Although HIV-related deaths have declined dramatically since the introduction of ART, HIV infection is becoming increasingly chronic and people infected with HIV continue to experience rised morbidity and mortality often due to events unrelated to AIDS (19). In fact, due to the inability of antiretroviral drugs to eradicate the virus from infected reservoir cells, treatment of HIV infection requires permanent systemic therapy. However, even when successfully treated, HIV patients still show higher incidence of age-associated co-morbidities than non-infected individuals. Chronic Immune Activation and Senescence (CIADIS), is a process characterized by a progressive decline of immune system function, usually detected by the expression of cellular or soluble markers derived from innate or adaptive immune responses. Immune activation is associated with progression of HIV disease and increased morbidity and mortality in HIV-infected patients despite ART (20). In this regard, the validation of a “CIADIS score” based on activation, senescence, and differentiation markers, could help physicians to identify patients at high risk for non-AIDS-related comorbidities (20).
Although ART has significantly improved both the quality and lifespan of patients, the life expectancy of treated patients is even shorter than that of uninfected individuals. In particular, while ART may counteract some features of HIV-associated immunosenescence, several anti-HIV drugs may themselves help to amplify other aspects of immune ageing and chronic inflammation (21).
The analysis conducted in the present study reveals that some categories of antiretroviral drugs emphasize the residual inflammation, partly linked to HIV infection itself (12, 13).
According to our findings, some inflammatory cytokines of innate immunity are more represented in patients taking PI than those receiving INI (Fig. 1A,C,G). Among these, IL-1ra, TNF-α, and IL-12p70, interfere directly with the HIV virus itself, stimulating viral replication (22). Other literature data correlate high cytokine levels with an increase in CVR in HIV positive patients, despite an effective ART regimen (23).
With regard to the pro-inflammatory chemokines tested, a statistical significant difference (p < 0.05) was achieved between “PI Group” vs “INI Group” for IL-8 and MIP-1β (Fig. 1B,F). The importance of this finding is strengthened by the fact that these 2 chemokines derived from monocytes interact with CXCR4 and CCR5, both of which are HIV co-receptors, and play an important role in inducing HIV-related inflammation (24). Furthermore, since monocytes are key cells in the pathogenesis of atherosclerosis, it can be assumed that high levels of these molecules may be predictable markers of CVR in HIV positive patients.
The IFN-γ induced protein 10 (IP-10 or CXCL-10) was significantly lower in patients treated with NNRTI compared to those treated with PI and INI (p = 0.003 and p = 0.007, respectively) (Fig. 1E). Alteration in IP-10 expression levels has been related with inflammatory diseases, immune dysfunction and tumor development in the general population (25).
The IFN-induced protein 10 (IP-10 or CXCL-10) was significantly lower in patients treated with NNRTI than in patients treated with PI and INI (p = 0.003 and p = 0.007, respectively) (Fig. 1E). The alteration of IP-10 expression levels was generally related to inflammatory diseases, immune dysfunction and tumor development in the general population (25). Among HIV-positive patients, IP-10 also known to be one of the first chemokines to increase following HIV infection (26) it is involved in immune cell trafficking to inflammatory sites. In particular, the continued production of IFN-γ in the lymphoid organs is responsible for a prolonged increase in IP-10 during chronic HIV infection, even in patients taking ART. In fact, IP-10, by increasing the susceptibility of naive T CD4 + T lymphocytes to HIV infection, improves the production (constitution) of HIV reserves.
As for eotaxin, also known as C-C chemokine ligand 11, CCL1, it showed lower levels in the "NNRTI Group" than in the "PI Group" (p = 0.010) (Fig. 1D). Recent studies have shown how high levels of this cytokine are related to cellular senescence, necroinflammation and hepatic fibrogenesis. These effects have been demonstrated in patients with liver disease, where a high level of eotaxin may also be a predictive marker of an adverse clinical course (27). Other results, carried out in experimental models, have shown that eotaxin triggered the infiltration of cardiac mast cells contributing to myocardial fibrosis after transplantation (28). In addition, IP-10 and Eotaxin have been reported to be higher in HIV patients who have experienced a recent HCV infection than in those monoinfected with HIV. These results may provide a potential explanation for accelerated liver fibrosis related to the high levels of these two immune mediators responsible for respectively pro-inflammatory and pro-fibrogenic action (29).
The present study is not without limitations, first of all with regard to the small sample size, followed by a cross sectional design and the lack of comparison of the immune mediators tested with other conventional inflammatory or procoagulant markers such as CRP and D-dimer respectively (30).
However, although with limitations, our study highlights the importance of how the choice of the third drug in an antiretroviral regimen can promote the imbalance of inflammation-related immune mediators. In particular, our results seem to discourage the administration of PI as a third drug in a virologically effective antiretroviral regimen, as its use is linked to the detection of higher levels of pro-inflammatory mediators than INI and NNRTI.
Further studies in larger cohorts are needed to confirm the results found and to provide their usefulness as a significant clinical tool to help clinicians in choosing a “tailored” antiretroviral regimen.