WU Li

Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA

1 HIV-1 persistence and viral reservoirs in AIDS patients

Human immunodeficiency virus type 1 (HIV-1) persistence is the major barrier to successful treatment of acquired immunodeficiency syndrome (AIDS) using highly active antiretroviral therapy (HAART). Understanding the mechanism underlying HIV-1 latency and persistence is challenging in AIDS research. Resting memory CD4+T cells that have been latently infected by HIV-1 are the major source of viral persistence in AIDS patients[1]. In addition to resting CD4+T cells, a significant long-lived compartment of HIV-1 infectioninvivoincludes blood monocytes and tissue macrophages. While much has been learned about the mechanisms of HIV-1 latency and persistence in resting CD4+T cells[2], there is a very limited understanding of how HIV-1 persists in monocytes and macrophages[3,4]. The mechanisms of HIV-1 latency in resting CD4+T cells involve at least three aspects: (1) HIV-1 proviral DNA integrated into host cell chromosomes can be subjected to repression by neighboringcis-acting sequences; (2) the transcriptional status of the HIV-1 genome is tightly regulated by the activation state of its host cell; and (3) HIV latency can also result from posttranscriptional restriction mechanisms, such as impaired HIV mRNA nuclear export and the expression of host or viral micro-RNAs[1]. It is unclear, however, whether these mechanisms are involved in HIV-1 persistent infection of monocyte-lineage cells.

2 The role of monocyte-lineage cells in HIV-1 infection

Monocyte-lineage cells, including monocytes, dendritic cells (DCs) and macrophages, play a significant role in HIV-1 infection and transmission[5,6]. Studying HIV-1 persistence in monocyte-lineage cells and the underlying mechanisms is critical because these cells are important HIV-1 target cellsinvivo. Based onexvivostudies using primary cell cultures, monocyte-lineage cells have been implicated as viral reservoirs that facilitate HIV-1 latency and persistence[3]. However, the precise role of monocyte-lineage cells and the molecular and cellular mechanisms in HIV-1 persistenceinvivoremain to be investigated.

Monocytes are generated from hematopoietic stem cells and constitute 3%-8% of blood leukocytes. Monocytes are precursors of macrophages and DCs, which are a group of professional antigen presenting cells that play an important role in HIV-1 pathogenesis[3]. In addition to CD4+T cells, monocytes, macrophages, and DCs are among the first target cells to encounter HIV-1 during the initial infection and transmission[5,6]. HIV-1 can persist in peripheral blood monocytes in infected individuals receiving HAART, suggesting that monocytesinvivoconstitute a continuous source of virus during HAART[3]. Macrophages and certain types of DCs support productive HIV-1 infection and, therefore, contribute to viral persistence[3,5,6]. In addition to resting CD4+T cells, viral reservoirs, including cells of the monocyte-macrophage lineage, are one of the challenges to eradication of HIV-1 with HAART[7].

There are three major DC subtypes in the blood or mucosal tissues: myeloid DCs, plasmacytoid DCs (pDCs), and Langerhans cells. These DC subtypes are characterized based on their locations, surface markers, and cytokine secretion profiles. In general, the half-life of DCs measures up to a few weeks; DCs can be replaced through proliferating hematopoietic progenitors, monocytes, or tissue resident cells[3,5]. Productive HIV-1 replication occurs in blood myeloid DCs for a few weeks[3]. DCs likely survive longer within the lymph nodes due to cytokine stimulation in the microenvironment, which may help spread HIV-1 infection and maintain viral reservoirs.

3 Significance of studying monocyte-lineage cells in HIV-1 persistence

HIV-1 infection is characterized by life-long viral persistence and continued decline of helper CD4+T cells. Long-term HAART cannot eradicate HIV-1 infection mainly due to HIV-1 persistence in viral reservoirs[8]. Recent studies suggest that residual HIV-1 viremia in patients treated with HAART does not come from circulating, latently infected CD4+T cells but from an unknown reservoir[2]. A better understanding of viral reservoirs and how they contribute to HIV-1 persistence is essential for developing effective strategies to eradicate HIV-1 infection.

