Incomplete functional T-cell reconstitution in immunological non-responders at one year after initiation of antiretroviral therapy possibly predisposes them to infectious diseases

Abstract

Background: Immunological non-responders (INR) represent a unique category of HIV-infected patients on antiretroviral therapy. These patients have suppressed viremia but a suboptimal increase in CD4 cell count, which might have opposing effects on functional immune reconstitution. Hence, the extent of immune reconstitution in INR patients was investigated in order to determine their susceptibility to opportunistic infections. Methods: Twenty-three INR patients (CD4 increase <50 cells/mm 3 , viral load <40 copies/ml), 40 age-, sex-, and baseline CD4 count-matched responders (CD4 increase >100 cells/mm 3 , viral load <40 copies/ml), and 18 treatment failures defined as per the national guidelines were enrolled at 1 year of antiretroviral therapy. The following examinations were performed: haemogram, phenotypic characterization by flow cytometry, and assessment of functional immune status by ELISPOT and intracellular cytokine assays. Results: A higher percentage of INR patients had clinically symptomatic infections than the responders. CD8 + activation and innate immune parameters, including the absolute neutrophil count and natural killer (NK) cell frequency and functionality, were restored in the INR patients. They had significantly higher non-HIV antigen-specific T-cell responses and activated CD4 + cells, but significantly compromised T-cell functionality, as assessed after anti-CD3 stimulation, and lower CD31 + and CD62L + CD4 + cells. Conclusions: INR patients showed lower thymic output, incomplete functional T-cell reconstitution, higher responses to HIV co-pathogens, and higher symptomatic events, indicating the need for close monitoring and intervention strategies to overcome their continuing immunocompromised status.

Possible role of plasma Galectin-9 levels as a surrogate marker of viremia in HIV infected patients on antiretroviral therapy in resource-limited settings

“…Immune activation markers are likely to be influenced by immune status of the patients and may vary depending on the extent of immunosuppression in these patients. Additionally, presence of other co-existing had also shown that patients with immunologic nonresponse were likely to have frequent co-existing infections [20] possibly impacting levels of immune activation markers. Receiver operating characteristic (ROC) curve for Galectin-9 levels.…”

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

“…Increase in the CD4 + T-cell count > 100 cells/µl from baseline at 1 year after ART initiation, with plasma HIV RNA < 40 copies/ml. 47 Total CD4 + T-cell count < 270 cells/µl at 2 years after ART initiation, with an undetectable plasma VL.…”

“…These studies suggest that in the case of lymphopenia, ongoing thymopoies may contribute to immune recovery in adult HIV‐1‐infected individuals. It has been shown that the frequency of CD4 + RTE cells, the numbers of sj‐TRECs and the sj/β‐TREC ratios are markedly lower in INRs than in IRs and healthy individuals, indicating that lower thymic output is the main cause of incomplete immune recovery in these patients . Furthermore, Menkova‐Garnier et al.…”

“…It has been shown that the frequency of CD4 + RTE cells, the numbers of sj-TRECs and the sj/ -TREC ratios are markedly lower in INRs than in IRs and healthy individuals, indicating that lower thymic output is the main cause of incomplete immune recovery in these patients. 37,[47][48][49] Furthermore, Menkova-Garnier et al found that the frequency of CD4 + RTEs was positively correlated with the peripheral CD4 + T-cell count. 37 A study by Li et al showed that INRs had a lower naïve CD4 + T-cell increase and a lower percentage of CD4 + RTE than immunological responders and healthy controls, indicating that reduced thymic output may be a major mechanism of incomplete immune reconstitution.…”

Stem cell therapy in coronavirus disease 2019: current evidence and future potential

“…These patients are categorized as non-immune responders (NIR). [58] In a pilot open labeled clinical trial, Zhang et al, administered 7 NIR patients with three doses of umbilical cord-MSCs and 6 NIRs served as controls. The results revealed an increase in circulating naive and central memory CD4 T-cell counts along with HIV-1-specific IFN-γ and IL-2 generation.…”