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(Journal of Leukocyte Biology. 2003;74:650-656.)
© 2003 by Society for Leukocyte Biology

Monocyte/macrophage traffic in HIV and SIV encephalitis

Woong-Ki Kim*, Sarah Corey*, Xavier Alvarez{dagger} and Kenneth Williams*,1

* Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and
{dagger} Department of Pathology, Tulane National Primate Research Center, Tulane University, Covington, Louisiana

1 Correspondence: Division of Viral Pathogenesis, RE-113, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. E-mail: Kennneth_Williams{at}hms.harvard.edu


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ABSTRACT
 
This short review focuses on the role of central nervous system (CNS) perivascular macrophages as targets of productive infection of the CNS. Data discussed include the importance of these cells as early targets of infection and their productive infection with AIDS. Many of the immune molecules on perivascular macrophages are also found on subsets of blood monocyte/macrophages, some of which are expanded during human immunodeficiency virus (HIV) infection. These observations paired with the known bone marrow (BM) origin of perivascular macrophages and the BM as a site of HIV infection underscore the importance of the study of monocyte populations in the BM and blood, which are activated and infected as a source of virus that enters the CNS. Data presented and discussed herein suggest a role of HIV-infected BM-derived monocytes as "Trojan horse" cells that traffic to the CNS to become perivascular macrophages. The study of such cells including their timing of infection, activation, and traffic and the role of HIV-specific immune responses controlling their accumulation in the CNS warrant study with regard to CNS neuropathogenesis.

Key Words: perivascular macrophages • CNS • CD14 • CD16 • PCNA


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INTRODUCTION
 
Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) occurs early after infection in the periphery, from hours to days, but neurological symptoms and HIV-associated dementia (HAD) often occur years later, concomitant with or following the development of AIDS. The presence of virus in the CNS, especially productively replicating virus, seems important for neurological disease. More importantly, the accumulation of macrophages within the CNS, some of which are HIV-infected, is necessary and an important correlate of histopathology and clinical signs. Taken together, these observations underscore the importance of inflammatory macrophages in the CNS as mediators of lentiviral disease. These cells are highly activated as a consequence of infection in the periphery and loss of normal immune system functions that occur with AIDS. Increasing evidence points to the importance of monocyte populations, derived from the bone marrow (BM), which transit through the blood and accumulate in the CNS as mediators of HIV-related CNS disease. Studies in our laboratory and others focus on the normal traffic of such cells, their augmented traffic with viral infection, and the role of the immune system controlling their level of viral infection in the BM and blood with their activation, traffic, and accumulation in the CNS. Understanding events leading to infection of BM cells, some of which are potentially programmed to become CNS macrophages, the traffic of activated and/or infected monocytes contributing to productive CNS infection, and the role of the immune system controlling such events seem critical and fundamental to elucidate the pathogenesis of CNS infection by HIV and HAD.


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HIV INFECTION OF THE CNS: THE ROLE OF PERIVASCULAR MACROPHAGES
 
CNS infection by HIV in humans and simian immunodeficiency virus (SIV) in nonhuman primates is found in scattered perivascular cuffs and is associated with perivascular macrophages [1 2 3 4 5 ]. Scattered HIV- or SIV-infected macrophages, which are viral DNA, RNA, and protein-positive, are consistently found during peak viremia, 7–14 days postinfection [1 , 5 ]. Although it is possible that virus enters the CNS as cell-free virus, it is more likely that macrophages in perivascular cuffs are important early targets and the "Trojan horse" cells responsible for bringing virus to the CNS throughout infection [5 , 6 ]. The traffic of BM-derived monocytes to the CNS is part of the normal physiology of brain macrophage turnover and is augmented with inflammation and viral infection [7 8 9 ]. After initial seeding of HIV and SIV in the CNS, viral RNA or proteins are not detected during the asymptomatic period of infection [5 , 10 11 12 ]. During this same asymptomatic period, HIV and SIV DNA are not detected or found at the lower range of detection in the CNS [10 , 11 , 13 ]. Whether such DNA, when found, is from contaminating cells within the CNS vasculature or instead, is the result of latent CNS infection is not well defined [10 , 11 , 13 ]. In a recent study using a rapid model of SIV neuropathogenesis, SIV DNA in the CNS was found when no viral RNA or proteins were present, supporting the notion of latent infection of the CNS. However, it is not clear whether the animals in this study are more similar to rapid progressors and whether they truly have an asymptomatic period [14 ]. In HIV and SIV, productive infection re-emerges with the development of AIDS [5 , 11 , 15 , 16 ]. These observations suggest that virus that enter the CNS early after infection can become latent and then re-emerge with AIDS [14 ] or that productive infection, which results with the development of AIDS, occurs from reseeding new virus from the periphery [11 , 17 ]. We believe that recent evidence, including studies of monocyte populations that are infected in the blood, the timing of productive BM infection, and viral sequence analysis, supports the latter hypothesis and underscores the dynamic role of BM-derived monocytes contributing to CNS disease. It is likely, however, that both mechanisms are in operation and contribute to productive infection of the CNS with end-stage disease.

