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Originally published online as doi:10.1189/jlb.0503204 on August 21, 2003

Published online before print August 21, 2003
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(Journal of Leukocyte Biology. 2003;74:635-641.)
© 2003 by Society for Leukocyte Biology

The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection

Suzanne Crowe*,1, Tuofu Zhu{dagger} and William A. Muller{ddagger}

* AIDS Pathogenesis & Clinical Research Programme, The Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia;
{dagger} Laboratory Medicine and Microbiology, University of Washington School of Medicine, Seattle, Washington;
{ddagger} Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York

1Correspondence: Macfarlane Burnet Institute for Medical Research and Public Health Ltd, GPO Box 2284, Melbourne Vic Australia 3001. E-mail: crowe{at}burnet.edu.au


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ABSTRACT
 
Cellular viral reservoirs and anatomic sanctuary sites allow continuing HIV-1 replication in patients with suppressed plasma viremia who are receiving highly active antiretroviral therapy and prevent eradication of HIV-1 by these regimens. Cells of macrophage lineage, including monocytes subsets within the blood, play a role in HIV-1 persistence. Evidence of sequence evolution in blood monocytes, in comparison to resting CD4+ T cells, demonstrates their distinct contribution to plasma viremia. There is evidence to suggest that a specific monocyte subset, of CD14loCD16hi phenotype, is more susceptible to HIV-1 infection than the majority of blood monocytes. Trafficking of monocytes through various tissues following their emigration from the bloodstream allows these cells to differentiate into tissue macrophages, or potentially to egress from the tissues as migratory dendritic cells. This review provides an evaluation of the contribution of monocytes to HIV-1 persistence and the HIV-1 reservoir, essential for the effective design of therapeutic eradication strategies.

Key Words: Monocyte • macrophage • HIV-1 reservoir • HIV-1 persistence • trafficking • eradication • highly active antiretroviral therapy


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INTRODUCTION
 
Treatment of HIV-infected persons with highly active antiretroviral therapy (HAART) has dramatically improved survival in the developed world but has not managed to eradicate HIV-1 [1 2 3 ]. Cellular reservoirs and tissue sanctuary sites allow either continuing low-level viral transcription [4 5 6 7 ], or are latently infected and contain integrated proviral DNA [3 , 8 ], despite maximal viral suppression with HAART (recent reviews [9 , 10 ]). The best characterized cellular reservoir is the latently infected resting memory CD4+ T cell [1 2 3 ], comprising only 103 to 107 cells per patient [11 ]. Other reservoirs exist, however, as following cessation of HAART, rebounding HIV-1 is genetically distinct from virus in the latent CD4+ T cell reservoir [12 , 13 ] with diversity attributable to rebound from multiple compartments [14 ]. Viral persistence is assisted by suboptimal levels of HAART in tissues such as the brain where penetration of some antiretroviral drugs, such as protease inhibitors, is restricted [15 , 16 ]. Furthermore, all known reverse transcriptase inhibitors are ineffective in chronically infected macrophages (reviewed in [17 ]), and the protease inhibitors have significantly lower activity in chronically infected macrophages when compared with lymphocytes [18 ].

Other reported sources of persistent HIV-1 include natural killer cells from patients treated with HAART for 1-2 years, which contain detectable proviral DNA [19 ], renal tubular cells, and mononuclear cells from semen, where genetic analyses suggest compartmentalization distinct from blood [20 21 22 ], astrocytes in which integrated HIV DNA may persist [9 ], parenchymal microglia, which some investigators suggest may comprise up to two-thirds of the infected cells in the brains of patients with encephalitis [23 ], and follicular dendritic cells, where trapped infectious HIV may persist for months or years [24 , 25 ]. Low-level viral replication occurs in recently infected monocytes in patients on HAART with prolonged viral suppression [26 27 28 29 ]. Detailed knowledge of cellular reservoirs is essential for the effective design of therapeutic eradication strategies.


