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Journal of Perinatal Medicine Jul 2023To date, four cases illustrate that stem cell transplantation (SCT) remains an option for cure of HIV in only few cases. Long-term follow-up data on viral shedding of... (Review)
Review
To date, four cases illustrate that stem cell transplantation (SCT) remains an option for cure of HIV in only few cases. Long-term follow-up data on viral shedding of reservoirs are still needed. So far, interruption of ART is the only way to validate long-term HIV remission.
Topics: Humans; HIV Infections; HIV-1; Hematopoietic Stem Cell Transplantation
PubMed: 36474363
DOI: 10.1515/jpm-2022-0508 -
Virologica Sinica Aug 2023Equine infectious anemia virus (EIAV) is a member of the lentivirus genus in the Retroviridae family and is considered an animal model for HIV/AIDS research. An... (Review)
Review
Equine infectious anemia virus (EIAV) is a member of the lentivirus genus in the Retroviridae family and is considered an animal model for HIV/AIDS research. An attenuated EIAV vaccine, which was successfully developed in the 1970s by classical serial passage techniques, is the first and only lentivirus vaccine that has been widely used to date. Restriction factors are cellular proteins that provide an early line of defense against viral replication and spread by interfering with various critical steps in the viral replication cycle. However, viruses have evolved specific mechanisms to overcome these host barriers through adaptation. The battle between the viruses and restriction factors is actually a natural part of the viral replication process, which has been well studied in human immunodeficiency virus type 1 (HIV-1). EIAV has the simplest genome composition of all lentiviruses, making it an intriguing subject for understanding how the virus employs its limited viral proteins to overcome restriction factors. In this review, we summarize the current literature on the interactions between equine restriction factors and EIAV. The features of equine restriction factors and the mechanisms by which the EIAV counteract the restriction suggest that lentiviruses employ diverse strategies to counteract innate immune restrictions. In addition, we present our insights on whether restriction factors induce alterations in the phenotype of the attenuated EIAV vaccine.
Topics: Horses; Animals; Humans; Infectious Anemia Virus, Equine; Antiviral Restriction Factors; Viral Proteins; Virus Replication; HIV-1
PubMed: 37419416
DOI: 10.1016/j.virs.2023.07.001 -
Immunity Jul 2023Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5) can cure HIV, yet mechanisms remain speculative. To...
Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4 T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.
Topics: Animals; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; HIV Infections; Macaca fascicularis; Hematopoietic Stem Cell Transplantation; Viral Load
PubMed: 37236188
DOI: 10.1016/j.immuni.2023.04.019 -
International Journal of Molecular... Jul 2023Adult T cell leukemia (ATL) is an aggressive hematologic disease caused by human T cell leukemia virus type 1 (HTLV-1) infection. Various animal models of HTLV-1... (Review)
Review
Adult T cell leukemia (ATL) is an aggressive hematologic disease caused by human T cell leukemia virus type 1 (HTLV-1) infection. Various animal models of HTLV-1 infection/ATL have been established to elucidate the pathogenesis of ATL and develop appropriate treatments. For analyses employing murine models, transgenic and immunodeficient mice are used because of the low infectivity of HTLV-1 in mice. Each mouse model has different characteristics that must be considered before use for different HTLV-1 research purposes. HTLV-1 and transgenic mice spontaneously develop tumors, and the roles of both Tax and HBZ in cell transformation and tumor growth have been established. Severely immunodeficient mice were able to be engrafted with ATL cell lines and have been used in preclinical studies of candidate molecules for the treatment of ATL. HTLV-1-infected humanized mice with an established human immune system are a suitable model to characterize cells in the early stages of HTLV-1 infection. This review outlines the characteristics of mouse models of HTLV-1 infection/ATL and describes progress made in elucidating the pathogenesis of ATL and developing related therapies using these mice.
Topics: Adult; Mice; Humans; Animals; Leukemia-Lymphoma, Adult T-Cell; Human T-lymphotropic virus 1; Retroviridae Proteins; HTLV-I Infections; Mice, Transgenic; Disease Models, Animal; Basic-Leucine Zipper Transcription Factors
PubMed: 37511495
DOI: 10.3390/ijms241411737 -
Nature Communications Sep 2023HIV-1 capsid (CA) stability is important for viral replication. E45A and P38A mutations enhance and reduce core stability, thus impairing infectivity. Second-site...
