Faculty Opinions recommendation of Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo.

The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component of a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields the reverse transcription complex from restriction factors while it enables trafficking to the nucleus by hijacking various adaptor proteins, such as FEZ1 and BICD2. In addition, the capsid facilitates the import and localization of the viral complex in the nucleus through interaction with NUP153, NUP358, TNPO3, and CPSF-6. In the later stages of the HIV-1 life cycle, CA plays an essential role in the maturation step as a constituent of the Gag polyprotein. In the final phase of maturation, Gag is cleaved, and CA is released, allowing for the assembly of CA into a fullerene cone, known as the capsid core. The fullerene cone consists of ~250 CA hexamers and 12 CA pentamers and encloses the viral genome and other essential viral proteins for the next round of infection. As research continues to elucidate the role of CA in the HIV-1 life cycle and the importance of the capsid protein becomes more apparent, CA displays potential as a therapeutic target for the development of HIV-1 inhibitors.

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High Natural Permissivity of Primary Rabbit Cells for HIV-1, with a Virion Infectivity Defect in Macrophages as the Final Replication Barrier

Journal of Virology ◽

10.1128/jvi.01607-10 ◽

2010 ◽

Vol 84 (23) ◽

pp. 12300-12314 ◽

Cited By ~ 14

Author(s):

Hanna-Mari Tervo ◽

Oliver T. Keppler

Keyword(s):

T Cells ◽

Late Phase ◽

Small Animal ◽

Receptor Complex ◽

Restriction Factors ◽

Cyclin T1 ◽

Primary Rabbit ◽

Species Specific ◽

Hiv 1

ABSTRACT An immunocompetent, permissive, small-animal model would be valuable for the study of human immunodeficiency virus type 1 (HIV-1) pathogenesis and for the testing of drug and vaccine candidates. However, the development of such a model has been hampered by the inability of primary rodent cells to efficiently support several steps of the HIV-1 replication cycle. Although transgenesis of the HIV receptor complex and human cyclin T1 have been beneficial, additional late-phase blocks prevent robust replication of HIV-1 in rodents and limit the range of in vivo applications. In this study, we explored the HIV-1 susceptibility of rabbit primary T cells and macrophages. Envelope-specific and coreceptor-dependent entry of HIV-1 was achieved by expressing human CD4 and CCR5. A block of HIV-1 DNA synthesis, likely mediated by TRIM5, was overcome by limited changes to the HIV-1 gag gene. Unlike with mice and rats, primary cells from rabbits supported the functions of the regulatory viral proteins Tat and Rev, Gag processing, and the release of HIV-1 particles at levels comparable to those in human cells. While HIV-1 produced by rabbit T cells was highly infectious, a macrophage-specific infectivity defect became manifest by a complex pattern of mutations in the viral genome, only part of which were deamination dependent. These results demonstrate a considerable natural HIV-1 permissivity of the rabbit species and suggest that receptor complex transgenesis combined with modifications in gag and possibly vif of HIV-1 to evade species-specific restriction factors might render lagomorphs fully permissive to infection by this pathogenic human lentivirus.

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Human Immunodeficiency Virus Inhibits Multilineage Hematopoiesis In Vivo

Journal of Virology ◽

10.1128/jvi.72.6.5121-5127.1998 ◽

1998 ◽

Vol 72 (6) ◽

pp. 5121-5127 ◽

Cited By ~ 42

Author(s):

Prasad S. Koka ◽

John K. Fraser ◽

Yvonne Bryson ◽

Gregory C. Bristol ◽

Grace M. Aldrovandi ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Progenitor Cells ◽

Ex Vivo ◽

Erythroid Differentiation ◽

Inhibitory Effect ◽

Immunodeficiency Virus ◽

The Many ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected individuals often exhibit multiple hematopoietic abnormalities reaching far beyond loss of CD4+ lymphocytes. We used the SCID-hu (Thy/Liv) mouse (severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues), which provides an in vivo system whereby human pluripotent hematopoietic progenitor cells can be maintained and undergo T-lymphoid differentiation and wherein HIV-1 infection causes severe depletion of CD4-bearing human thymocytes. Herein we show that HIV-1 infection rapidly and severely decreases the ex vivo recovery of human progenitor cells capable of differentiation into both erythroid and myeloid lineages. However, the total CD34+ cell population is not depleted. Combination antiretroviral therapy administered well after loss of multilineage progenitor activity reverses this inhibitory effect, establishing a causal role of viral replication. Taken together, our results suggest that pluripotent stem cells are not killed by HIV-1; rather, a later stage important in both myeloid and erythroid differentiation is affected. In addition, a primary virus isolated from a patient exhibiting multiple hematopoietic abnormalities preferentially depleted myeloid and erythroid colony-forming activity rather than CD4-bearing thymocytes in this system. Thus, HIV-1 infection perturbs multiple hematopoietic lineages in vivo, which may explain the many hematopoietic defects found in infected patients.