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Involvement of cells of macrophage lineage in HIV persistence
 
Cells of macrophage lineage, which are important targets of HIV-1 infection, are among the first to become infected in vivo and potentially contribute to viral reservoirs during all stages of HIV-1 disease (reviewed in [2 6]). Peripheral blood monocytes harbor variants of HIV that are distinguishable from those present in CD4+ T cells [28 , 29 ]. Although HIV-1 DNA is present in <1% of blood monocytes in infected patients [30 ], tissue macrophages (e.g., within lung, brain, etc.) are generally regarded as more important long-lived reservoirs (reviewed in [31 , 32 ]), and these cells often support high levels of viral replication, especially during opportunistic infection [33 ] or when T cells have been depleted [34 ].

Macrophages are long-lived, and infected cells may continue to shed virus for the duration of their life span. For example, HIV-infected perivascular macrophages and resident microglia in the brain have a low turnover, with life spans of 2-3 months and decades, respectively [35 , 36 ]. Thus, continued HAART would be required for prolonged periods to achieve eradication. Within the brains of SIV-infected macaques and of patients with HIV-related dementia, CD16-expressing perivascular macrophages are the predominant cell that is productively infected, rather than the parenchymal microglia [36 , 37 ]. Although data are lacking, it is generally considered that HIV and other lentiviruses enter the brain by the continuous trafficking of infected (and uninfected) monocytes, the so-called Trojan horse mechanism [38 , 39 ]. As perivascular macrophages have a fairly rapid turnover and replacement by peripheral blood monocytes, any alteration in the inherent capacity of monocytes to migrate across endothelial barriers as a consequence of HIV infection (for example, by alteration in expression of adhesion molecules) could potentially provide an increase in the number of tissue macrophages in the brain and persistence of this viral reservoir.

Peripheral blood monocytes are generally resistant to infection when compared with tissue macrophages and monocyte-derived macrophages [40 ]. The block to HIV replication occurs at or prior to reverse transcription and integration [40 ], with some investigators suggesting the block is predominantly at entry and related to lower CCR5 expression than on more mature cells [41 ], while others suggesting a postentry mechanism at the level of early reverse transcription [42 ]. Poor replication in monocytes is supported by a lack of the transcriptionally active p50p65 heterodimer of NF-kB in monocytes and a predominance of the transcriptionally inactive p55 homodimer, when compared with macrophages [43 ]. However it is also clear from our work [29 , 44 , 45 ] and others [46 ] that this resistance to infection is not absolute.


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Pronounced HIV-1 replication in monocytes in patients with early HAART: Comparison of HIV-1 replication in blood monocytes and resting and activated CD4+ T cells
 
To examine whether HIV-1 replicates in vivo in monocytes, as well as its role as potential source of virus, we isolated highly purified monocytes by a two-step procedure of immunoprecipitation depletion and cell-sorting [29 ] in samples obtained sequentially during the course of HIV-1 infection. Monocytes purified by this assay represent the majority of heterogeneous blood monocytes circulating in vivo. HIV-1 DNA was detected in blood monocytes throughout the course of study in both untreated patients and in those whose viral load (VL) was <200 copies/ml for 3 years during HAART. Although significant variation in the decay slopes of HIV-1 DNA was seen among treated patients, viral decay in monocytes was slower on average than that in activated and resting CD4+ T cells [29 ]. Estimates of the half-lives of HIV-1 DNA in each cell compartment during the period in which patients’ VL was maintained at levels below the detection limit of conventional assays revealed a significant variation between monocytes and T cells, as well as among individual patients. The mean half-life of HIV-1 DNA in monocytes (41.3 months, 95% confidence interval [CI]: 17.9-infinite) was longer than that in resting CD4+ T cells (23.5 months, CI: 12.5-196.6), and in activated CD4+ T cells (19.8 months, CI: 11.9–59.8). [29 ]. These apparent half-lives of HIV-1-infected cells from our patients were much longer than the estimated mean intermitotic life-spans [47 48 49 50 51 52 53 ] of monocyte-macrophages (14 days), activated (2 days), and resting memory (6 months) CD4+ T cells, suggesting that these reservoirs may be renewed as a result of continued viral replication. The most surprising finding in these studies is the persistence of provirus and its long half-life in monocytes from those treated patients with VL below detection. Given the fact that monocytes may circulate in peripheral blood for only 1-3 days before migration and differentiation into tissue macrophages [54 ], the presence of HIV-1 DNA in blood monocytes itself suggests recent infection and/or ongoing virus replication in monocytes or in its precursor cells.

