Macrophages Transmit Human Immunodeficiency Virus Type 1 Products to CD4-Negative Cells: Involvement of Matrix Metalloproteinase 9

Abstract

It was previously reported that human immunodeficiency virus type 1 (HIV-1) spreads in CD4 lymphocytes through cell-to-cell transmission. Here we report that HIV-1-infected macrophages, but not lymphocytes, transmit HIV-1 products to CD4-negative cells of either epithelial, neuronal, or endothelial origin in the absence of overt HIV-1 infection. This phenomenon was detectable as early as 1 h after the start of cocultivation and depended on cell-to-cell contact but not on the release of viral particles from donor cells. Transfer of HIV-1 products occurred upon their polarization and colocalization within zones of cell-to-cell contact similar to virological synapses. Neither HIV-1 Env nor Nef expression was required but, interestingly, we found that an HIV-1-dependent increase in matrix metalloproteinase 9 production from donor cells significantly contributed to the cell-to-cell transmission of the viral products. The macrophage-driven transfer of HIV-1 products to diverse CD4-negative cell types may have a significant role in AIDS pathogenesis.It is widely documented that viruses can spread through mechanisms alternative to receptor-mediated cell internalization. These include transcytosis (31), transinfection (57), and cell-to-cell infection. This latter way of infection has been documented for human herpesviruses (13), human cytomegalovirus (17), measles virus (22), and human hepatitis C virus (58). The human T-lymphotropic virus type 1 retrovirus was found to propagate exclusively through the formation of zones of tight cell-to-cell adhesion (virological synapses) very similar to the contact between antigen-presenting cells and lymphocytes (immunological synapses) (32). Human immunodeficiency virus type 1 (HIV-1) was found to propagate very efficiently by cell-to-cell transmission (33, 48, 53) through a mechanism requiring expression of HIV Env receptors in donor cells and of CD4 and CXCR4 or CCR5 cell receptors in target cells, although coreceptor-independent HIV-1 transfer to peripheral blood mononuclear cells was also described (5).HIV infection can lead either to cell death, mostly in activated CD4 lymphocytes, or to persistent infection in cells controlling HIV gene expression and/or resisting its cytopathic effects, as is the case with macrophages (55). These cells play a critical role in AIDS pathogenesis, both as viral reservoirs during highly active anti-retroviral therapy (36) and by affecting the pattern of released soluble factors involved in both innate and adaptive immunity. In addition, the nature of macrophages as migratory blood cells strongly favors their interaction with cells of different types, e.g., epithelial, stromal, or endothelial cells. This is also the case with the central nervous system counterpart of macrophagic cells, i.e., microglia cells (41).Macrophages are good producers of matrix metalloproteinases (MMPs), i.e., zinc-dependent extracellular proteases that function at a neutral pH to cleave a wide variety of substrates (61). These include basement membrane and extracellular ...

Astrocytes contacting HIV‐1‐infected macrophages increase the release of CCL2 in response to the HIV‐1‐dependent enhancement of membrane‐associated TNFα in macrophages

“…Hence, blood cells crossing the BBB are expected to closely interact with BBB-associated astrocytes (Abbott, 2002). We established a cell system useful for investigating the consequences of the cell-cell contact of astrocytes with HIV-1-infected macrophages in a first instance using the U251 astrocytoma cell line (Bigner et al, 1981) in co-cultivation with U937 macrophagic cells, i.e., a cell line that can be rapidly and efficiently infected by HIV-1 (Muratori et al, 2007).…”

Exosomes from Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Cells License Quiescent CD4 + T Lymphocytes To Replicate HIV-1 through a Nef- and ADAM17-Dependent Mechanism

“…For the detection of intracytoplasmic HIV-1 CAp24, cells were treated with trypsin for 15 min at 37°C. Then, they were labeled using the KC57-RD anti-CAp24 monoclonal antibody (Coulter) upon permeabilization with Cytofix/Cytoperm solutions (BD Pharmingen) as previously described (17).…”

miR-146a controls CXCR4 expression in a pathway that involves PLZF and can be used to inhibit HIV-1 infection of CD4+ T lymphocytes

“…We used the HIV-1 chronically infected U937 cell line (U937 HIV-1 ) (Muratori et al, 2007) to infect U937(E) control cells, as compared to U937(miR-146a) cells.…”

“…U937 HIV-1 is a cell line derived from U937 cells recovered upon chronic infection with the human T-lymphotropic virus IIIB HIV-1 isolated, as previously described (Muratori et al, 2007).…”