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Impact of HMGB1/TLR Ligand Complexes on HIV-1 Replication: Possible Role for Flagellin during HIV-1 Infection

International Journal of Microbiology ◽

10.1155/2012/263836 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Piotr Nowak ◽

Samir Abdurahman ◽

Annica Lindkvist ◽

Marius Troseid ◽

Anders Sönnerborg

Keyword(s):

Immune Responses ◽

Cpg Odn ◽

Cell Necrosis ◽

Adaptive Immune ◽

Microbial Product ◽

P24 Antigen ◽

Culture Supernatants ◽

Hiv 1

Objective. We hypothesized that HMGB1 in complex with bacterial components, such as flagellin, CpG-ODN, and LPS, promotes HIV-1 replication. Furthermore, we studied the levels of antiflagellin antibodies during HIV-1-infection.Methods. Chronically HIV-1-infected U1 cells were stimulated with necrotic extract/recombinant HMGB1 in complex with TLR ligands or alone. HIV-1 replication was estimated by p24 antigen in culture supernatants 48–72 hours after stimulation. The presence of systemic anti-flagellin IgG was determined in 51 HIV-1-infected patients and 19 controls by immunoblotting or in-house ELISA.Results. Flagellin, LPS, and CpG-ODN induced stronger HIV-1 replication when incubated together with necrotic extract or recombinant HMGB1 than activation by any of the compounds alone. Moreover, the stimulatory effect of necrotic extract was inhibited by depletion of HMGB1. Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy.Conclusions. Our findings implicate a possible role of HGMB1-bacterial complexes, as a consequence of microbial translocation and cell necrosis, for immune activation in HIV-1 pathogenesis. We propose that flagellin is an important microbial product, that modulates viral replication and induces adaptive immune responsesin vivo.

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Revisiting an IgG Fc Loss-of-Function Experiment: the Role of Complement in HIV Broadly Neutralizing Antibody b12 Activity

mBio ◽

10.1128/mbio.01743-21 ◽

2021 ◽

Author(s):

Benjamin S. Goldberg ◽

Chengzi I. Kaku ◽

Jérémy Dufloo ◽

Timothée Bruel ◽

Olivier Schwartz ◽

...

Keyword(s):

Neutralizing Antibody ◽

Loss Of Function ◽

Wild Type ◽

Suboptimal Outcome ◽

Antiviral Activities ◽

Broadly Neutralizing Antibody ◽

Hiv 1 ◽

Prevention Of Hiv

Given the suboptimal outcome of VRC01 antibody-mediated prevention of HIV-1 infection in its first field trial, means to improve diverse antiviral activities in vivo have renewed importance. This work revisits a loss-of-function experiment that investigated the mechanism of action of b12, a similar antibody, and finds that the reason why complement-mediated antiviral activities were not observed to contribute to protection may be the inherent lack of activity of wild-type b12, raising the prospect that this mechanism may contribute in the context of other HIV-specific antibodies.

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Interactions with Commensal and Pathogenic Bacteria Induce HIV-1 Latency in Macrophages through Altered Transcription Factor Recruitment to the LTR

Journal of Virology ◽

10.1128/jvi.02141-20 ◽

2021 ◽

Author(s):

Gregory A. Viglianti ◽

Vicente Planelles ◽

Timothy M. Hanley

Keyword(s):

