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Inefficient HIV-1 infection of CD4 T cells by macrophages from HIV-1 nonprogressors is associated with altered membrane cholesterol and DC-SIGN.

Inefficient HIV-1  infection of CD4 T cells by macrophages from HIV-1 nonprogressors is associated with altered membrane cholesterol and DC-SIGN.
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DeLucia DC, Rinaldo CR, Rappocciolo G,


DeLucia DC, Rinaldo CR, Rappocciolo G, (click to view)

DeLucia DC, Rinaldo CR, Rappocciolo G,

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Journal of virology 2018 04 11() pii 10.1128/JVI.00092-18

Abstract

Professional antigen presenting cells (APC: myeloid dendritic cells (DC) and macrophages (MΦ); B lymphocytes) mediate highly efficient HIV-1 infection of CD4 T cells, termed infection, that could contribute to HIV-1 pathogenesis. We have previously shown that lower cholesterol content in DC and B lymphocytes is associated with a lack of HIV-1 infection in HIV-1 infected nonprogressors (NP). Here we assessed whether HIV-1 infection mediated by another major APC, MΦ, is deficient in NP due to altered cholesterol metabolism. When comparing healthy HIV-1 seronegatives (SN), rapid progressors (PR), and NP, we found that monocyte-derived MΦ from NP did not mediate HIV-1 infection of autologous CD4 T cells, in contrast to efficient infection mediated by SN and PR MΦ. MΦ infection efficiency was directly associated with the number of DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)-expressing MΦ. Significantly fewer NP MΦ expressed DC-SIGN. Unesterified (free) cholesterol in MΦ cell membranes and lipid rafting was significantly lower in NP than PR, as well as virus internalization in early endosomes. Furthermore, simvastatin (SIMV), decreased the subpopulation of DC-SIGN MΦ, as well as MΦ and infection. Notably, SIMV decreased cell membrane cholesterol and led to lipid raft dissociation, effectively mimicking the incompetent APC infection environment characteristic of NP. Our data support that DC-SIGN and membrane cholesterol are central to MΦ infection, and a lack of these limits HIV-1 disease progression. Targeting the ability of MΦ to drive HIV-1 dissemination in could enhance HIV-1 therapeutic strategies. Despite the success of combination anti-retroviral therapy, neither a vaccine nor a cure for HIV infection has been developed, demonstrating a need for novel prophylactic and therapeutic strategies. Here we show that efficiency of macrophage (MΦ) -mediated HIV infection of CD4 T cells is a unique characteristic associated with control of disease progression, and it is impaired in HIV-infected nonprogressors (NP). treatment of MΦ from healthy donors with simvastatin (SIMV) lowers their cholesterol content which results in a strongly reduced infection ability, similar to the levels of MΦ from NP. Taken together, our data support the hypothesis that MΦ-mediated HIV-1 infection plays a role in HIV infection and disease progression and demonstrate that the use of SIMV to decrease this mechanism of virus transfer should be considered for future HIV therapeutic development.

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