Antigen Presenting Cells Contribute to Persistent Immune Activation Despite Antiretroviral Therapy Initiation During Hyperacute HIV-1 Infection.

Kewreshini K. Naidoo,Thumbi Ndung’u,Okechukwu C. Ndumnego,Krista L. Dong,Nasreen Ismail

doi:10.3389/fimmu.2021.738743

Abstract

Human immunodeficiency virus (HIV)-induced changes in immune cells during the acute phase of infection can cause irreversible immunological damage and predict the rate of disease progression. Antiretroviral therapy (ART) remains the most effective strategy for successful immune restoration in immunocompromised people living with HIV and the earlier ART is initiated after infection, the better the long-term clinical outcomes. Here we explored the effect of ART on peripheral antigen presenting cell (APC) phenotype and function in women with HIV-1 subtype C infection who initiated ART in the hyperacute phase (before peak viremia) or during chronic infection. Peripheral blood mononuclear cells obtained longitudinally from study participants were used for immunophenotyping and functional analysis of monocytes and dendritic cells (DCs) using multiparametric flow cytometry and matched plasma was used for measurement of inflammatory markers IL-6 and soluble CD14 (sCD14) by enzyme-linked immunosorbent assay. HIV infection was associated with expansion of monocyte and plasmacytoid DC (pDC) frequencies and perturbation of monocyte subsets compared to uninfected persons despite antiretroviral treatment during hyperacute infection. Expression of activation marker CD69 on monocytes and pDCs in early treated HIV was similar to uninfected individuals. However, despite early ART, HIV infection was associated with elevation of plasma IL-6 and sCD14 levels which correlated with monocyte activation. Furthermore, HIV infection with or without early ART was associated with downmodulation of the co-stimulatory molecule CD86. Notably, early ART was associated with preserved toll-like receptor (TLR)-induced IFN-α responses of pDCs. Overall, this data provides evidence of the beneficial impact of ART initiated in hyperacute infection in preservation of APC functional cytokine production activity; but also highlights persistent inflammation facilitated by monocyte activation even after prolonged viral suppression and suggests the need for therapeutic interventions that target residual immune activation.

Highlights

In the absence of antiretroviral therapy, infection with human immunodeficiency virus type 1 (HIV-1) is characterised by prolonged viremia, progressive CD4+ T cell loss, and persistent immune activation that leads to compromised immune responses
Higher CD4+ T cell activation was observed in the Antiretroviral therapy (ART) chronic phase treated group at 1-month (p=0.076) and at 12-months (p=0.019) compared to Human immunodeficiency virus (HIV) negative individuals
CD86 expression on plasmacytoid DC (pDC) was only downregulated in the ART hyperacute group (p=0.0003 at 1-month, p=0.012 at 12-months, Figure 3F), while ART chronic groups displayed no differences in pDC CD86 expression compared to uninfected individuals. These results indicate differential impact of hyperacute ART on antigen presenting cell (APC) such that whereas it may prevent the downregulation of CD69 on monocytes and pDCs, it does not prevent downmodulation of CD86 on monocytes and mDCs, and it may lead to downmodulation of CD86 on pDCs that does not appear to be HIV-1 infection driven

Summary

Introduction

In the absence of antiretroviral therapy, infection with human immunodeficiency virus type 1 (HIV-1) is characterised by prolonged viremia, progressive CD4+ T cell loss, and persistent immune activation that leads to compromised immune responses. Chronic immune activation and inflammation persist in these individuals which translates into higher risk of coinfections and comorbidities [1, 2], and long-term viral suppression does not necessarily equate to full immune restoration [3]. Initiation of therapy as close as possible to the time of infection is clinically beneficial but it may lead to post treatment control of viremia following antiretroviral therapy interruption in a subset of individuals [6, 7]. A better understanding of the impact of treatment of acute HIV infection before or around peak viremia is needed to develop new interventions for preservation or restoration of immunity and to inform HIV cure or post-treatment control strategies in the absence of antiretroviral therapy

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