Abstract
Despite the suppression of viral replication induced by the highly active anti-retroviral therapy (HAART), an increased immune activation and inflammatory state persists in HIV-infected patients, contributing to lower treatment response and immune reconstitution, and development of non-AIDS conditions. The chronic activation and inflammation affect the functionality and differentiation of CD8+ T-cells, particularly reducing their cytotoxic capacity, which is critical in the control of HIV replication. Although previous studies have shown that HAART induce a partial immune reconstitution, its effect on CD8+ T-cells cytotoxic function, as well as its relationship with the inflammatory state, is yet to be defined. Here, we characterized the functional profile of polyclonal and HIV-specific CD8+ T cells, based on the expression of cell activation and differentiation markers, in individuals chronically infected with HIV, under HAART. Compared with seronegative controls, CD8+ T-cells from patients on HAART exhibited a low degranulation capacity (surface expression of CD107a), with consequent low secreted levels and high intracellular expression of granzyme B and perforin. This degranulation defect was particularly observed in those cells expressing the activation marker HLA-DR, which were further characterized as effector memory cells with high expression of CD57. The expression of CD107a, but not of granzyme B and perforin, in CD8+ T-cells from HIV-infected patients on HAART reached levels similar to those in seronegative controls when the treatment duration was higher than 25 months. In addition, the expression of CD107a was negatively correlated with the expression of exhaustion markers on CD8+ T-cells and the plasma inflammatory molecule sCD14. Thus, despite HAART-induced viral suppression, CD8+ T-cells from HIV-infected patients have an alteration in their cytotoxic program. This defect is associated with the cellular activation, differentiation and exhaustion state, as well as with the inflammation levels, and can be partially recovered with a long and continuous treatment.
Highlights
It is well stablished that CD8+ T-cells are critical in the control of HIV infection [1]
In seronegative individuals, the dynamics of the surface expression of the activation markers HLA-DR and CD38, the exhaustion marker Programmed Death (PD)-1, the degranulation marker CD107a, and the intracellular expression of perforin, granzyme B and IFN-γ, from 0 to 24 hours after polyclonal stimulation with PMA-Ionomycin, following the gating strategy shown in S1A Fig. At the beginning of the culture, HLA-DR- CD38- cells had the highest proportion, followed by HLA-DR- CD38+, HLA-DR+ CD38- and HLA-DR+ CD38+ cells (Fig 1A)
This pattern was observed in HLA-DR/CD38-expressing CD8+ T-cells, with the highest expression of PD-1 in HLA-DR+ CD38+ cells (Fig 1B), consistent with their activated phenotype
Summary
It is well stablished that CD8+ T-cells are critical in the control of HIV infection [1]. The cytotoxic function of circulating HIV-specific CD8+ T-cells has been associated with the control of viral replication and a delayed progression, highlighting the importance of this effector function [7,8,9]. One of the major pitfalls of anti-retroviral therapy is the persistent immune activation and inflammation, caused by residual viral replication, ongoing co-infections or microbial translocation across a disturbed gastrointestinal mucosa. These defects are associated with the development of non-AIDS conditions [12], such as cardiovascular disease or stroke, which reach up to the 42% of deaths among HIV-infected patients [13]. An important proportion of deaths in HIV-infected patients on HAART results from a poor immune response against new infectious challenges [13,14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