Adaptor Protein ◽

Type I ◽

Major Barrier ◽

E Coli ◽

Tissue Microenvironment ◽

Viral Spread ◽

Latent Hiv ◽

Hiv 1

Macrophages are infected by HIV-1 in vivo and contribute to both viral spread and pathogenesis. Recent human and animal studies suggest that HIV-1-infected macrophages serve as a reservoir that contributes to HIV-1 persistence during anti-retroviral therapy. The ability of macrophages to serve as persistent viral reservoirs is likely influenced by the local tissue microenvironment, including interactions with pathogenic and commensal microbes. Here we show that the sexually transmitted pathogen Neisseria gonorrhoeae (GC) and the gut-associated microbe Escherichia coli (E. coli), which encode ligands for both Toll-like receptor 2 (TLR2) and TLR4, repressed HIV-1 replication in macrophages and thereby induced a state reminiscent of viral latency. This repression was mediated by signaling through TLR4 and the adaptor protein TRIF and was associated with increased production of type I interferons. Inhibiting TLR4 signaling, blocking type 1 interferon, or knocking-down TRIF reversed LPS- and GC-mediated repression of HIV-1. Finally, the repression of HIV-1 in macrophages was associated with the recruitment of interferon regulatory factor 8 (IRF8) to the interferon stimulated response element (ISRE) downstream of the 5’ HIV-1 long terminal repeat (LTR). Our data indicate that IRF8 is responsible for repression of HIV-1 replication in macrophages in response to TRIF-dependent signaling during GC and E. coli co-infection. These findings highlight the potential role of macrophages as HIV-1 reservoirs as well as the role of the tissue microenvironment and co-infections as modulators of HIV-1 persistence. IMPORTANCE The major barrier toward the eradication of HIV-1 infection is the presence of a small reservoir of latently infected cells, which include CD4+ T cells and macrophages that escape immune-mediated clearance and the effects of anti-retroviral therapy. There remain crucial gaps in our understanding of the molecular mechanisms that lead to transcriptionally silent or latent HIV-1 infection of macrophages. The significance of our research is in identifying microenvironmental factors, such as commensal and pathogenic microbes, that can contribute to the establishment and maintenance of latent HIV-1 infection in macrophages. It is hoped that identifying key processes contributing to HIV-1 persistence in macrophages may ultimately lead to novel therapeutics to eliminate latent HIV-1 reservoirs in vivo.

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Role of SIRT1 in HIV-associated kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00140.2020 ◽

2020 ◽

Vol 319 (2) ◽

pp. F335-F344 ◽

Cited By ~ 1

Author(s):

Xuan Wang ◽

Ruijie Liu ◽

Weijia Zhang ◽

Deborah P. Hyink ◽

Gokul C. Das ◽

...

Keyword(s):

Kidney Disease ◽

Drug Targets ◽

Cell Injury ◽

Kidney Diseases ◽

Sirtuin 1 ◽

Kidney Cells ◽

Sirt1 Expression ◽

Hiv 1

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.

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FoxP3+CD4+ regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2−/−γC−/− mice in vivo

Blood ◽

10.1182/blood-2008-03-145946 ◽

2008 ◽

Vol 112 (7) ◽

pp. 2858-2868 ◽

Cited By ~ 74

Author(s):

Qi Jiang ◽

Liguo Zhang ◽

Rui Wang ◽

Jerry Jeffrey ◽

Michael L. Washburn ◽

...

Keyword(s):

T Cells ◽

Treg Cells ◽

Lymphoid Organs ◽

Robust Model ◽

Acute Hiv ◽

Infected Cells ◽

Treg Phenotype ◽

Hiv 1

Abstract The role of FoxP3+CD4+ regulatory T (Treg) cells in HIV-1 disease in vivo is poorly understood due to the lack of a robust model. We report here that CD4+FoxP3+ T cells are developed in all lymphoid organs in humanized Rag2−/−γC−/− (DKO-hu HSC) mice and they display both Treg phenotype and Treg function. These FoxP3+ Treg cells are preferentially infected and depleted by a pathogenic HIV-1 isolate in HIV-infected DKO-hu HSC mice; and depletion of Treg cells is correlated with induction of their apoptosis in vivo. When CD4+CD25+/hi Treg cells are depleted with the IL-2–toxin fusion protein (denileukin diftitox), HIV-1 infection is significantly impaired. This is demonstrated by reduced levels of productively infected cells in lymphoid organs and lower plasma viremia. Therefore, FoxP3+ Treg cells are productively infected and play an important role in acute HIV-1 infection in vivo. The DKO-hu HSC mouse will be a valuable model to study human Treg functions and their role in HIV-1 pathogenesis in vivo.

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