The Apparent Interferon Resistance of Transmitted HIV-1 is Likely A Consequence of Enhanced Replicative Fitness
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PROVIDER: PRJEB54607 | ENA |
REPOSITORIES: ENA
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Project description:Type I interferons, particularly interferon-alpha (IFN-α), play a vital role in the host's anti-viral defenses by interfering with viral replication. However, the virus rapidly evolves to exploit the IFN-α response for its replication, spread, and pathogenic function. In this study, we attempted to determine IFN-α susceptibility and productivity of infectious transmitted/founder (TF) (n = 8) and non-transmitted (NT) viruses (n = 8) derived from HIV-1 infected infants. Independent experiments were carried out to determine IFN-α resistance, replication fitness, and viral productivity in CD4+ T cells over a short period. In vitro studies showed that TF viruses were resistant to IFN-α during the very near moment of transmission, but in the subsequent time points, they became susceptible to IFN-α. We did not observe much difference in replicative fitness of the TF viruses in cultures treated with and without IFN-α, but the difference was significant in the case of NT viruses obtained from the same individual. Despite increased susceptibility to IFN-α, NT viruses produced more viral particles than TF viruses. Similar results were also obtained in cultures treated with maraviroc (MVC). The study identified unique characteristics of TF viruses thus prompting further investigation into virus-host interaction occurring during the early stages of HIV infection.
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Project description:HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1-induced immunopathology and subsequent CD4(+) T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8(+) T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4(+) T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1-related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.
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Project description:HIV is able to outpace the innate immune response, including the response mediated by interferon (IFN), to establish a productive infection. However, monocyte derived macrophages (MDMs) may be protected from HIV infection by treatment with type I IFN before virus exposure. The ability of HIV to modulate the type I IFN-mediated innate immune response when it encounters a cell that has already been exposed to IFN was investigated. To investigate the presence of HIV on an established IFN response, MDMs were subjected to four different conditions: (1) IFN-treated only, (2) IFN-treated followed by HIV infection, (3) HIV infected only, and (4) a mock-treated and mock-infected control. Microarray gene expression analysis was performed on a total of 24 samples derived from the 4 conditions assessed at 3 time points (1, 4 and 8 days following treatment/infection) for both IFN-α2 or -ω. Initially, ISGs were identified as those that were upregulated greater than 2-fold by IFN alone (condition 1) at both Days 4 and 8. Then, the IFN-treated condition was compared to the IFN-treated followed by HIV-infection condition in order to identify those ISGs that were downregulated at least 1.5-fold by the presence of HIV at both days. Assuming that it would be counterproductive for HIV infection by itself to induce the expression of ISGs with putative anti-HIV effects, those ISGs that were upregulated greater than 2-fold in the HIV control were removed. Finally, ISGs that passed these filters and were concordant with both IFN-treatments (IFN-α2 and -ω) were identified and corresponded to the following 8 ISGs: AXL receptor tyrosine kinase (AXL), interferon-alpha inducible protein 27 (IFI27), interferon-induced protein 44 (IFI44), interferon-induced protein 44-like (IFI44L), ISG15, OAS1, OAS3 and XIAP associated factor 1 (XAF1). It should be noted that the IFN-α2 and -ω microarray experiments were performed in different batches but batch effects were not corrected since genes were identified by the filtering approach just described within each batch.
2013-01-01 | E-GEOD-41731 | biostudies-arrayexpress
Project description:Interferon ε (IFNε) is a unique type I IFN that is not induced by pattern-recognition response elements. IFNε is constitutively expressed in mucosal tissues including the female genital mucosa. We show here that IFNε induces an antiviral state in human macrophages that blocks HIV-1 replication. In this work, we examined effects and underlying mechanisms of IFNε in HIV infection of monocyte-derived macrophages (MDMs). We found that IFNε blocked HIV replication in macrophages. It acted on early stages of the HIV life cycle including entry and reverse transcription. It did not appear to operate through known IFN-induced HIV host restriction factors. IFNε induced immune responses in primary macrophages distinct from those induced by IFNα. Importantly, we discovered a novel protective effect of IFNε in primary macrophages against HIV by surging reactive oxygen species (ROS).
