scholarly journals Cell-to-cell infection by HIV contributes over half of virus infection

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Shingo Iwami ◽  
Junko S Takeuchi ◽  
Shinji Nakaoka ◽  
Fabrizio Mammano ◽  
François Clavel ◽  
...  
Keyword(s):  
Virus Infection ◽  
Viral Infection ◽  
Quantitative Information ◽  
Viral Fitness ◽  
Cell Infection ◽  
Immunodeficiency Virus ◽  
Mathematical Investigation ◽  
Infection Mode ◽  
Hiv 1

Cell-to-cell viral infection, in which viruses spread through contact of infected cell with surrounding uninfected cells, has been considered as a critical mode of virus infection. However, since it is technically difficult to experimentally discriminate the two modes of viral infection, namely cell-free infection and cell-to-cell infection, the quantitative information that underlies cell-to-cell infection has yet to be elucidated, and its impact on virus spread remains unclear. To address this fundamental question in virology, we quantitatively analyzed the dynamics of cell-to-cell and cell-free human immunodeficiency virus type 1 (HIV-1) infections through experimental-mathematical investigation. Our analyses demonstrated that the cell-to-cell infection mode accounts for approximately 60% of viral infection, and this infection mode shortens the generation time of viruses by 0.9 times and increases the viral fitness by 3.9 times. Our results suggest that even a complete block of the cell-free infection would provide only a limited impact on HIV-1 spread.

scholarly journals Interleukin 7 Increases Human Immunodeficiency Virus Type 1 LAI-Mediated Fas-Induced T-Cell Death

2005 ◽  
Vol 79 (5) ◽  
pp. 3195-3199 ◽  
Author(s):  
Jean-Daniel Lelièvre ◽  
Frédéric Petit ◽  
Damien Arnoult ◽  
Jean-Claude Ameisen ◽  
Jérôme Estaquier
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Infection ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Fas-mediated T-cell death is known to occur during human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 LAI (HIV-1LAI) primes CD8+ T cells from healthy donors for apoptosis, which occurs after Fas ligation. This effect is counteracted by a broad caspase inhibitor (zVAD-fmk). Fas-mediated cell death does not depend on CD8+ T-cell infection, because it occurred in the presence of reverse transcriptase inhibitors. However, purified CD8+ T cells are sensitive to Fas only in the presence of soluble CD4. Finally, we found that interleukin 7 (IL-7) increases Fas-mediated CD4+ and CD8+ T-cell death induced by HIV-1LAI. Since high levels of IL-7 are a marker of poor prognosis during HIV infection, our data suggest that enhancement of Fas-mediated T-cell death by HIV-1LAI and IL-7 is one of the mechanisms involved in progression to AIDS.

scholarly journals Mononuclear Phagocyte Differentiation, Activation, and Viral Infection Regulate Matrix Metalloproteinase Expression: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

2001 ◽  
Vol 75 (14) ◽  
pp. 6572-6583 ◽  
Author(s):  
Anuja Ghorpade ◽  
Raisa Persidskaia ◽  
Radhika Suryadevara ◽  
Myhanh Che ◽  
Xiao Juan Liu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Infection ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
De Novo ◽  
Mononuclear Phagocyte ◽  
Monocyte Migration ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) is mediated mainly by mononuclear phagocyte (MP) secretory products and their interactions with neural cells. Viral infection and MP immune activation may affect leukocyte entry into the brain. One factor that influences central nervous system (CNS) monocyte migration is matrix metalloproteinases (MMPs). In the CNS, MMPs are synthesized by resident glial cells and affect the integrity of the neuropil extracellular matrix (ECM). To ascertain how MMPs influence HAD pathogenesis, we studied their secretion following MP differentiation, viral infection, and cellular activation. HIV-1-infected and/or immune-activated monocyte-derived macrophages (MDM) and human fetal microglia were examined for production of MMP-1, -2, -3, and -9. MMP expression increased significantly with MP differentiation. Microglia secreted high levels of MMPs de novo that were further elevated following CD40 ligand-mediated cell activation. Surprisingly, HIV-1 infection of MDM led to the down-regulation of MMP-9. In encephalitic brain tissue, MMPs were expressed within perivascular and parenchymal MP, multinucleated giant cells, and microglial nodules. These data suggest that MMP production in MP is dependent on cell type, differentiation, activation, and/or viral infection. Regulation of MMP expression by these factors may contribute to neuropil ECM degradation and leukocyte migration during HAD.

