Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Abstract

The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

Regulation of Gut Microbiota on Immune Reconstitution in Patients With Acquired Immunodeficiency Syndrome

“…Among the factors affecting immune reconstitution, changes in the gut microbiota are one of the key factors (Yang et al, 2020). Dysregulation of the gut microbiome has been associated with the recovery of CD4 + T cells (Lu et al, 2018), which is the main determinant of immune reconstitution after cART (Kaufmann et al, 2005;Brenchley et al, 2006b;Marchetti et al, 2008;Lu et al, 2018).…”

“…Immune non-responders show severe immune dysfunction, and the influencing factors include bone marrow hematopoietic progenitor cell reduction, thymus dysfunction, abnormal immune activation, immune failure, imbalance of immune regulatory cells, such as regulatory T cells (Tregs) and Th17 cells, and continuous replication of the virus in reservoirs (Yang et al, 2020). Considering the close relationship between the gut microbiota and the immune system, gut microbiota dysbiosis may mediate immune dysfunction of INRs, thus affecting immune reconstitution (Figure 1).…”

Factors Associated with the Effectiveness of National Free Antiretroviral Treatment Program in HIV Infected Patients of Yi Nationality from Southwest China: Evidence from A Cohort Study to Provide Clues for Improvement

“…Generally, immune recovery is measured as absolute CD4+ count or the absolute or percentage increase of CD4+ count with suppressed viral replication after certain period of ART (39). The cutoff values of CD4+ count for optimal and suboptimal immune recovery are 200, 250, 350, 400 and 500 cells/μL and the duration of ART varies from 1 to 12 years across studies.…”

High circulating SDF-1and MCP-1 levels and genetic variations in CXCL12, CCL2 and CCR5: Prognostic signature of immune recovery status in treated HIV-positive patients

“…[1] However, approximately 30% of people living with HIV (PLW) with optimal treatment and fully suppressed viral replication fail to recover their CD4 + T-cell counts. [2,3] These patients are referred to as "immunodiscordants" or "immunological nonresponders" (INRs), and are linked to an increased risk of disease progression and death compared with PLW who achieve complete immune reconstitution. [4,5] The CD4 + T-cell count is the result of the production, destruction, and trafficking between secondary lymphoid organs and peripheral tissues of CD4 + T-cells, [2,6] and INRs may have both excessive destruction and alterations in the production of CD4 + T-cells, resulting in an increase in cycling and proliferation before cART.…”

“…[2,3] These patients are referred to as "immunodiscordants" or "immunological nonresponders" (INRs), and are linked to an increased risk of disease progression and death compared with PLW who achieve complete immune reconstitution. [4,5] The CD4 + T-cell count is the result of the production, destruction, and trafficking between secondary lymphoid organs and peripheral tissues of CD4 + T-cells, [2,6] and INRs may have both excessive destruction and alterations in the production of CD4 + T-cells, resulting in an increase in cycling and proliferation before cART. [7] Although the underlying mechanisms of incomplete immune reconstitution are very complex and may be multifactorial, perturbation of chemokine secretion could play a key role in CD4 + T-cell turnover, [8À10] and chemokine modulation has been proposed as a promising therapeutic strategy to improve immune reconstitution.…”