CNS macrophages are heterogeneous with respect to their morphology, location, and functions. There are at least four distinct populations of CNS macrophages, including macrophages of the choroid plexus and the meninges, the resident parenchymal microglia, and the perivascular macrophages [18 19 20 21 ]. Choroid plexus macrophages and meningeal macrophages are demonstrated to be HIV- or SIV-infected early but are not considered as major targets later in disease [22 , 23 ]. Parenchymal microglia are the resident CNS macrophages and have low-to-nondetectable turnover in rodents and humans [8 , 24 ]. Early studies of HIV infection and particularly in vitro studies point to microglia as important targets of infection [25 26 27 28 ]. These studies, however, characterized the infected cell types mainly by morphology and did not differentiate parenchymal microglial populations and other CNS macrophages. Few if any studies used more than one marker to identify infected parenchymal microglia in situ. When double-label studies were done, the markers used for microglia were pan-macrophage markers that identify all brain macrophages [29 ].

In contrast to parenchymal microglia, perivascular macrophages have a continuous rate of turnover, which is augmented with inflammation [8 , 20 , 21 , 24 ]. These cells are situated next to CNS vessels and, with foot processes of parenchymal microglia and astrocytes, compose the blood-brain barrier [8 , 30 ]. Perivascular macrophages accumulate in the CNS with inflammation, as demonstrated by studies in the animal model of multiple sclerosis, experimental allergic encephalomyelitis (EAE) [31 ]. It is interesting that when clinical signs in EAE subside, the accumulation of CNS perivascular macrophages is no longer detected. In animals that relapse, perivascular macrophage accumulation again occurs, underscoring the dynamic process of monocyte traffic from the BM and the accumulation of such cells in the CNS. Questions concerning the stimulus for such cells to traffic to the CNS and more importantly, signals for these cells to remain need to be addressed. Clear evidence of elevated chemokines and colony-stimulating factors (CSF) in the CNS including monocyte chemoattractant protein-1, which correlates with HIV and SIV CNS disease, exists [32 , 33 ]. These studies underscore the role of chemokines as attractants for cells entering the CNS. Mechanisms by which perivascular macrophages exit the CNS with the resolution of inflammation are less well defined but might include apoptosis in the CNS or the ability of these cells to traffic out (reviewed in ref. [30 ]). Evidence of perivascular macrophages leaving the CNS has been shown in CNS transplantation studies where ED2-positive macrophages, which were transplanted into the CNS within grafts, are detected in cervical draining lymph nodes and the spleen [34 ]. In contrast to this, studies using India ink injected into the CNS have demonstrated labeled macrophages 1 year postinjection [35 ]. More recent studies using dextran amine dyes demonstrate a dynamic traffic of perivascular macrophages in the rodent brain [36 , 37 ]. Overall, these studies suggest that there are different populations of these cells: one, which is immunologically active and can traffic into and perhaps out of the CNS [30 ], and another that is phagocytic and remains for long periods of time. With regard to HIV and SIV infection, it is possible that infection results in increased longevity of perivascular macrophage. McGrath and colleagues [38 ] have recently shown, using CNS tissues from HIV-infected patients with dementia, HIV insertion into genomic DNA proximal to genes that encode factors associated with signal-transduction, apoptosis. and the regulation of transcription. Whether such integration mediates dysregulation of specific genes responsible for macrophage activation, inhibition of apoptosis, and the secretion of factors that recruit additional macrophages to the CNS lesion is potentially interesting.

