Restriction of HIV Replication in Infected T Cells and Monocytes by Interferon-α

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...

Section: Discussionmentioning

confidence: 90%

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confidence: 99%

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

Vendrame

Sourisseau

Perrin

et al. 2009

“…interferon have been shown to inhibit HIV-1 infection in MDM (22,26). While the inhibitory effects of CD40L on HIV-1 infection may be regulated by both chemokines and cytokines acting in tandem, the individual contributions of these factors to the CD40L-mediated inhibition of HIV-1 infection require further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…As innate immune cells, MP play an integral role in the host immune response against the virus. This activity occurs through a wide range of effector functions, including phagocytosis, antigen presentation, and, upon activation, secretion of proinflammatory and antiviral factors, such as interferons (13,16,18,22). During the process of antigen presentation, interactions between T lymphocytes and MP can lead to the activation of both types of cells (26,39,43,55,56,65).…”

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confidence: 99%

Regulation of Human Immunodeficiency Virus Type 1 Infection, β-Chemokine Production, and CCR5 Expression in CD40L-Stimulated Macrophages: Immune Control of Viral Entry

Cotter

Zheng

Che

et al. 2001

Self Cite

Mononuclear phagocytes (MP) and T lymphocytes play a pivotal role in the host immune response to human immunodeficiency virus type 1 (HIV-1) infection. Regulation of such immune responses can be mediated, in part, through the interaction of the T-lymphocyte-expressed molecule CD40 ligand (CD40L) with its receptor on MP, CD40. Upregulation of CD40L on CD4؉ peripheral blood mononuclear cells during advanced HIV-1 disease has previously been reported. Based on this observation, we studied the influence of CD40L-CD40 interactions on MP effector function and viral regulation in vitro. We monitored productive viral infection, cytokine and ␤-chemokine production, and ␤-chemokine receptor expression in monocyte-derived macrophages ( Mononuclear phagocytes (MP), which include circulating monocytes, tissue macrophages, and dendritic cells, are one of the first cell types to encounter and be infected by human immunodeficiency virus type 1 (HIV-1) (19,24,37,47,68,76,83). As innate immune cells, MP play an integral role in the host immune response against the virus. This activity occurs through a wide range of effector functions, including phagocytosis, antigen presentation, and, upon activation, secretion of proinflammatory and antiviral factors, such as interferons (13,16,18,22). During the process of antigen presentation, interactions between T lymphocytes and MP can lead to the activation of both types of cells (26,39,43,55,56,65). The interaction of the T-lymphocyte-expressed molecule CD40 ligand (CD40L) with its MP-expressed receptor, CD40, represents one mechanism through which such immune activation can be induced (5,15,35,39,40,50,52,70).Expressed primarily by activated T lymphocytes, CD40L has been shown to regulate both humoral and cellular immune responses (5,15,35,39,40,50,52,70). Such regulatory effects are mediated, in part, by the ability of CD40L to stimulate the production of proinflammatory cytokines, including interleukin-1␤ (IL-1␤), IL-6, IL-12, and tumor necrosis factor alpha (TNF-␣) (35, 39). CD40L-CD40 interactions have also been shown to induce the production of chemoattractant cytokines, such as macrophage inhibitory proteins 1␣ and 1␤ (MIP-1␣ and MIP-1␤, respectively) and RANTES (regulated upon activation normal T-cell expressed and secreted), in MP (39, 40, 52). Importantly, many of these factors have been linked to the inhibition of 4,8,9,32,36,39,41,45,55,59,61,64,74). Based on these observations, we hypothesized that immune activation of MP by CD40L can affect the host immune response to HIV-1 infection. Specifically, our experiments were designed to determine whether CD40L-CD40 interactions inhibit HIV-1 infection in macrophages and whether such events are directly related to the production of ␤-chemokines or other proinflammatory factors. For this work, monocyte-derived macrophages (MDM) were infected with HIV-1 ADA and then stimulated with soluble trimeric CD40L. Virus production was

“…At later stages of HIV-1 infection, an aberrant, acid-labile form of IFN-␣ with impaired functional activity has been described (24,49). Peripheral blood mononuclear cells (PBMC) of HIV-1-infected patients have an impaired ability to produce IFN-␣ in response to in vitro virus challenge (1,19,31,(38)(39)(40)110). The hyporesponsiveness of the IFN-␣ system observed at later stages of HIV-1 infection is associated with reduced numbers of IFN-␣ receptors on PBMC (68).…”

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confidence: 99%

The Relationship between Simian Immunodeficiency Virus RNA Levels and the mRNA Levels of Alpha/Beta Interferons (IFN-α/β) and IFN-α/β-Inducible Mx in Lymphoid Tissues of Rhesus Macaques during Acute and Chronic Infection

Abel

Alegria-Hartman

Rothaeusler

et al. 2002

To define the role of alpha/beta interferons (IFN-α/β) in simian immunodeficiency virus (SIV) infection, IFN-α and IFN-β mRNA levels and mRNA levels of Mx, an antiviral effector molecule, were determined in lymphoid tissues of rhesus macaques infected with pathogenic SIV. IFN-α/β responses were induced during the acute phase and persisted in various lymphoid tissues throughout the chronic phase of infection. IFN-α/β responses were most consistent in tissues with high viral RNA levels; thus, IFN-α/β responses were not generally associated with effective control of SIV replication. IFN-α/β responses were differentially regulated in different lymphoid tissues and at different stages of infection. The most consistent IFN-α/β responses in acute and chronic SIV infection were observed in peripheral lymph nodes. In the spleen, only a transient increase in IFN-α/β mRNA levels during acute SIV infection was observed. Further, IFN-α and IFN-β mRNA levels showed a tissue-specific expression pattern during the chronic, but not the acute, phase of infection. In the acute phase of infection, SIV RNA levels in lymphoid tissues of rhesus macaques correlated with mRNA levels of both IFN-α and IFN-β, whereas during chronic SIV infection only increased IFN-α mRNA levels correlated with the level of virus replication in the same tissues. In lymphoid tissues of all SIV-infected monkeys, higher viral RNA levels were associated with increased Mx mRNA levels. We found no evidence that monkeys with increased Mx mRNA levels in lymphoid tissues had enhanced control of virus replication. In fact, Mx mRNA levels were associated with high viral RNA levels in lymphoid tissues of chronically infected animals.