Role of Monocyte/Macrophages during HIV/SIV Infection in Adult and Pediatric Acquired Immune Deficiency Syndrome

Abstract

Monocytes/macrophages are a diverse group of cells that act as first responders in innate immunity and then as mediators for adaptive immunity to help clear infections. In performing these functions, however, the macrophage inflammatory responses can also contribute to pathogenesis. Various monocyte and tissue macrophage subsets have been associated with inflammatory disorders and tissue pathogeneses such as occur during HIV infection. Non-human primate research of simian immunodeficiency virus (SIV) has been invaluable in better understanding the pathogenesis of HIV infection. The question of HIV/SIV-infected macrophages serving as a viral reservoir has become significant for achieving a cure. In the rhesus macaque model, SIV-infected macrophages have been shown to promote pathogenesis in several tissues resulting in cardiovascular, metabolic, and neurological diseases. Results from human studies illustrated that alveolar macrophages could be an important HIV reservoir and humanized myeloid-only mice supported productive HIV infection and viral persistence in macrophages during ART treatment. Depletion of CD4+ T cells is considered the primary cause for terminal progression, but it was reported that increasing monocyte turnover was a significantly better predictor in SIV-infected adult macaques. Notably, pediatric cases of HIV/SIV exhibit faster and more severe disease progression than adults, yet neonates have fewer target T cells and generally lack the hallmark CD4+ T cell depletion typical of adult infections. Current data show that the baseline blood monocyte turnover rate was significantly higher in neonatal macaques compared to adults and this remained high with disease progression. In this review, we discuss recent data exploring the contribution of monocytes and macrophages to HIV/SIV infection and progression. Furthermore, we highlight the need to further investigate their role in pediatric cases of infection.

Keywords: Acquired Immune Deficiency Syndrome; HIV; SIV; macrophages; monocytes; pediatrics.

Figure 1

Summary of blood monocyte and dendritic cells (DC) differentiation in rhesus macaques. Myeloid precursor cells in the bone marrow migrate into blood and give rise to CD14⁺CD16⁻ classical monocytes. A large proportion of these classical monocytes rapidly disappear from the circulation to become tissue macrophages. A fraction of the classical monocytes differentiate into CD14⁺CD16⁺ intermediate monocytes and then into CD14⁻CD16⁺ non-classical monocytes in the circulation. The populations of mDCs, pDCs, and perhaps other unidentified DCs appear to differentiate from various DC precursors directly in the bone marrow prior entering the blood circulation. Figure modified from Ref. (8). Copyright 2015. The American Association of Immunologists, Inc.

Figure 2

Patterns observed for monocyte turnover, CD4 T cell counts and simian immunodeficiency virus (SIV) infection differ depending on age at infection. Results from Kuroda and colleagues showing monocyte turnover determined by quantification of bromodeoxyuridine (BrdU) incorporation by flow cytometry in monocytes at 24 h post-BrdU intravenous injection, CD4 T cell count obtained by peripheral blood cellular immunophenotyping via flow cytometry in conjunction with complete blood count (CBC), and SIV RNA plasma viremia as determined by quantitative PCR. Distinct patterns emerged for clinical progression of SIV in rhesus macaques illustrated in (A) adults, (B) newborns, and (C) as what we refer to as an “intermediate” phenotype in older infants infected at ~3–4 months of age.

Figure 3

Infection and replication of simian immunodeficiency virus (SIV) in interstitial macrophages (IM) and AM contribute to the viral load in lung tissues and higher death rate of lung IM correlates with increased blood monocyte turnover rate in adult SIV-infected rhesus macaques. (A) Confocal microscopy was performed on lung tissues obtained from SIV-infected monkeys with higher (>30%) blood monocyte turnover levels (n = 6). Anti-CD163 (Green) antibody was used to identify macrophages, and SIV RNA (Red) was detected with anti-sense riboprobes. (B) IM, AM and CD4+ T cells were sorted via FACS from single-cell suspensions of lung tissues from SIV-infected monkeys with low (n = 5) and high (n = 4) blood monocyte turnover, and SIV DNA levels were quantitated and standardized against RNase P levels. Figure modified from Ref. (54). Copyright 2015. The American Association of Immunologists, Inc.

Figure 4

Proposed mechanism of simian immunodeficiency virus (SIV) reservoir establishment in the lung of SIV-infected macaques. The lung contains at least two types of macrophages: short-lived interstitial macrophages (IM) and longer-lived alveolar macrophages (AM). IM become massively infected with SIV and undergo a high rate of apoptosis that correlates with increased blood monocyte turnover in SIV-infected newborn macaques from the beginning of infection (Acute). This is in contrast to SIV-infected adults where massive infection of macrophages occurs later during disease progression. Conversely, SIV infection of the longer-lived AM does not lead to a high rate of apoptosis compared to that of IM. Elimination of SIV-infected longer-lived AM, and CD4+ T cells, is crucial for reducing SIV/HIV reservoirs and consequently reducing lung tissue damage.

Figure 5

Relative levels of human immunodeficiency virus (HIV) RNA (red) and CD4 cells (blue) in adults (dotted lines) and children (solid lines) in the years following acquisition of HIV-1. Gray boxes highlight the median time to AIDS/Death for infants by region and route of infection in comparison to adults. US, United States. Figure from Ref. (114) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Immunological Reviews 254/2013.

Figure 6

High monocyte turnover in uninfected infant rhesus macaques is further increased with simian immunodeficiency virus (SIV) infection. Bromodeoxyuridine (BrdU) incorporation was analyzed at 24 h by multicolor flow cytometry to determine the percent of BrdU+ monocytes (HLA−DR+ CD3− CD8− CD20− CD14+). Monocyte turnover rates were (A) compared between infant rhesus macaques and adult rhesus macaques and (B) examined in 20 uninfected macaques ranging from 3 to 190 days of age. (C) Statistical significance of comparisons between monocyte turnover rates of newborn and adult rhesus macaques before infections (UN = uninfected) and during acute, chronic and SAIDS stages of SIV-infected macaques were determined by Kruskal–Wallis test corrected for multiple comparisons using Dunn’s post-test; P < 0.05*, P < 0.01**, P < 0.001***. Figure modified from Ref. (135).

Figure 7

Longitudinal course of changes observed during progression to simian AIDS (SAIDS) in infant macaques infected with SIVmac251 at 3–4 months of age. (A) Bromodeoxyuridine (BrdU) incorporation was evaluated for monocyte turnover at 24 h. Blood monocyte turnover rates were measured every 4–6 weeks during the course of infection until progression to SAIDS or at indicated time-points (†). Mean monocyte turnover rates (i.e., %BrdU+ CD14+ monocytes) of the four infected adults are shown for comparison (dotted line). (B) Statistical analysis of monocyte turnover rates in infant macaques was performed by Kruskal–Wallis test corrected for multiple comparisons using Dunn’s post-test; P < 0.05*. UN; pre-infection, wpi; weeks post-infection. Chronic; all infant time-points after 8 wpi. Figure modified from Ref. (135).