HIV-1 capsid (CA) stability is important for viral replication. E45A and P38A mutations enhance and reduce core stability, thus impairing infectivity. Second-site mutations R132T and T216I rescue infectivity. Capsid lattice stability was studied by solving seven crystal structures (in native background), including P38A, P38A/T216I, E45A, E45A/R132T CA, using molecular dynamics simulations of lattices, cryo-electron microscopy of assemblies, time-resolved imaging of uncoating, biophysical and biochemical characterization of assembly and stability. We report pronounced and subtle, short- and long-range rearrangements: (1) A38 destabilized hexamers by loosening interactions between flanking CA protomers in P38A but not P38A/T216I structures. (2) Two E45A structures showed unexpected stabilizing CA-CA inter-hexamer interactions, variable R18-ring pore sizes, and flipped N-terminal β-hairpin. (3) Altered conformations of E45A α9-helices compared to WT, E45A/R132T, WT, WT, and WT decreased PF74, CPSF6, and Nup153 binding, and was reversed in E45A/R132T. (4) An environmentally sensitive electrostatic repulsion between E45 and D51 affected lattice stability, flexibility, ion and water permeabilities, electrostatics, and recognition of host factors.
Topics: Capsid Proteins; HIV-1; Cryoelectron Microscopy; Capsid; Biophysics
PubMed: 37699872
DOI: 10.1038/s41467-023-41197-7 -
Nature Immunology Mar 2024The persistence of CD4 T cells carrying latent human immunodeficiency virus-1 (HIV-1) proviruses is the main barrier to a cure. New therapeutics to enhance...
The persistence of CD4 T cells carrying latent human immunodeficiency virus-1 (HIV-1) proviruses is the main barrier to a cure. New therapeutics to enhance HIV-1-specific immune responses and clear infected cells will probably be necessary to achieve reduction of the latent reservoir. In the present study, we report two single-chain diabodies (scDbs) that target the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16). We show that the scDbs promoted robust and HIV-1-specific natural killer (NK) cell activation and NK cell-mediated lysis of infected cells. Cocultures of CD4 T cells from people with HIV-1 on antiretroviral therapy (ART) with autologous NK cells and the scDbs resulted in marked elimination of reservoir cells that was dependent on latency reversal. Treatment of human interleukin-15 transgenic NSG mice with one of the scDbs after ART initiation enhanced NK cell activity and reduced reservoir size. Thus, HIV-1-specific scDbs merit further evaluation as potential therapeutics for clearance of the latent reservoir.
Topics: Animals; Mice; Humans; Antibodies, Bispecific; HIV-1; Killer Cells, Natural; Cytotoxicity, Immunologic; Cell Death; Mice, Transgenic
PubMed: 38278966
DOI: 10.1038/s41590-023-01741-5 -
MBio Apr 2024A member of the Retroviridae, human immunodeficiency virus type 1 (HIV-1), uses the RNA genome packaged into nascent virions to transfer genetic information to its... (Review)
Review
A member of the Retroviridae, human immunodeficiency virus type 1 (HIV-1), uses the RNA genome packaged into nascent virions to transfer genetic information to its progeny. The genome packaging step is a highly regulated and extremely efficient process as a vast majority of virus particles contain two copies of full-length unspliced HIV-1 RNA that form a dimer. Thus, during virus assembly HIV-1 can identify and selectively encapsidate HIV-1 unspliced RNA from an abundant pool of cellular RNAs and various spliced HIV-1 RNAs. Several "" features facilitate the packaging of a dimeric RNA genome. The viral polyprotein ag orchestrates virus assembly and mediates RNA genome packaging. During this process, Gag preferentially binds unpaired uanosines within the highly structured 5' untranslated region (UTR) of HIV-1 RNA. In addition, the HIV-1 unspliced RNA provides a scaffold that promotes Gag:Gag interactions and virus assembly, thereby ensuring its packaging. Intriguingly, recent studies have shown that the use of different uanosines at the junction of U3 and R as transcription start sites results in HIV-1 unspliced RNA species with 99.9% identical sequences but dramatically distinct 5' UTR conformations. Consequently, one species of unspliced RNA is preferentially packaged over other nearly identical RNAs. These studies reveal how conformations affect the functions of HIV-1 RNA elements and the complex regulation of HIV-1 replication. In this review, we summarize - and -acting elements critical for HIV-1 RNA packaging, locations of Gag:RNA interactions that mediate genome encapsidation, and the effects of transcription start sites on the structure and packaging of HIV-1 RNA.
Topics: Humans; HIV-1; RNA, Viral; Virus Assembly; Genome, Viral
PubMed: 38411060
DOI: 10.1128/mbio.00861-23 -
Nature Communications Aug 2023Route of immunization can markedly influence the quality of immune response. Here, we show that intradermal (ID) but not intramuscular (IM) modified vaccinia Ankara...