scholarly journals Insertions in the Reverse Transcriptase Increase both Drug Resistance and Viral Fitness in a Human Immunodeficiency Virus Type 1 Isolate Harboring the Multi-Nucleoside Reverse Transcriptase Inhibitor Resistance 69 Insertion Complex Mutation

2002 ◽  
Vol 76 (20) ◽  
pp. 10546-10552 ◽  
Author(s):  
Miguel E. Quiñones-Mateu ◽  
Mahlet Tadele ◽  
Mariona Parera ◽  
Antonio Mas ◽  
Jan Weber ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Viral Fitness ◽  
Wild Type ◽  
Sequence Context ◽  
Recombinant Viruses ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT Recent studies have shown that the accumulation of multiple mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance may be grouped as multi-NRTI resistance (MNR) complexes. In this study, we have examined the viral fitness of recombinant viruses carrying the reverse transcriptase (RT) of a human immunodeficiency virus type 1 (HIV-1) primary isolate harboring mutations comprising the MNR 69 insertion complex. Different RT mutants were prepared in the sequence context of either the wild-type RT sequence of the HIV-1BH10 isolate or the sequence found in a clinical HIV-1 isolate with the MNR 69 insertion mutation. As expected, in the presence of zidovudine, recombinant viruses harboring the MNR RT from the patient were more fit than wild-type viruses. However, in the absence of drug, the virus with the RT from the original clinical isolate (SS) was more fit than (i) the wild-type virus with an engineered serine insertion between residues 69 and 70 (T69SSS) and (ii) the recombinant virus with the MNR RT where the insertion was removed (2S0S). These results suggest that RT insertions, in the right sequence context (i.e., additional mutations contained in the MNR 69 insertion complex), enhance NRTI resistance and may improve viral fitness. Thus, comparing complex mutation patterns with viral fitness may help to elucidate the role of uncharacterized drug resistance mutations in antiretroviral treatment failure.

scholarly journals Inhibitory role of CXCR4 glycan in CD4-independent X4-tropic human immunodeficiency virus type 1 infection and its abrogation in CD4-dependent infection

2007 ◽  
Vol 88 (11) ◽  
pp. 3139-3144 ◽  
Author(s):  
Yoshinao Kubo ◽  
Masaru Yokoyama ◽  
Hiroaki Yoshii ◽  
Chiho Mitani ◽  
Chika Tominaga ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Infection ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Envelope ◽  
Extracellular Region ◽  
Immunodeficiency Virus ◽  
Env Protein ◽  
Hiv 1

CXCR4 functions as an infection receptor of X4 human immunodeficiency virus type 1 (HIV-1) . CXCR4 is glycosylated at the N-terminal extracellular region, which is important for viral envelope (Env) protein binding. We compared the effects of CXCR4 glycan on the CD4-dependent and –independent infections in human cells by X4 viruses. We found that transduction mediated by Env proteins of CD4-independent HIV-1 strains increased up to 5.5-fold in cells expressing unglycosylated CXCR4, suggesting that the CXCR4 glycan inhibits CD4-independent X4 virus infection. Co-expression of CD4 on the target cell surface or pre-incubation of virus particles with soluble CD4 abrogates the glycan-mediated inhibition of X4 virus infection, suggesting that interaction of Env protein with CD4 counteracts the inhibition. These findings indicate that it will be advantageous for X4 HIV-1 to remain CD4-dependent. A structural model that explains the glycan-mediated inhibition is discussed.

scholarly journals Changes in Human Immunodeficiency Virus Type 1 Gag at Positions L449 and P453 Are Linked to I50V Protease Mutants In Vivo and Cause Reduction of Sensitivity to Amprenavir and Improved Viral Fitness In Vitro