Evidence of HIV-1 replication (viral mRNA and sequence evolution) and HIV-1 transcription activity (cell-associated multiply spliced (tat), and unspliced (gag) viral mRNA) in samples obtained from patients when VL was below assay detection for >1 year [29 ]) were both consistently present in monocytes from each time point sample. The mean concentrations of gag and tat mRNA in monocytes were significantly higher than those in resting CD4+ T cells. Further, the mean ratios of tat and gag mRNA/DNA in monocytes and activated CD4+ T cells were similar, and significantly higher than resting CD4+ T cells [29 ], indicating ongoing higher levels of viral transcription in monocytes and activated CD4+ T cells compared with resting CD4+ T cells in patients receiving suppressive HAART.


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Genetic evidence for the contribution of HIV-1 in monocytes to viral persistence in patients with HAART
 
We evaluated HIV-1 envelope sequence evolution in monocytes obtained from patients at sequential time points (preantiretroviral therapy to 3 years after commencement of HAART), since mutational changes accumulate as a result of completed rounds of viral replication in vivo [29 ]. Similar to previous reports, sequence evolution was found to vary between patients [55 , 56 ] and by cell populations. The majority of patients on suppressive HAART had minor to undetectable sequence evolution over the course of follow-up, while ~30% patients exhibited significant sequence evolution. In the 3 patients with sequence evolution, significant genetic evolution of HIV-1 envelope was observed in monocytes from 2 patients and in activated or resting CD4+ T cells from one patient. When HIV-1 sequences from all treated patients were analyzed together, we found a significant genetic evolution in monocytes (p=0.02). [29 ]. The sequence evolution in the two CD4+ T cell populations was evident, but not statistically significant (p=0.08 for activated CD4+ T cells, P=0.45 for resting CD4+ T cells). Further comparison of HIV-1 sequences among monocytes, activated and resting CD4+ T cells, and peripheral blood plasma by phylogenetic analyses indicated that after prolonged HAART the viral populations related or identical to those found only in monocytes were also seen in plasma from three of the seven patients, indicating that monocytes may serve as a potentially important source of HIV-1 in patients taking HAART. This hypothesis is supported by our findings of higher levels of HIV-1 transcripts and sequence evolution in monocytes than in resting CD4+ T cells, which suggests a relatively higher level of HIV-1 replication in monocytes compared with resting CD4+ T cells.


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Recovery of infectious HIV from blood monocytes of patients on HAART with viral suppression
 
Small numbers of monocytes can be productively infected with HIV-1 in vitro, and infectious HIV can be recovered from purified blood monocytes of HAART patients who have had prolonged viral suppression [26 , 27 , 29 , 45 ]. We have analyzed patients with VL <50 copies/ml for at least 3 months from whom infectious HIV was isolated from 1 to 3 x 106 monocytes (11 of 16 patients), by coculture with uninfected CD8-depleted, PHA-activated peripheral blood mononuclear cells [45 ]. Although monocytes are generally refractory to HIV-1, a subset appears to be highly susceptible to HIV-1 infection when compared with most blood monocytes.


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Two distinct monocyte subsets exist in peripheral blood
 
Most monocytes (>85%) express high levels of CD14 (a glycosyl-phosphatidylinositol-anchored surface molecule that is a component in the lipopolysaccharide recognition complex on monocytes), express little or no CD16 (Fc{gamma}RIII, a transmembrane-anchored glycoprotein that serves as a phagocytic receptor and low-affinity receptor for IgG), and are phenotypically described as CD14hi (reviewed in [57 ]). A minor subset (5-15% of peripheral blood monocytes) coexpresses low levels of CD14 and high CD16 and is known as the CD14loCD16hi monocyte subset [58 59 60 ]. CCR5 expression is low on CD14hi monocytes and highly expressed on CD14loCD16hi monocytes [61 ]. CD14 expression decreases [62 ] and CD16 is induced with in vitro maturation of monocytes [63 , 64 ] or by exposure to cytokines, including transforming growth factor-ß, GM-CSF, or M-CSF [65 66 67 ]. The CD14loCD16hi monocytes may represent a stage in myeloid maturation, either to tissue macrophages or immature dendritic cells (DCs). The cytokine environment may influence this process.

