Scientists identify rare, paradoxical response to ART

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Antiretroviral therapy (ART) is usually very effective at suppressing HIV in the body, allowing a person’s immune system to recover by preventing the virus from destroying CD4+ T cells. Scientists have now identified a rare, paradoxical response to ART known as extreme immune decline (EXID). Five individuals evaluated at the National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health, experienced a significant decline in CD4+ T cell levels despite suppression of HIV below detectable levels for more than three years, according to a study. The research team was led by Dr Irini Sereti, chief of the HIV pathogenesis section in NIAID’s Laboratory of Immunoregulation, and Dr Andrea Lisco.

The NIAID researchers found that the immune systems of people with EXID fared even worse than those of another subset of individuals defined as immunological-non-responders, or INRs, who respond inadequately to ART. INR participants consistently taking ART for four years had CD4+ T cell counts that increased on average by 193 cells per microliter (?L) of blood. Participants who responded normally to ART increased their CD4+ T cell count by more than twice that amount. In contrast, the five participants with EXID experienced an average decline of 157 CD4+ T cells/?L while consistently maintaining viral suppression on ART.

According to the NIAID team, there seems to be no single cause of EXID among the five individuals studied. Their analyses revealed that genes influencing immune cell activity and autoimmunity – the immune system attacking a body’s own healthy tissue – may play a role. Specifically, two of the individuals with EXID produced antibodies that attacked their own T cells, while two others had overactive cellular immune responses that lead to increased inflammation.

All five participants with EXID had HIV strains other than clade B HIV (the most common strain circulating in North America and Europe), indicating that certain combinations of an individual’s genes and the HIV strain may be associated with EXID.

While EXID is likely an extremely rare response to ART, the researchers indicate that studying this phenomenon may further illuminate CD4+ T cell reconstitution and inflammation in HIV disease and suggest possible treatment strategies for INRs and individuals with EXID.

Abstract
Background: The goal of antiretroviral therapy (ART) is to suppress HIV-1 replication and reconstitute CD4+ T cells. Here, we report on HIV-infected individuals who had a paradoxical decline in CD4+ T cells despite ART-mediated suppression of plasma HIV-1 load (pVL). We defined such an immunological outcome as extreme immune decline (EXID).
Methods: EXID’s clinical and immunological characteristics were compared to immunological responders (IRs), immunological nonresponders (INRs), healthy controls (HCs), and idiopathic CD4+ lymphopenia (ICL) patients. T cell immunophenotyping and assembly/activation of inflammasomes were evaluated by flow cytometry. PBMC transcriptome analysis and genetic screening for pathogenic variants were performed. Levels of cytokines/chemokines were measured by electrochemiluminescence. Luciferase immunoprecipitation system and NK-mediated antibody-dependent cellular cytotoxicity (ADCC) assays were used to identify anti-lymphocyte autoantibodies.
Results: EXIDs were infected with non-B HIV-1 subtypes and after 192 weeks of consistent ART-mediated pVL suppression had a median CD4+ decrease of 157 cells/μl, compared with CD4+ increases of 193 cells/μl and 427 cells/μl in INR and IR, respectively. EXID had reduced naive CD4+ T cells, but similar proportions of cycling CD4+ T cells and HLA-DR+CD38+CD8+ T cells compared with IR and INR. Levels of inflammatory cytokines were also similar in EXID and INR, but the IL-7 axis was profoundly perturbed compared with HC, IR, INR, and ICL. Genes involved in T cell and monocyte/macrophage function, autophagy, and cell migration were differentially expressed in EXID. Two of the 5 EXIDs had autoantibodies causing ADCC, while 2 different EXIDs had an increased inflammasome/caspase-1 activation despite consistently ART-suppressed pVL.
Conclusions: EXID is a distinct immunological outcome compared with previously described INR. Anti–CD4+ T cell autoantibodies and aberrant inflammasome/caspase-1 activation despite suppressed HIV-1 viremia are among the mechanisms responsible for EXID.

Authors
Andrea Lisco, Chun-Shu Wong, Silvia Lucena Lage, Itzchak Levy, Jason Brophy, Jeffrey Lennox, Maura Manion, Megan V Anderson, Yolanda Mejia, Christopher Grivas, Harry Mystakelis, Peter D Burbelo, Ainhoa Perez-Diez, Adam Rupert, Craig A Martens, Sarah L Anzick, Caryn Morse, Shanna Chan, Claire Deleage, Irini Sereti

National Institute of Allergy and Infectious Diseases (NIAID) material
JCI Insight abstract


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