Plasmatic Levels of IL-18, IP-10, and Activated CD8+ T Cells Are Potential Biomarkers to Identify HIV-1 Elite Controllers With a True Functional Cure Profile.

Fernanda H Côrtes,Beatriz Grinsztejn,Marcelo Ribeiro-Alves,Gonzalo Bello,Suwellen S D De Azevedo,Hury H S De Paula,Sylvia L M Teixeira,Mariza G Morgado,Brenda Hoagland,Valdilea G Veloso,Diogo G Caetano,Monick L Guimarães

doi:10.3389/fimmu.2018.01576

Fernanda H Côrtes, Beatriz Grinsztejn + Show 10 more

Open Access

https://doi.org/10.3389/fimmu.2018.01576

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Abstract

Elite controllers (ECs) are rare individuals able to naturally control HIV-1 replication below the detection limit of viral load (VL) commercial assays. It is unclear, however, whether ECs might be considered a natural model of a functional cure because some studies have noted CD4+ T cell depletion and disease progression associated with abnormally high levels of immune activation and/or inflammation in this group. Here, we propose the use of immunological parameters to identify HIV-1 ECs that could represent the best model of a functional cure. We compared plasma levels of six inflammatory biomarkers (IP-10, IL-18, sCD163, sCD14, CRP, and IL-6) and percentages of activated CD8+ T cells (CD38+HLA-DR+) between 15 ECs [8 with persistent undetectable viremia (persistent elite controllers) and 7 with occasional viral blips (ebbing elite controllers)], 13 viremic controllers (VCs—plasma VL between 51 and 2,000 RNA copies/mL), and 18 HIV-1 infected patients in combined antiretroviral therapy, with suppressed viremia, and 18 HIV-uninfected controls (HIV-neg). The two groups of ECs presented inflammation and activation profiles similar to HIV-neg individuals, and there was no evidence of CD4+ T cell decline over time. VCs, by contrast, had higher levels of IL-18, IP-10, and CRP and a lower CD4/CD8 ratio than that of HIV-neg (P < 0.05). Plasma levels of IL-18 and IP-10 correlated positively with CD8+ T cell activation and negatively with both CD4/CD8 and CD4% in HIV-1 controllers. These results suggest that most ECs, defined using stringent criteria in relation to the cutoff level of viremia (≤50 copies/mL) and a minimum follow-up time of >5 years, show no evidence of persistent inflammation or immune activation. This study further suggests that plasmatic levels of IL-18/IP-10 combined with the frequency of CD8+CD38+HLA-DR+ T cells can be important biomarkers to identify models of a functional cure among HIV-1 ECs.

Highlights

HIV controllers (HICs) are HIV-1-infected individuals able to control viral replication in the absence of combined antiretroviral therapy [1]
We evaluated inflammation, CD8+ T cell activation, CD4%, and CD4+/CD8+ T cell dynamics in HICs with long-term (>5 years) viral control at different levels
Presented an inflammation and activation profile similar to that observed among HIV-1 negative individuals, in agreement with previous studies using comparable stringent criteria for Elite controllers (ECs) definition [10,11,12]

Summary

Introduction

HIV controllers (HICs) are HIV-1-infected individuals able to control viral replication in the absence of combined antiretroviral therapy (cART) [1]. The disease progression in those individuals appears to be mostly driven by persistent immune activation and inflammation likely associated with residual viremia [3,4,5]. Consistent with this evidence, some studies suggest that the cART might lead to a marked decrease in immune activation and increased CD4+ T cell counts in ECs, reducing the risk of non-AIDS-related events [6,7,8]. Other studies describe that elevated levels of T cell activation and soluble inflammation markers are not associated with a faster rate of CD4+ T cell decline in ECs [9, 10] or that ECs maintain absolute CD4+ T cell counts and T cell activation levels within the normal range over time [10,11,12], concluding that these individuals may not have benefited from early cART initiation

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