Human Primary Macrophages Derived In Vitro from Circulating Monocytes Comprise Adherent and Non-Adherent Subsets with Differential Expression of Siglec-1 and CD4 and Permissiveness to HIV-1 Infection.

Ousman Jobe,Nelson L Michael,Sayali Onkar,Mangala Rao,Carl R Alving,Jiae Kim,Eric Tycksen

doi:10.3389/fimmu.2017.01352

Abstract

Macrophages are a major target for human immunodeficiency virus type 1 (HIV-1) infection. However, macrophages are largely heterogeneous and may exhibit differences in permissiveness to HIV-1 infection. This study highlights the interplay of macrophage heterogeneity in HIV-1 pathogenesis. We show that monocyte-derived macrophages (MDMs) could be divided into two distinct subsets: CD14+Siglec-1hiCD4+ (non-adherent MDM) and CD14+Siglec-1LoCD4− (adherent MDM). The CD14+Siglec-1hiCD4+MDM subset represented the smaller proportion in the macrophage pool, and varied among different donors. Fractionation and subsequent exposure of the two MDM subsets to HIV-1 revealed opposite outcomes in terms of HIV-1 capture and infection. Although the CD14+Siglec-1hiCD4+MDM captured significantly more HIV-1, infection was significantly higher in the CD14+Siglec-1LoCD4−MDM subset. Thus, CD14+Siglec-1hiCD4+MDM were less permissive to infection. Depletion of CD14+Siglec-1hiCD4+MDM or a decrease in their percentage, resulted in increased infection of MDM, suggestive of a capacity of these cells to capture and sequester HIV-1 in an environment that hinders its infectivity. Increased expression of innate restriction factors and cytokine genes were observed in the non-adherent CD14+Siglec-1hiCD4+MDM, both before and after HIV-1 infection, compared to the adherent CD14+Siglec-1LoCD4−MDM. We speculate that the differential expression of gene expression profiles in the two macrophage subsets may provide an explanation for the differences observed in HIV-1 infectivity.

Highlights

Macrophages are important targets of human immunodeficiency virus type 1 (HIV-1) infection [1,2,3,4] and may represent specialized viral reservoirs, with the ability to store HIV-1 particles in intracellular compartments [5, 6]
We have previously demonstrated that blocking Siglec-1 receptor on monocyte-derived macrophages (MDMs) resulted in 90–95% inhibition of HIV-1 infection, whereas blocking CD4 receptor inhibited infection in 50–55% of MDM [21]
We investigated the possible existence of subsets of MDM that coexpressed varying amounts of Siglec-1 and CD4

Summary

Introduction

Macrophages are important targets of human immunodeficiency virus type 1 (HIV-1) infection [1,2,3,4] and may represent specialized viral reservoirs, with the ability to store HIV-1 particles in intracellular compartments [5, 6]. It has been reported that infectious HIV-1 within macrophages are protected from neutralizing antibodies [7], further complicating HIV-1 eradication. Due to their dissemination over different tissues and their capacity to infiltrate virtually all organs including the brain, macrophages could likely contribute to the spread of HIV-1 and HIV-related pathologies, including immune dysfunction, persistent hyperimmune activation, and the onset of opportunistic infections [4, 8, 9]. Earlier reports defined circulating monocytes as the precursors of tissue macrophages, recent studies have shown that tissue macrophages with self-renewal properties could arise from yolk sac, liver, and bone-marrow independent of monocyte precursors [10,11,12]. The necessity of the circulating monocytes to repopulate macrophages in certain tissues versus the ability of macrophages to self renew in other tissues independent of circulating monocytes [13], highlights the complexity of tissue resident macrophage populations

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