Intradermal but not intramuscular modified vaccinia Ankara immunizations protect against intravaginal tier2 simian-human immunodeficiency virus challenges in female macaques.
Route of immunization can markedly influence the quality of immune response. Here, we show that intradermal (ID) but not intramuscular (IM) modified vaccinia Ankara (MVA) vaccinations provide protection from acquisition of intravaginal tier2 simian-human immunodeficiency virus (SHIV) challenges in female macaques. Both routes of vaccination induce comparable levels of serum IgG with neutralizing and non-neutralizing activities. The protection in MVA-ID group correlates positively with serum neutralizing and antibody-dependent phagocytic activities, and envelope-specific vaginal IgA; while the limited protection in MVA-IM group correlates only with serum neutralizing activity. MVA-ID immunizations induce greater germinal center Tfh and B cell responses, reduced the ratio of Th1 to Tfh cells in blood and showed lower activation of intermediate monocytes and inflammasome compared to MVA-IM immunizations. This lower innate activation correlates negatively with induction of Tfh responses. These data demonstrate that the MVA-ID vaccinations protect against intravaginal SHIV challenges by modulating the innate and T helper responses.
Topics: Animals; Humans; Female; Simian Acquired Immunodeficiency Syndrome; Vaccinia; Macaca mulatta; Simian Immunodeficiency Virus; Vaccinia virus; Vaccination; HIV; Antibodies, Viral
PubMed: 37553348
DOI: 10.1038/s41467-023-40430-7 -
Viruses Jan 2024The principal barrier to an HIV-1 cure is the persistence of infected cells harboring replication-competent proviruses despite antiretroviral therapy (ART). HIV-1... (Review)
Review
The principal barrier to an HIV-1 cure is the persistence of infected cells harboring replication-competent proviruses despite antiretroviral therapy (ART). HIV-1 transcriptional suppression, referred to as viral latency, is foremost among persistence determinants, as it allows infected cells to evade the cytopathic effects of virion production and killing by cytotoxic T lymphocytes (CTL) and other immune factors. HIV-1 persistence is also governed by cellular proliferation, an innate and essential capacity of CD4+ T cells that both sustains cell populations over time and enables a robust directed response to immunological threats. However, when HIV-1 infects CD4+ T cells, this capacity for proliferation can enable surreptitious HIV-1 propagation without the deleterious effects of viral gene expression in latently infected cells. Over time on ART, the HIV-1 reservoir is shaped by both persistence determinants, with selective forces most often favoring clonally expanded infected cell populations harboring transcriptionally quiescent proviruses. Moreover, if HIV latency is incomplete or sporadically reversed in clonal infected cell populations that are replenished faster than they are depleted, such populations could both persist indefinitely and contribute to low-level persistent viremia during ART and viremic rebound if treatment is withdrawn. In this review, select genetic, epigenetic, cellular, and immunological determinants of viral transcriptional suppression and clonal expansion of HIV-1 reservoir T cells, interdependencies among these determinants, and implications for HIV-1 persistence will be presented and discussed.
Topics: Humans; CD4-Positive T-Lymphocytes; T-Lymphocytes, Cytotoxic; HIV Seropositivity; Cell Division; Clone Cells; HIV-1
PubMed: 38257808
DOI: 10.3390/v16010108 -
International Journal of Molecular... Feb 2024Early gene therapy studies held great promise for the cure of heritable diseases, but the occurrence of various genotoxic events led to a pause in clinical trials and a... (Review)
Review
Early gene therapy studies held great promise for the cure of heritable diseases, but the occurrence of various genotoxic events led to a pause in clinical trials and a more guarded approach to progress. Recent advances in genetic engineering technologies have reignited interest, leading to the approval of the first gene therapy product targeting genetic mutations in 2017. Gene therapy (GT) can be delivered either in vivo or ex vivo. An ex vivo approach to gene therapy is advantageous, as it allows for the characterization of the gene-modified cells and the selection of desired properties before patient administration. Autologous cells can also be used during this process which eliminates the possibility of immune rejection. This review highlights the various stages of ex vivo gene therapy, current research developments that have increased the efficiency and safety of this process, and a comprehensive summary of Human Immunodeficiency Virus (HIV) gene therapy studies, the majority of which have employed the ex vivo approach.
Topics: Humans; HIV; Genetic Vectors; Genetic Therapy; Genetic Engineering; RNA; HIV Infections
PubMed: 38474018
DOI: 10.3390/ijms25052771