Monocyte-lineage cells include important HIV target cellsinvivo, such as monocytes, DCs and macrophages, which play critical roles in HIV-1 infection and transmission. These cells have been proposed to act as viral reservoirs in HIV-1 persistence and latency (Fig.1). It is conceivable that monocyte-lineage cells play an important role in HIV-1 persistenceinvivo. These cells may represent the major unknown reservoir in HAART-treated individuals.

Monocytes are precursors of macrophages (M?) and dendritic cells (DCs). HIV-1 can persistently infect monocytes. HIV-1 latency in monocytes and viral activation during macrophage differentiation are critical for HIV-1 persistence.

Fig.1 The vital role of monocyte-lineage cells in HIV-1 persistence

HIV-1 persistence is the major barrier to successful AIDS treatment. Although we have begun to accrue significant amount of information on the mechanisms underlying persistence in resting CD4+T cells, the crucial, yet unanswered question of HIV-1 persistence in monocyte-lineage cells has not been extensively addressed due to technical challenges. Monocytes are precursors of DCs and macrophages, and these cell types play an important and multifaceted role in HIV-1 infection and persistence[5,6]. HIV-1 can persist in blood monocytes in infected individuals receiving antiretroviral therapy, indicating that monocytes are an important viral reservoir and a contributor to HIV-1 persistence.

4 Macrophage differentiation significantly enhances HIV-1 replication

HIV-1 suppression in monocytes contributes to viral latency and persistence through multiple potential mechanisms. Undifferentiated monocytes are resistant to HIV-1 post-entry infectioninvitro, while monocyte-derived macrophages and DCs are permissive for productive HIV-1 infection[3,5]. Differentiation-dependent cellular factors may account for HIV-1 post-entry restriction in primary monocytes. However, the mechanisms of HIV-1 activation during monocyte differentiation into macrophages are unclear. Thus, studying HIV-1 interactions with monocyte-lineage cells can provide important new insights into understanding fundamental mechanisms and biology of HIV-1 persistence. It is critical that the mechanisms that regulate HIV-1 latency and viral activation in the monocyte-macrophage lineage are elucidated. We have identified potent post-entry restriction of HIV-1 in primary monocytes, and that macrophage differentiation increases HIV-1 infection over 100-fold[9]. Primary monocyte differentiation into macrophages can support productive HIV-1 replication. Our results suggest that HIV-1-infected monocytes can function as a cellular reservoir and their differentiation into macrophages efficiently stimulates productive HIV-1 infection[9].

The molecular mechanisms of HIV-1 persistence in monocytes and macrophages remain poorly understood. A critical and yet unanswered question in studying HIV-1 persistence is how host factors significantly affect HIV-1 latent infection in monocytes and viral activation in macrophages[3]. Furthermore, research on HIV-1 pathogenesis has been hampered by the lack of suitable small animal models. Immunodeficient mice transplanted with human hematopoietic stem cells have been recently developed to study HIV-1 infection, pathogenesis and treatment[10]. The humanized mouse model may also be used as an important tool to identify HIV-1 cellular reservoirs and viral disseminationinvivo. Non-human primates infected with simian immunodeficiency virus (SIV) or chimeric HIV-1 and SIV remain an important animal model in studying HIV-1 pathogenesis, despite the limitations of high-cost and accessibility and the differences in disease progression.

5 Summary

A better understanding of HIV-1 interactions with monocyte-lineage cells can aid in development of novel approaches for AIDS therapy and prevention. To address the fundamental questions of cellular reservoir and viral factors in HIV-1 persistence, it is essential to develop a combination of cellular and molecular approaches with a suitable animal model. These basic studies will provide new insight into HIV-1 pathogenesis and will shed light on more effective antiviral therapy for AIDS patients.

Acknowledgements

The author thanks members of the Wu laboratory for stimulating discussions.

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