FOXO1 transcription factor plays a key role in T cell-HIV-1 interaction.

HIV-1 is dependent on the host cell for providing the metabolic resources for completion of its viral replication cycle. Thus, HIV-1 replicates efficiently only in activated CD4+ T cells. Barriers preventing HIV-1 replication in resting CD4+ T cells include a block that limits reverse transcription and also the lack of activity of several inducible transcription factors, such as NF-κB and NFAT. Because FOXO1 is a master regulator of T cell functions, we studied the effect of its inhibition on T cell/HIV-1 interactions. By using AS1842856, a FOXO1 pharmacologic inhibitor, we observe that FOXO1 inhibition induces a metabolic activation of T cells with a G0/G1 transition in the absence of any stimulatory signal. One parallel outcome of this change is the inhibition of the activity of the HIV restriction factor SAMHD1 and the activation of the NFAT pathway. FOXO1 inhibition by AS1842856 makes resting T cells permissive to HIV-1 infection. In addition, we found that FOXO1 inhibition by either AS1842856 treatment or upon FOXO1 knockdown induces the reactivation of HIV-1 latent proviruses in T cells. We conclude that FOXO1 has a central role in the HIV-1/T cell interaction and that inhibiting FOXO1 with drugs such as AS1842856 may be a new therapeutic shock-and-kill strategy to eliminate the HIV-1 reservoir in human T cells.

Virus-Mediated Cell-Cell Fusion.

Cell-cell fusion between eukaryotic cells is a general process involved in many physiological and pathological conditions, including infections by bacteria, parasites, and viruses. As obligate intracellular pathogens, viruses use intracellular machineries and pathways for efficient replication in their host target cells. Interestingly, certain viruses, and, more especially, enveloped viruses belonging to different viral families and including human pathogens, can mediate cell-cell fusion between infected cells and neighboring non-infected cells. Depending of the cellular environment and tissue organization, this virus-mediated cell-cell fusion leads to the merge of membrane and cytoplasm contents and formation of multinucleated cells, also called syncytia, that can express high amount of viral antigens in tissues and organs of infected hosts. This ability of some viruses to trigger cell-cell fusion between infected cells as virus-donor cells and surrounding non-infected target cells is mainly related to virus-encoded fusion proteins, known as viral fusogens displaying high fusogenic properties, and expressed at the cell surface of the virus-donor cells. Virus-induced cell-cell fusion is then mediated by interactions of these viral fusion proteins with surface molecules or receptors involved in virus entry and expressed on neighboring non-infected cells. Thus, the goal of this review is to give an overview of the different animal virus families, with a more special focus on human pathogens, that can trigger cell-cell fusion.

Cell-to-Cell Spreading of HIV-1 in Myeloid Target Cells Escapes SAMHD1 Restriction.

Dendritic cells (DCs) and macrophages as well as osteoclasts (OCs) are emerging as target cells of HIV-1 involved in virus transmission, dissemination, and establishment of persistent tissue virus reservoirs. While these myeloid cells are poorly infected by cell-free viruses because of the high expression levels of cellular restriction factors such as SAMHD1, we show here that HIV-1 uses a specific and common cell-to-cell fusion mechanism for virus transfer and dissemination from infected T lymphocytes to the target cells of the myeloid lineage, including immature DCs (iDCs), OCs, and macrophages, but not monocytes and mature DCs. The establishment of contacts with infected T cells leads to heterotypic cell fusion for the fast and massive transfer of viral material into OC and iDC targets, which subsequently triggers homotypic fusion with noninfected neighboring OCs and iDCs for virus dissemination. These two cell-to-cell fusion processes are not restricted by SAMHD1 and allow very efficient spreading of virus in myeloid cells, resulting in the formation of highly virus-productive multinucleated giant cells. These results reveal the cellular mechanism for SAMHD1-independent cell-to-cell spreading of HIV-1 in myeloid cell targets through the formation of the infected multinucleated giant cells observed in vivo in lymphoid and nonlymphoid tissues of HIV-1-infected patients.IMPORTANCE We demonstrate that HIV-1 uses a common two-step cell-to-cell fusion mechanism for massive virus transfer from infected T lymphocytes and dissemination to myeloid target cells, including dendritic cells and macrophages as well as osteoclasts. This cell-to-cell infection process bypasses the restriction imposed by the SAMHD1 host cell restriction factor for HIV-1 replication, leading to the formation of highly virus-productive multinucleated giant cells as observed in vivo in lymphoid and nonlymphoid tissues of HIV-1-infected patients. Since myeloid cells are emerging as important target cells of HIV-1, these results contribute to a better understanding of the role of these myeloid cells in pathogenesis, including cell-associated virus sexual transmission, cell-to-cell virus spreading, and establishment of long-lived viral tissue reservoirs.