One way to address the role of perivascular macrophages and parenchymal microglia in CNS infection by HIV and SIV is to differentiate between these populations using myeloid markers. This had been done previously in EAE and multiple sclerosis studies and more recently in the HIV- or SIV-infected CNS [39 40 41 42 43 44 45 46 ]. Perivascular macrophages can be differentiated from parenchymal microglia based on their level of CD14 and CD45 expression. CD14, which is expressed on the cell surface of 80–90% blood monocytes, is readily detected on perivascular macrophages and is not detectable on parenchymal microglia [41 , 42 , 45 , 47 ]. Similarly, CD45 is strongly expressed on perivascular macrophages in the CNS and is expressed at low levels on parenchymal microglia [42 ]. Using combinations of monoclonal antibodies against CD14 or CD45 with antibodies against HIV and SIV viral proteins or RNA, it has been demonstrated that perivascular macrophages are a major CNS cell population that is productively infected early and terminally with AIDS [5 , 45 , 48 ]. Such productive infection occurs with an accumulation of macrophages in perivascular cuffs, an event that correlates with entry of virus to the CNS [4 ]. In addition to CD14 and CD45 markers used to differentiate between parenchymal microglia and perivascular macrophages, CD16, CD69, and human leukocyte antigen-DR are expressed on perivascular macrophages (Fig. 1 ) [7 , 20 , 30 ]. These markers and CD14 have also been used to identify unique blood monocyte populations that are expanded in the blood following HIV infection [49 50 51 52 53 ]. The increase in the percent or absolute numbers of subpopulations of activated monocytes in the blood is a good correlate of HAD. In addition to tissue macrophages, subpopulations of monocytes are also thought to be significant reservoirs of HIV, even in patients on highly active antiretroviral therapy (HAART) [52 , 54 55 56 ]. Taken together, these data point to the importance of understanding the biology of CNS perivascular macrophages and the identification of cells in the BM and blood, which might serve as precursors to CNS perivascular macrophages to better understand their role in CNS viral infection. Part of the difficulty with such studies is to have a marker that will allow for one to trace such cells from the marrow through the blood and ultimately into the brain. Studies in rodents and BM transplantation have made use of mismatched major histocompatibility complex class I antigens or in the case of BM transplantation in humans, the Y chromosome [57 , 58 ]. We have recently reported that CNS perivascular macrophages that are productively infected with SIV also strongly express the proliferation cellular nuclear antigen (PCNA) [59 ]. In our studies, we demonstrated that expression of PNCA correlates well with SIV RNA in the same cell and that the cells that are PCNA-positive are not undergoing significant, detectable cell proliferation but are more likely undergoing DNA repair, a process that might be induced by viral infection [59 , 60 ]. Our group and others have found similar PCNA expression in the BM of HIV-infected humans and SIV-infected rhesus macaques in monocyte/macrophage populations that are infected with HIV or SIV (Fig. 2 ). This marker, in conjunction with markers of blood monocytes that are also expressed on CNS perivascular macrophages, might be useful to study monocyte/macrophages in the BM and blood, which are HIV- or SIV-infected and can traffic to the CNS.



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  		Figure 1. CD14 (A)-, CD16 (B)-, and CD69 (C)-positive perivascular macrophages accumulate in the CNS of an animal with AIDS and SIV.



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  		Figure 2. (A) Confocal microscopic image demonstrating PCNA (green) within a SIV p27-positive (red) macrophage from the BM of a SIV-infected animal with AIDS. (B) Confocal microscopic image demonstrating PCNA (green) within CD68 (red) macrophages in the BM of a SIV-infected animal with AIDS.


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BM INFECTION WITH HIV AND SIV
 
Although BM is the major hematopoietic organ in adults, little is known about the timing of HIV infection, subsequent pathology as a result of HIV infection or the effect of infection on hematopoietic differentiation of cells of monocyte/macrophage lineage. Disruption to the BM and subsequent hematologic abnormalities such as anemia frequently occur in HIV-infected individuals [61 ]. It is interesting that the prevalence of anemia correlates with disease progression in SIV and is the best-known predictor of HIV dementia [62 63 64 ]. Although pathogenesis of BM following infection is not clearly understood, HIV and SIV infection occurs early and then later in disease with AIDS [65 ]. Although several different cell types within the bone marrow including CD34+ progenitor cells, megakaryocytes, and CD4+ T cells have been shown to be susceptible in vitro to HIV infection [66 67 68 ], monocyte/macrophages or monocyte-myeloid precursors are a major target [69 70 71 72 ]. As in humans, BM monocyte/macrophages are a major target of SIV [62 , 65 ]. Notably, SIV-infected monocyte/macrophages are found as early as 3 days postinoculation, suggesting an important role in the pathogenesis of virus-induced hematologic abnormalities [65 ]. Viral RNA expression in BM correlates with the severity of disease [72 ] and similar to infection in the CNS, is detected early postinfection and then re-emerges with AIDS [62 , 72 ]. The frequency of BM macrophages in HIV-infected patients significantly increases, as does PCNA expression in these infected cells [60 , 73 ]. The notion that HIV- or SIV-infected monocyte/macrophages in the BM arise from the redistribution of virus from the immune system is an interesting possibility and is supported by studies of monocyte populations in the blood of patients with AIDS and viral sequence analyses of tissues including the brain, gut, lung, and BM.