The CD14loCD16hi subset can also be further separated from CD14hi monocytes by size, CD14loCD16hi monocytes being smaller than CD14hi monocytes with an average diameter of 14 µm vs. 18µm, respectively [68 ]. CD14loCD16hi monocytes have some features of mature macrophages [68 ], including their cytokine profile [58 ], and are the major producers of TNF-{alpha} in blood [69 ]. CD14loCD16hi monocytes also have phagocytic capacity [70 ], although perhaps lower than that of CD14hi monocytes [60 ]. This CD14loCD16hi subset expands (to greater than 20-40% of circulating monocytes) in response to inflammation [60 ] and malignancy [71 ]. Their expansion in peripheral blood may result from mobilization from the marginal pool [72 ]. These cells are implicated in the pathogenesis of sepsis [73 74 ], in which increased CD16 expression aids phagocytosis and low CD14 may contribute to cytokine perturbation; and increases in plasma TNF-{alpha} and IL-6 precede their expansion during sepsis [74 ]. Although some evidence suggests they represent a stage in maturation to macrophages, the CD14loCD16hi monocytes also possess DC-like characteristics, including expression of DC markers such as high expression of MHC class II and an elongated fibroblastoid shape in culture, typical of migratory cells [75 ]. Recent in vitro and in vivo data suggest this subpopulation of CD14loCD16hi monocytes may become migratory DCs that transiently survey tissues [75 76 77 78 ]. These studies support earlier findings that bone marrow-derived DCs arise from terminal monocyte differentiation [79 , 80 ].


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Normal monocyte migration and trafficking
 
The trafficking of monocytes into tissues is a key issue in the understanding of HIV pathogenesis and viral persistence during HAART. Continuous slow trafficking of monocytes and other immune cells (notably T cells) through tissues allows the differentiation and maturation of monocytes into tissue macrophages or under certain circumstances into immature dendritic cells and the establishment of cellular reservoirs that may be untouched by HAART due to tissue restrictions in drug penetration.

Early kinetics studies revealed that monocytes leave the bone marrow ~13-26 h after completing their last division, remaining in the circulation for 36-104 h after which they may become marginated in capillaries [81 82 83 ]. These monocytes then move through endothelial walls, undergoing differentiation to become tissue macrophages. During this process, they may alternatively differentiate into DCs and enter the lymphatics [76 , 84 ], possibly as a result of encountering antigen [76 ], or may possibly re-enter the blood [82 , 85 , 86 ]. Thus, they can migrate to distant sites (e.g., to regional lymph nodes to present antigen [87 ] or to the reticulo-endothelial system for subsequent clearance). Recent data, described below, has shown that monocytes that remain in the subendothelial tissue and differentiate into tissue macrophages and those that egress into the lymphatics are distinct populations.


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Monocyte subsets differ in their ability to traffic through tissues
 
Cell adhesion molecules and chemokine receptors, including the ß-2-integrins, monocyte chemoattractant protein 1 (CCL2) receptor CCR2, E-selectin, CD99, PECAM (CD31), and tissue factor have been reported to play important roles in transendothelial migration of polymorphonuclear cells and monocytes, especially during inflammation [88 89 90 91 92 93 94 95 96 ]. Work in the Muller laboratory and by others has provided definition of many of the heterotypic and homotypic sequential interactions that occur between monocytes and endothelial cells during the emigration of monocytes from the bloodstream, using panels of monoclonal antibodies (reviewed in [97 ]).

