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 (Mø) 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.

[1] Trono D, Van Lint C, Rouzioux C, Verdin E, Barre-Sinoussi F, Chun TW, Chomont N. HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals [J]. Science, 2010, 329 (5988):174-180.

[2] Coiras M, Lopez-Huertas MR, Perez-Olmeda M, Alcami J. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs [J]. Nat Rev Microbiol, 2009, 7 (11):798-812.

[3] Coleman CM, Wu L. HIV interactions with monocytes and dendritic cells: viral latency and reservoirs [J]. Retrovirology, 2009, 6:51.

[4] Le Douce V, Herbein G, Rohr O, Schwartz C. Molecular mechanisms of HIV-1 persistence in the monocyte-macrophage lineage [J]. Retrovirology, 2010, 7:32.

[5] Wu L, KewalRamani VN. Dendritic-cell interactions with HIV: infection and viral dissemination [J]. Nat Rev Immunol, 2006, 6 (11):859-868.

[6] Wu L. Biology of HIV mucosal transmission [J]. Curr Opin HIV AIDS, 2008, 3 (5):534-540.

[7] Shen L, Siliciano RF. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection [J]. J Allergy Clin Immunol, 2008, 122 (1):22-28.

[8] Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ, Cranmer L, O'Shea A, Callender M, Spivak A, Brennan T, Kearney MF, Proschan MA, Mican JM, Rehm CA, Coffin JM, Mellors JW, Siliciano RF, Maldarelli F. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy [J]. Proc Natl Acad Sci USA, 2009, 106 (23):9403-9408.

[9] Dong C, Kwas C, Wu L. Transcriptional restriction of human immunodeficiency virus type 1 gene expression in undifferentiated primary monocytes [J]. J Virol, 2009, 83 (8):3518-3527.

[10] Van Duyne R, Pedati C, Guendel I, Carpio L, Kehn-Hall K, Saifuddin M, Kashanchi F. The utilization of humanized mouse models for the study of human retroviral infections [J]. Retrovirology, 2009, 6:76.