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

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.

Systems analysis reveals complex biological processes during virus infection fate decisions

“…S1A,B; Wherry et al 2007). Altogether this strengthens the previous suggestion that accumulative virus loads rather than the virus load per se determine the observed differences in the immune responses and infection fates (Bocharov 1998;Côrtes et al 2018).…”

HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood

“…Several studies have shown that HIC exhibit cellular and serological markers of immune activation and inflammation despite a spontaneous control of HIV replication (21-24). However, no evidence of persistent inflammation was observed when HIC were defined using stringent criteria in relation to the cutoff level of viremia (Յ50 copies/ml) and a minimum follow-up time of Ͼ5 years, compared to HIV-uninfected subjects (25). We found here that, compared to cART patients, the level of inflammatory gene expression remains still dramatically reduced in HIC with a significant downregulation of TLRs, TRIM1, and CXCL8/IL-8.…”

Distinct lipid profile, low-level inflammation and increased antioxidant defense as a signature in HIV-1 elite control status

“…Besides, increased oxidative stress during HIV-1 infection, rising either directly from the virus or indirectly from HIV-related inflammation, supports the activation of latently HIV-1-infected cells (13). Less is known about the role of inflammation in EC, although some studies, including an earlier study from our group, suggest that gene expression and/or levels of inflammatory markers are low and comparable to HIV-uninfected individuals (3,19,20). In contrast, one study reported increased levels of inflammatory markers in EC(4).…”