In addition to recruitment during inflammation, monocytes constitutively leave the blood stream to enter tissues [91 ]. These monocytes can subsequently diverge along two distinct pathways: ~50% remain within tissues to differentiate into resident macrophages, and the rest migrate as immature DCs via reverse transmigration (basal to apical direction) into the afferent lymphatics [76 , 77 ]. This was initially demonstrated in an in vitro model, in which monocytes were shown to migrate across endothelium to enter underlying connective tissue and then later migrate back across the endothelium in the reverse direction [78 ]. Monocytes that remained in the subendothelial matrix differentiated into macrophages, while those that reverse-migrated were phenotypically and functionally immature DCs [78 ]. This has subsequently been confirmed in an in vivo murine model demonstrating that most monocytes that migrated into tissues remained there as macrophages while those monocytes within tissues that were destined to become DCs migrated out to the regional lymph node and developed a DC phenotype [77 ]. Recently, it has been shown that while both monocyte subsets efficiently migrate across unstimulated endothelium, the CD14loCD16hi monocytes have an intrinsically higher reverse transmigration capacity than CD14hi cells in vitro and are predisposed to become migratory DCs [76 ].


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Alteration of monocyte subset ratios during HIV infection
 
A number of investigators describe an increase in the numbers of CD14loCD16hi monocytes in the blood in HIV-infected patients compared with seronegative individuals [98 99 100 ]. Thieblemont et al. [98 ] report that up to 40% of monocytes from HIV-infected persons express CD16 (compared with 5% of those from seronegative persons) and varying according to the stage of disease. These data correlate with findings of Locher et al. [99 ] in terms of expansion during HIV infection, although in this study there was no trend observed with disease progression. Supporting data are provided by studies of cynomolgus macaques experimentally infected with SIVmac239, in which expansion of the CD14loCD16hi monocyte subset was contemporaneous with peak SIV viremia [101 ]. An increase in soluble CD14 in the serum of patients with HIV infection, when compared with controls, which correlated with disease progression [102 ] might be related to CD14 loss in association with CD14loCD16hi monocyte expansion [100 ]. As this subset produces very high levels of TNF-{alpha}, it has been proposed that the increase in these cells during HIV infection may be in part responsible for the qualitative dysregulation of the cytokine network and that the emergence of this subset could result directly from the alteration in cytokines [98 ]. Expansion of this subset in blood [103 , 104 ] as well as in brains [37 ; and M. Gonzales and S. Crowe, unpublished data], has been described in patients with AIDS-related dementia.


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HIV-1 may preferentially infect a specific peripheral blood monocyte subset
 
We and others [61 ] have shown that the CD14loCD16hi monocytes express higher levels of CCR5, a coreceptor for M-tropic (R5) HIV-1 strains, and CD4 [71 ] than the major monocyte subset. As surface CCR5 expression correlates with viral entry [105 ], an increase in CCR5 on CD14loCD16hi monocytes may be related to their increase in susceptibility to HIV-1 infection when compared with CD14hi monocytes. Our preliminary data suggest, in fact, that the CD14loCD16hi subset is more susceptible to HIV infection in vitro and in vivo [106 ]. In further support, Eisert et al. [42 ] report that high CD14 expression on cultured human monocytes is associated with low viral replication.


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CONCLUSIONS
 
As reservoirs of infected cells that are capable of producing replication-competent HIV persist for possibly decades after institution of suppressive HAART, new strategies must be developed to eradicate the virus. Studies in macaques using pathogenic simian-human immunodeficiency virus (SHIV) indicate that macrophages can sustain viremia in the presence of antiretroviral agents for several months, indicating that the macrophage reservoir half-life is not consistent with the second-phase viral decay of 14 days originally described in earlier studies and attributed to these cells [34 , 50 51 52 ]. Monocytes, and possibly a specific monocyte subset, play an important role in longer-term viral persistence. Monocytes constitutively leave the blood and enter tissues as part of normal immune surveillance. Changes in trafficking patterns of peripheral blood monocytes as a result of HIV infection may alter the reservoir of infected cells in tissues providing an additional therapeutic challenge.


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ACKNOWLEDGEMENTS
 
Suzanne Crowe was supported by the NH&MRC (Principal Research Fellow) and the National Centre for HIV Virology Research. Tuofu Zhu was supported by Public Health Service grants AI 49109 and AI 45402.

Received May 6, 2003; revised July 7, 2003; accepted July 8, 2003.


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