Partial Inhibition of Human Immunodeficiency Virus Replication by Type I Interferons: Impact of Cell-to-Cell Viral Transfer

Abstract

Type I interferons (IFN) inhibit several steps of the human immunodeficiency virus type 1 (HIV) replication cycle. Some HIV proteins, like Vif and Vpu, directly counteract IFN-induced restriction factors. Other mechanisms are expected to modulate the extent of IFN inhibition. Here, we studied the impact of IFN on various aspects of HIV replication in primary T lymphocytes. We confirm the potent effect of IFN on Gag p24 production in supernatants. Interestingly, IFN had a more limited effect on HIV spread, measured as the appearance of Gag-expressing cells. Primary isolates displayed similar differences in the inhibition of p24 release and virus spread. Virus emergence was the consequence of suboptimal inhibition of HIV replication and was not due to the selection of resistant variants. Cell-to-cell HIV transfer, a potent means of virus replication, was less sensitive to IFN than infection by cell-free virions. These results suggest that IFN are less active in cell cultures than initially thought. They help explain the incomplete protection by naturally secreted IFN during HIV infection and the unsatisfactory outcome of IFN treatment in HIV-infected patients.The inhibition of human immunodeficiency virus type 1 (HIV) replication by type I interferons (IFN) was demonstrated soon after the discovery of the virus (4,16,20,23,49,71). Different steps of the virus cycle are sensitive to IFN (reviewed in references 24, 25, and 47). IFN treatment of primary T lymphocytes, macrophages, and some T-cell lines efficiently inhibits early phases of infection, including HIVinduced cell fusion and reverse transcription (15,16,26,27,46,60,61,70). IFN also impair later steps of the HIV replication cycle, ranging from reduced virus protein processing and stability to altered virion release and composition (2,8,17,19,20,23,26,28,39,49,63,71,72). In these early reports, the experimental systems were optimized to measure the effect of IFN on either early or late steps of the virus replication cycle but did not fully explore the long-term efficacy of IFN.Some potential IFN-induced anti-HIV effectors were identified. Both the protein kinase R and the 2Ј,5Ј-oligoadenylate synthetase-directed RNase L pathways are activated by HIV components and may participate in the inhibition of HIV replication (32, 37, 59). IFN-␣ treatment also enhances the expression of TRIM5␣ and APOBEC3G (6, 53), two cellular factors that mediate potent intrinsic immunity against HIV and other viruses (reviewed in references 33 and 66). Moreover, recent studies have characterized IFN-induced antiviral factors that decrease virus particle release. In particular, IFN-stimulated gene 15 (ISG15) interferes with the recruitment of the cellular machinery required for viral assembly (43), TRIM22 appears to perturb virus precursor protein trafficking (3), and BST-2/CD317/HM1.24 (also called tetherin) acts by tethering mature virus particles to the cell surface (41, 67).HIV counteracts some of these antiviral systems, confirming that endogenous IFN exert a selective pressure...

Loss of a Conserved N-Linked Glycosylation Site in the Simian Immunodeficiency Virus Envelope Glycoprotein V2 Region Enhances Macrophage Tropism by Increasing CD4-Independent Cell-to-Cell Transmission

“…Consistent with our results, previous studies showed that infected macrophages can transmit HIV to T cells (68)(69)(70) and that Env determinants of macrophage tropism in the V1V2 region influence entry and spread infections in macrophages (11,36). Cell-to-cell transmission is more efficient than cell-free virus infection (69,71,72) and has been shown to protect viruses from inhibition by neutralizing antibodies, antiretroviral drugs, and cellular restriction fac- tors (72)(73)(74)(75)(76)(77). This mechanism may be important to promote cellto-cell spread and replication of macrophage-tropic SIVs in vivo, since these viruses are typically neutralization sensitive.…”

SAMHD1 Restricts HIV-1 Cell-to-Cell Transmission and Limits Immune Detection in Monocyte-Derived Dendritic Cells

“…The high multiplicity of infection generated during the formation of virological synapses may allow escape from antiviral immune responses and therapeutics (37,44). The antiviral activity of some restriction factors is saturable.…”

HIV Cell-to-Cell Transmission Requires the Production of Infectious Virus Particles and Does Not Proceed through Env-Mediated Fusion Pores

“…Virus transmission from cell to cell may overcome some conditions that are restrictive for cell-free virus infection. For instance, we have reported that this means of virus propagation limits the effect of type I interferon on HIV spread in culture (58) and that it allows the replication of viruses carrying mutations in Env that have a strong impact on the infectivity of cell-free HIV (2). In the confined space of the virological synapses, viruses are relatively protected from the environment and find elevated receptor concentrations, favoring virus entry.…”