Myeloid Cell Interaction with HIV: A Complex Relationship

Abstract

Cells of the myeloid lineage, particularly macrophages, serve as primary hosts for HIV in vivo, along with CD4 T lymphocytes. Macrophages are present in virtually every tissue of the organism, including locations with negligible T cell colonization, such as the brain, where HIV-mediated inflammation may lead to pathological sequelae. Moreover, infected macrophages are present in multiple other tissues. Recent evidence obtained in humanized mice and macaque models highlighted the capacity of macrophages to sustain HIV replication in vivo in the absence of T cells. Combined with the known resistance of the macrophage to the cytopathic effects of HIV infection, such data bring a renewed interest in this cell type both as a vehicle for viral spread as well as a viral reservoir. While our understanding of key processes of HIV infection of macrophages is far from complete, recent years have nevertheless brought important insight into the uniqueness of the macrophage infection. Productive infection of macrophages by HIV can occur by different routes including from phagocytosis of infected T cells. In macrophages, HIV assembles and buds into a peculiar plasma membrane-connected compartment that preexists to the infection. While the function of such compartment remains elusive, it supposedly allows for the persistence of infectious viral particles over extended periods of time and may play a role on viral transmission. As cells of the innate immune system, macrophages have the capacity to detect and respond to viral components. Recent data suggest that such sensing may occur at multiple steps of the viral cycle and impact subsequent viral spread. We aim to provide an overview of the HIV-macrophage interaction along the multiple stages of the viral life cycle, extending when pertinent such observations to additional myeloid cell types such as dendritic cells or blood monocytes.

Keywords: antiretroviral therapy; macrophages; reservoir; restriction factors; sensing; viral assembly; virus-containing compartment.

Figure 1

Schematic view of HIV-1 sensing by macrophages. (A) Macrophages sense HIV-1 at two independent steps of the viral cycle. Left panel—Early sensing of HIV-1 by macrophages requires viral fusion with the plasma membrane but precedes retro-transcription (RT). This sensing step is detectable by 4 h after cell exposure to the virus and declines after 24 h when RT is inhibited. While the actual sensor involved remains to be identified, it activates the kinase tank-binding kinase-1 (TBK1), leading to production of type I IFN, signaling via IFNAR, and triggering of interferon-stimulated genes (ISGs). Right panel—The second wave on HIV-1 sensing is measurable only 48 h after cell exposure to the virus. It requires integration of the viral genome in the host DNA and transcription of viral RNAs, which appear to be the viral component triggering the late ISG response. Here also, the actual sensor remains to be identified, but retinoic acid-inducible gene I (RIG-I) is a likely candidate as the signaling cascade involves the adaptor MAVS and IRF-1 and IRF-7, leading to type I IFN production. (B) Schematic representation of the two ISG waves induced by the sensing steps described in panel (A). The full line represents the putative measurable ISG response, whereas the dashed lines indicate the contribution of the individual waves for the measurable response. (C) This table resumes the main characteristics associated with the two sensing mechanisms through which macrophages detect HIV-1 and was established based on Ref. (67, 70).

Figure 2

The virus-containing compartment (VCC) in macrophages. (A) Electron micrograph depicting HIV-1-infected monocyte-derived macrophages (MDMs). MDMs were differentiated from monocytes purified from the peripheral blood of healthy human donors, by culture over 7 days in the presence of M-cerebrospinal fluid. Cells were then infected with HIV-1 NL-AD8 and fixed and embedded in epon 5 days postinfection. Ultrathin sections were processed for electron microscopy and imaged using a Philips 120 keV. For clarity, VCC is pseudo-colored in green and mitochondria in blue. (B,C) Magnifications of VCC present in the MDM depicted in panel (A). Arrowheads indicate viral buds. A thick molecular coat, electron dense and often associated with the VCC limiting membrane of the VCC can be seen in panel (C), see arrowheads. (D) Schematic representation of the late phases of the HIV life cycle in macrophages. (1) Gag monomers initiate oligomerization in the cytoplasm, forming dimers with the viral genomic RNA and (2) subsequently bind the plasma membrane via interactions with acidic phospholipids. (3) In macrophages, high-order Gag multimerization and formation of a viral bud only occurs at the limiting membrane of the VCC. (4) Gag subsequently recruits the components of the ESCRT complex that ensure fission of the budding viral particle into the lumen of the VCC. (5) Immature viral particles accumulate inside the VCC and (6) convert into mature viral particles via the activity of the viral protease. The restriction factor BST2/tetherin and Siglec-1/CD169 may contribute to the retention of viral particles within the lumen of the VCC. The limiting membrane of the VCC is tightly associated with the microtubule network on which kinesins may drive the transport of the VCC toward the cell periphery. Inset: Magnification of a region associated with a molecular coat: the VCC limiting membrane constitutes a platform for viral assembly where Gag oligomerization will lead to virus production. Therefore, the viral and VCC membranes share similar composition. They are enriched in particular lipids such as cholesterol and transmembrane proteins. These include the tetraspanins CD9, CD53, CD81, and CD82, the scavenger receptor CD36, the integrins CD18/CD11, or the surface glycoprotein CD44 (see text for details and references). The electron micrograph depicted in this figure panel results from original work performed in our lab and has not been published elsewhere previously.