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ROLE OF BLOOD MONOCYTES IN AIDS AND AIDS DEMENTIA
 
Although early in vitro studies showed that HIV could infect blood monocytes [74 , 75 ], it has not been known whether monocytes could support productive infection. Sonza et al. [55 ] have shown that monocytes harbor replication-competent HIV-1 during effective HAART and that the type of HIV nucleic acids present (circular DNA and multiply spliced RNA) suggests a recent and active infection. Zhu et al. [56 ] have shown the presence of HIV DNA in CD14+ monocytes from patients with and without HAART, making the case for a longer half-life of HIV DNA in CD14+ monocytes than resting or activated CD4+ T cells. More importantly, this study also found HIV mRNA in blood monocytes with sequences identical to those found in viral particles in the plasma. Taken together, these studies suggest that CD14+ monocytes are a source of HIV, even with HAART therapy.

There are a number of reports describing CD14+ monocyte populations and subpopulations in normal and HIV-infected individuals. From these, it is clear that they are not a homogeneous population. Flow cytometric studies showed that CD14+ monocytes can be differentiated based on relative levels of CD14 expression and CD16. Among subtypes of monocytes, a minor subset expressing CD14/CD16 expands in response to systemic challenge, including HIV infection [51 , 76 77 78 79 80 ]. CD14+CD16+ and CD14+CD69+ subsets of monocytes are described in the blood of patients with AIDS, where increased percentages correlate with HAD [52 ]. The expansion of such populations does not appear to be HIV-specific but is likely to signify the general activation of the innate-immune system [53 , 81 ]. In vitro, macrophage-CSF and HIV-envelope gp120 mimic this immune activation, resulting in increased CD16 expression on CD14-positive monocytes [82 83 84 ], and HAART reverses the expansion of this subset [85 ], suggesting the involvement of virus in control of monocyte activation. It is interesting that Philip Ellery et al. presented preliminary data at the 5th International Workshop on HIV and Cells of the Macrophage Lineage and Other Reservoirs, showing that a CD14loCD16hi monocyte subset preferentially harbors HIV in vitro (see article in this edition). CNS perivascular macrophages are similar, phenotypically and with respect to HIV and SIV infection, to this subpopulation found in the blood.

Although it is tempting to postulate that HIV-associated neurological diseases may result from increased trafficking of activated and/or infected blood monocytes into the CNS, currently no direct association exists between degree of activation and/or infection of blood monocytes and incidence of HIV-related neurological disease resulting from the traffic of such cells. Nevertheless, it is likely that such activation, and certainly productive viral infection, is important for these cells to stay in the CNS. Studies in rodents show an accumulation of perivascular macrophages with inflammation, which goes away with the termination of inflammatory events. However, if India ink is injected into the CNS, labeled perivascular macrophages can be found in the CNS up to 2 years after injection [35 ]. To date, few studies have found changes in absolute monocyte cell numbers or relative percentages based on CD14 and CD16, which correlate with HIV disease progression. A recent cohort study of HIV-infected children have indicated that high CD14+ monocyte counts are a better surrogate marker than CD4+ T cell counts and viral load of HIV/CNS disease [86 ]. In addition, plasma and CSF levels of soluble CD14 (shed from activated monocytes) increase in HIV-infected patients and even more in patients with AIDS and dementia [45 , 78 , 87 , 88 ], which indicates immune activation following HIV infection and AIDS and the potential usefulness of soluble CD14 levels to evaluate HIV dementia. Furthermore, CD14+CD16+ and CD14+CD69+ subsets of monocytes are described in the blood of patients with AIDS, where increased percentages correlate with HAD. It is likely that expanded monocyte populations in the blood are infected with HIV or SIV and are cells that carry virus to the CNS. Regardless, the presence of these activated cells in the blood are clear markers of CNS disease.