2016-10-03 | GSE83716 | GEO
Project description:Clonal hematopoiesis (CH) results from enhanced fitness of a mutant hematopoietic stem and progenitor cell (HSPC), but how such clones expand is unclear. Here, we developed a technique that combines mosaic mutagenesis with color labeling of HSPCs to study how acquired mutations affect clonal fitness in a native environment. Mutations in CH-associated genes, like asxl1, promoted clonal dominance. Single-cell transcriptional analysis revealed that mutations stimulated expression of proinflammatory genes in mature myeloid cells and anti-inflammatory genes in progenitor cells of the mutant clone. Biallelic loss of one such immunomodulator, nr4a1, abrogated the ability of asxl1-mutant clones to establish clonal dominance. These results support a model where clonal fitness of mutant clones is driven by enhanced resistance to inflammatory signals from their mutant mature cell progeny.
2021-12-02 | GSE150373 | GEO
Project description:Clonal hematopoiesis (CH) results from enhanced fitness of a mutant hematopoietic stem and progenitor cell (HSPC), but how such clones expand is unclear. Here, we developed a technique that combines mosaic mutagenesis with color labeling of HSPCs to study how acquired mutations affect clonal fitness in a native environment. Mutations in CH-associated genes, like asxl1, promoted clonal dominance. Single-cell transcriptional analysis revealed that mutations stimulated expression of proinflammatory genes in mature myeloid cells and anti-inflammatory genes in progenitor cells of the mutant clone. Biallelic loss of one such immunomodulator, nr4a1, abrogated the ability of asxl1-mutant clones to establish clonal dominance. These results support a model where clonal fitness of mutant clones is driven by enhanced resistance to inflammatory signals from their mutant mature cell progeny.
2021-12-02 | GSE176036 | GEO
Project description:HIV is able to outpace the innate immune response, including the response mediated by interferon (IFN), to establish a productive infection. However, monocyte derived macrophages (MDMs) may be protected from HIV infection by treatment with type I IFN before virus exposure. The ability of HIV to modulate the type I IFN-mediated innate immune response when it encounters a cell that has already been exposed to IFN was investigated.
2013-01-01 | GSE41731 | GEO
Project description:To explore if specific host responses are linked to HIV disease severity, we here investigated blood gene expression profiles comparing different progressor groups, including those with HIV-1, HIV-2 or HIV-1/HIV-2 dual infection and HIV seronegative individuals. We found interferon alpha-inducible protein 27 (IFI27) to be the most strongly, and significantly, upregulated gene in HIV infected, compared with HIV seronegative, individuals. The expression of IFI27 was higher in HIV-1, compared with HIV-2, infected individuals and correlated with both plasma viral load (pVL) and CD4% levels.
2022-05-31 | GSE200606 | GEO
Project description:Type I interferon plays a critical role in the control of viral infections, including HIV-1. Interferon induces a number of restriction factors that block HIV-1 entry, replication and release from the host cell. Currently, systemic treatment of HIV-1 infection with interferon has little efficacy in the clinic due to side effects including fatigue and flu-like symptoms. However, understanding the role of interferon in HIV-1 restriction, and developing molecular tools to generate type I interferons locally, provide an opportunity to inhibit HIV-1 replication while avoiding the side effects associated with systemic administration. Here, we tested a constitutively active inducer of high levels of interferon beta (dLMP1-MAVS). Supernatant from cell transfected with dLMP1-MAVS inhibited HIV-1 replication in both culture cells and primary human CD4+ T cells. CD4+ T cells upregulated a number of known HIV-1 restriction factors, including Viperin, Tetherin, MxB, and ISG56 in response to dLMP1-MAVS. In addition, dLMP1-MAVS activated human dendritic and acted as a molecular adjuvant in a mouse HIV-1 vaccine model. Our study generates new insights into the role of type I interferon in HIV-1 restriction, and provides a novel strategy to induce both type I interferon and anti-HIV-1 immune responses at sites of ongoing viral replication.
2015-06-01 | GSE65541 | GEO
Project description:Interferon (IFN) inhibits HIV replication by inducing an array of antiviral effectors. Here we describe a novel CRISPR knockout screening approach to identify the ensemble of these HIV restriction factors. We assembled a CRISPR sgRNA library specific for Interferon Stimulated Genes (ISGs) into a modified lentiviral vector that allows for packaging of sgRNA-encoding genomes in trans into budding HIV-1 particles. We observed that knockout of Zinc Antiviral Protein (ZAP) improved the performance of the screen due to ZAP-mediated inhibition of the vector. We identify a small panel of IFN-induced HIV restriction factors, including MxB, IFITM1, Tetherin/BST2 and TRIM5 which together explain the inhibitory effects of IFN on the HIV-1 LAI strain in THP-1 cells. Further, we identify novel HIV dependency factors, including SEC62 and TLR2. The ability of IFN-induced restriction factors to inhibit an HIV strain to replicate in human cells suggests that these human restriction factors are incompletely antagonized.
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