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

Abstract

<jats:p>Background: Mycobacterium tuberculosis (Mtb) infection is inferred from positive results of T-cell immune conversion assays measuring Mtb-specific interferon gamma production (IGRA) or tuberculin skin test (TST) reactivity. Certain exposed individuals, termed resisters or early clearers, do not display T-cell immune conversion in these assays. Here we report a hitherto unknown extreme form of this phenotype: HIV-1-infected persistently TB, tuberculin and IGRA negative (HITTIN). Methods: A community-based case-control design was used to systematically screen and identify HIV-1-infected persons (aged 35-60 years) who met stringent study criteria, and follow 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&lt;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-infected persons can be persistently non-immunoreactive to Mtb, yet develop species-specific antibody responses. Exposure is evidenced by Mtb-specific antibody titers. Identifying individuals displaying such extreme resistance to T-cell immune conversion indicates the importance of early events of TB pathophysiology in the context of HIV-infection that so far have received only scant attention. Funding: Funding provided by National Institutes of Health [1R01AI124349-01].</jats:p>

Alveolar macrophages from persons living with HIV show impaired epigenetic response to Mycobacterium tuberculosis

“…One critical difference between the mouse model and humans is the ability of a subgroup of Mtb-exposed persons to avoid the development of classical T-cell immunity and TB disease even in the presence of long lasting Mtb exposure (9). Recently, the phenotype of strong resistance to immune conversion of persons living in high Mtb exposure settings has been confirmed for HIVinfected but immune-reconstituted people (21). While the underlying mechanisms that preclude the development of classical T cell immunity are unknown, initial results implicate both nonclassical T cells and B cells (21,22).…”

“…Recently, the phenotype of strong resistance to immune conversion of persons living in high Mtb exposure settings has been confirmed for HIVinfected but immune-reconstituted people (21). While the underlying mechanisms that preclude the development of classical T cell immunity are unknown, initial results implicate both nonclassical T cells and B cells (21,22). How and where AM interact with these cells of the acquired immunity arm is not known.…”

Shedding of Mycobacterium bovis in respiratory secretions of free‐ranging wild dogs ( Lycaon pictus ): Implications for intraspecies transmission

“…The finding of the positive BAL and negative IGRA (wild dog 1) results could possibly suggest early infection, or recent inhalation of mycobacteria without infection; however, when opportunistically sampled 14 months after the positive BAL culture, this individual had a positive IGRA result, suggesting that this animal may have been infected at the time of the BAL sample and later developed immune sensitization. Studies have shown that Mycobacterium tuberculosis complex (MTBC) infection in other species (including humans) does not result in a positive IGRA result for all infected individuals (van der Heijden et al., 2020; Kroon et al., 2020; Nguyen et al., 2018). Negative immunoreactivity can either be indicative of a truly uninfected animal; an M. bovis infected animal in which a detectable immune response has not developed at the time of sampling (i.e.…”

BCG‐induced protection against Mycobacterium tuberculosis infection: Evidence, mechanisms, and implications for next‐generation vaccines

“…Interestingly, three out of seven subjects that produced these protective antibodies were IGRA negative. Another study from South Africa in HIV‐infected patients with no TB, and persistently negative TST/IGRA despite living in an area of TB hyperendemicity showed the presence of antibodies specific for Mtb 90 …”

“…Another study from South Africa in HIV-infected patients with no TB, and persistently negative TST/IGRA despite living in an area of TB hyperendemicity showed the presence of antibodies specific for Mtb. 90 There are several potential mechanisms of antibody-mediated resistance against Mtb in the context of early clearance. Antibody could bind to Mtb bacteria to prevent entry into cells, drive antibodydependent cellular phagocytosis to increase bacterial killing, mediate antibody-dependent cellular cytotoxicity to kill infected cells, or mediate the recruitment of innate immune cells that express the Fc receptor.…”