We have made parallel observations of peripheral blood monocyte activation in a CD8-depletion, SIV-infection model of neuro-AIDS (Fig. 3 ). It has been demonstrated that the rhesus monkeys, which are SIV-infected and then treated with a CD8+ T cell-depleting antibody, have a high incidence of AIDS, SIV encephalitis, and severe CNS disease. When blood monocytes of these animals are monitored, we find an early rise in a CD14loCD16hi monocyte subset, which peaks at 7 days postinfection, the earliest time-point when SIV-infected macrophages can be found in CNS [5 , 30 ]. The percentage of these activated cells then drops but reappears with the development of AIDS and SIV.



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  		Figure 3. Phenotypic changes in peripheral blood monocytes in a SIV-infected, CD8-depleted rhesus macaques. (A) Changes in the percentage of CD14loCD16hi monocyte subpopulation during SIV infection. (B) Fluorescence-activated cell sorter (FACS) sorting of CD14hiCD16lo and CD14loCD16hi monocytes. The individual populations shown in two gates were FACS-sorted and snap-frozen for SIV nucleic acid analyses.

Kinetics of BM infection and expansion of monocyte populations in the blood with viral sequence data point to these important populations as a source of virus that seeds the CNS early after infection and then again with AIDS. It is likely that the second wave or waves of infection with AIDS contribute to productive infection of the CNS. Perhaps it is more appropriate to refer to these successive waves of BM monocytes as the Trojan herd. Evidence for this can be found from recent HIV and SIV sequence data.


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CNS INFECTION, VIRAL SEQUENCES, NEUROTROPISM
 
There have been numerous studies analyzing HIV and SIV viral sequences in the CNS. Some studies suggest "neurotropic" sequences based on regions of env and nef [89 90 91 ]. Others suggest highly divergent strains of virus, some of which cluster phylogenetically with similar brain sequences and others that are closely related to sequences found in the BM, gut, and lung [11 , 17 , 92 93 94 ]. Several important points can be made from such studies. First, macrophage tropism seems required for HIV and SIV to replicate in the CNS [95 , 96 ]. The second is that although it is possible to detect HIV and SIV sequences early after infection, they are detected at low levels and in the case of HIV, often undetectable until the emergence of AIDS and CNS disease [10 , 11 ]. In fact, the presence of HIV and SIV in the CNS and in the gut, lung, and BM where macrophages are major targets of infection clearly correlates with histopathology and symptoms of AIDS [59 , 97 , 98 ]. In vitro studies investigating whether different strains of HIV replicate differentially in brain-derived microglia versus macrophages failed to find unique tropism of virus for different macrophage populations [99 ]. Moreover, analysis of HIV env and gp160 sequences demonstrate phylogenetic clusters of virus in the brain that are often similar to clusters found in the BM and gut, organs where macrophage infection is significant [17 , 94 ]. These observations with our report of similar populations of SIV-infected macrophages in the brain, gut, and lung, which are also PCNA-positive, suggest that subsets of macrophages in these organs might be of similar origin [59 ]. Such studies question whether CNS infection is unique from that of other organs where macrophage infection plays a major role.


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SUMMARY
 
Data described in this brief review support the notion that a population of CNS perivascular macrophages is a major target of HIV and SIV infection in the CNS. These cells accumulate early in disease and correlate with initial viral entry. They are not found in significant numbers during the asymptomatic stage of infection but are readily found with the development of AIDS, encephalitis, and HAD. The immune phenotype of the HIV- or SIV-infected perivascular macrophages is similar to a subset of blood monocyte populations that is expanded with infection and that has been identified as reservoirs for HIV in infected patients with and without HAART. Similar populations of cells are found in the BM, which are HIV- or SIV-infected and express PCNA with infection. Whether such cells represent precursors to CNS perivascular macrophages and can be studied as Trojan horse cells that traffic to the CNS and other organs warrants further study. Moreover, the role of the immune system and specific CD4+ and CD8+ T cell responses, as well as cytotoxic lymphocyte viral escape sequences contributing to CNS disease with AIDS, is a field of future study.


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ACKNOWLEDGEMENTS
 
Public Health Service Grants NS37654 (K. W.), NS40237 (K. W.), and RR00164 (X. A.) supported this work.

Received May 7, 2003; revised July 15, 2003; accepted July 18, 2003.


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