Mtb from a specimen, there is no direct test to prove current Mtb infection. Hence, infection needs to be inferred from tests that measure Mtb T-cell immunoreactivity. Once Mtb is inhaled, pulmonary innate immune cells, so-called alveolar macrophages, are the first to make contact with the bacilli. Mtb -infected alveolar macrophages traverse from the alveoli to the lung interstitium where Mtb is transferred to inflammatory macrophages that present the bacilli to T-cells and initiate the adaptive immune response, including the generation of memory T-cells. The current Mtb T-cell immunoreactivity tests indicate infection if positive. A major caveat with these tests is an inability to distinguish between a current infection or a persistent immune response after a previous infection that was cleared. In addition it is important to clarify that persisting negative immunoreactivity does not simply imply that individuals are not infected. They could have had previous immunoreactivity which has reverted, could not have been exposed to Mtb or they were exposed but cleared Mtb without a classical IFN-γ T-cell immunoreactive response. The latter is a novel concept and previous studies in HIV-negative subjects have focused on this resistance to ‘infection’- or to be more precise failure of IFN-γ T-cell and TST immune conversion to Mtb . However, these studies found Mtb -specific antibodies in their HIV-negative ‘resister’ subjects. The presence of especially IgG antibodies confirmed and indicated long term exposure to Mtb and pointed to current or cleared infection. T-cell responses are required for antigen-specific B-cells to release class-switched IgG. Since these individuals test persistently negative for TST and IFN-γ T-cell immunoreactivity, innate and alternative adaptive IFN-γ independent T-cell responses should be investigated. This is a developing field and as research emerges, it is increasingly important to clearly characterize and define the TB resistance phenotype. Added value of this study HIV-positive (HIV+) persons are at increased risk of infection with Mtb and rapid progression to tuberculosis making the phenotype we describe here especially important in this population segment. However, there is a major lack of data in HIV+ persons describing persisting lack of response to TST and Mtb IFN-γ T-cell immune conversion. Here we show that this phenotype can be identified in immune-reconstituted HIV+ persons. We describe the recruitment and define this conversion resistance phenotype as HIV-1-positive persistently TB, tuberculin and IGRA negative (HITTIN). The presence of specific antibodies confirms exposure to Mtb . Our study suggests possible innate mechanisms and non-classical adaptive mechanisms that subvert early stages of tuberculosis pathogenesis in a substantial proportion of HIV-infected patients. Harnessing such TST and IFN-γ T- cell independent mechanisms of resistance is of particular interest for prevention of tuberculosis in the HIV+ population. Implications of all the available evidence Understanding the mechanisms of resistance will enable us to develop TB prevention and treatment modalities.

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