Abstract
Current antiretroviral therapy (ART) effectively suppresses Human Immunodeficiency Virus type 1 (HIV-1) in infected individuals. However, even long term ART does not eradicate HIV-1 infected cells and the virus persists in cellular reservoirs. Beside memory CD4+ T cells, cells of the myeloid lineage, especially macrophages, are believed to be an important sanctuary for HIV-1. Monocytes and macrophages are key players in the innate immune response to pathogens and are recruited to sites of infection and inflammation. Due to their long life span and ability to reside in virtually every tissue, macrophages have been proposed to play a critical role in the establishment and persistence of the HIV-1 reservoir. Current HIV-1 cure strategies mainly focus on the concept of “shock and kill” to purge the viral reservoir. This approach aims to reactivate viral protein production in latently infected cells, which subsequently are eliminated as a consequence of viral replication, or recognized and killed by the immune system. Macrophage susceptibility to HIV-1 infection is dependent on the local microenvironment, suggesting that molecular pathways directing differentiation and polarization are involved. Current latency reversing agents (LRA) are mainly designed to reactivate the HIV-1 provirus in CD4+ T cells, while their ability to abolish viral latency in macrophages is largely unknown. Moreover, the resistance of macrophages to HIV-1 mediated kill and the presence of infected macrophages in immune privileged regions including the central nervous system (CNS), may pose a barrier to elimination of infected cells by current “shock and kill” strategies. This review focusses on the role of monocytes/macrophages in HIV-1 persistence. We will discuss mechanisms of viral latency and persistence in monocytes/macrophages. Furthermore, the role of these cells in HIV-1 tissue distribution and pathogenesis will be discussed.
Highlights
Antiretroviral therapy (ART) has dramatically improved the clinical outcome of Human Immunodeficiency Virus type 1 (HIV-1) infection
Macrophages are found in all lymphoid as well as non-lymphoid tissues and their origin was originally described to be dependent on circulating monocytes, which would replenish the tissue-resident macrophage pool if needed
Viral latency in cells of the monocyte/macrophage lineage can be regulated by diverse molecular mechanisms either at a transcriptional or post-transcriptional level and this is most likely dependent on the activation and differentiation state of these cells
Summary
Antiretroviral therapy (ART) has dramatically improved the clinical outcome of Human Immunodeficiency Virus type 1 (HIV-1) infection. Macrophages can be found in all lymphoid as well as non-lymphoid tissues and could serve as a tissue reservoir for Human Immunodeficiency Virus type 1(HIV-1) This figure summarizes findings on HIV-1 latency in monocytes/macrophages in vivo, showing anatomical sanctuaries, the presence of HV-1 DNA and RNA and whether the virus was replication competent or not. During HIV-1 infection, circulating activated monocytes express increased levels of CCR2, and have an increased ability to migrate in response to MCP1 into the arterial wall (Ancuta et al, 2004; Williams et al, 2013, 2014) These infiltrating monocytes further increase arterial inflammation by cytokine production [interleukin 1ß (IL-1ß) and IL-6] and uptake of (modified) lipoproteins, thereby accelerating atherosclerosis and CVD progression (Hansson, 2005). 18F-FDG PET-CT activity was associated with serum levels of soluble CD163 (sCD163), a marker of monocyte/macrophage activation (Subramanian et al, 2012; Tawakol et al, 2017), clearly indicating a role of these cells in accelerated onset of atherosclerosis and CVD in HIV-1 infection
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