2002 ◽  
Vol 76 (15) ◽  
pp. 7398-7406 ◽  
Author(s):  
Michael F. Maguire ◽  
Rosario Guinea ◽  
Philip Griffin ◽  
Sarah Macmanus ◽  
Robert C. Elston ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Fitness ◽  
Wild Type Virus ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Gag protease cleavage sites (CS) undergo sequence changes during the development of resistance to several protease inhibitors (PIs). We have analyzed the association of sequence variation at the p7/p1 and p1/p6 CS in conjunction with amprenavir (APV)-specific protease mutations following PI combination therapy with APV. Querying a central resistance data repository resulted in the detection of significant associations (P < 0.001) between the presence of APV protease signature mutations and Gag L449F (p1/p6 LP1′F) and P453L (p1/p6 PP5′L) CS changes. In population-based sequence analyses the I50V mutant was invariably linked to either L449F or P453L. Clonal analysis revealed that both CS mutations were never present in the same genome. Sequential plasma samples from one patient revealed a transition from I50V M46L P453L viruses at early time points to I50V M46I L449F viruses in later samples. Various combinations of the protease and Gag mutations were introduced into the HXB2 laboratory strain of HIV-1. In both single- and multiple-cycle assay systems and in the context of I50V, the L449F and P453L changes consistently increased the 50% inhibitory concentration of APV, while the CS changes alone had no measurable effect on inhibitor sensitivity. The decreased in vitro fitness of the I50V mutant was only partially improved by addition of either CS change (I50V M46I L449F mutant replicative capacity ≈ 16% of that of wild-type virus). Western blot analysis of Pr55 Gag precursor cleavage products from infected-cell cultures indicated accumulation of uncleaved Gag p1-p6 in all I50V viruses without coexisting CS changes. Purified I50V protease catalyzed cleavage of decapeptides incorporating the L449F or P453L change 10-fold and 22-fold more efficiently than cleavage of the wild-type substrate, respectively. HIV-1 protease CS changes are selected during PI therapy and can have effects on both viral fitness and phenotypic resistance to PIs.

Mucosal Dendritic Cell Subsets Control HIV-1’s Viral Fitness

2020 ◽  
Vol 7 (1) ◽  
pp. 385-402
Author(s):  
Bernadien M. Nijmeijer ◽  
Catharina J.M. Langedijk ◽  
Teunis B.H. Geijtenbeek
Keyword(s):  
Dendritic Cell ◽  
Sexual Transmission ◽  
Treatment Strategies ◽  
Viral Fitness ◽  
Immunodeficiency Virus ◽  
Novel Treatment Strategies ◽  
Hiv 1 ◽  
Selection Of

Dendritic cell (DC) subsets are abundantly present in genital and intestinal mucosal tissue and are among the first innate immune cells that encounter human immunodeficiency virus type 1 (HIV-1) after sexual contact. Although DCs have specific characteristics that greatly enhance HIV-1 transmission, it is becoming evident that most DC subsets also have virus restriction mechanisms that exert selective pressure on the viruses during sexual transmission. In this review we discuss the current concepts of the immediate events following viral exposure at genital mucosal sites that lead to selection of specific HIV-1 variants called transmitted founder (TF) viruses. We highlight the importance of the TF HIV-1 phenotype and the role of different DC subsets in establishing infection. Understanding the biology of HIV-1 transmission will contribute to the design of novel treatment strategies preventing HIV-1 dissemination.

scholarly journals Impact of Protease Polymorphisms and Viral Fitness on Human Immunodeficiency Virus (HIV) Type 1 Viremia in Untreated HIV‐1 Infection

2002 ◽  
Vol 185 (12) ◽  
pp. 1844-1846 ◽  
Author(s):  
Yvonne Märki ◽  
Gilbert R. Kaufmann ◽  
Manuel Battegay ◽  
Thomas Klimkait ◽  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Fitness ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1

scholarly journals Mutations in the Thumb Allow Human Immunodeficiency Virus Type 1 Reverse Transcriptase To Be Cleaved by Protease in Virions

2009 ◽  
Vol 83 (23) ◽  
pp. 12336-12344 ◽  
Author(s):  
Linda L. Dunn ◽  
Mary Jane McWilliams ◽  
Kalyan Das ◽  
Eddy Arnold ◽  
Stephen H. Hughes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Fitness ◽  
Western Blots ◽  
Immunodeficiency Virus ◽  
The Stability ◽  
Hiv 1

ABSTRACT Although human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has been extensively studied, there are still significant questions about the effects of mutations on the maturation and stability of RT. We show here that a significant fraction (>80%) of the single point mutations we generated in the thumb subdomain of HIV-1 (RT) affect the stability of RT in virions. Fragments of the unstable mutant RTs can be detected in Western blots of virion proteins; however, the degree of degradation varies. The titers of the mutants whose virions contain degraded RTs are reduced. Some, but not all, of the unstable RT thumb subdomain mutants we analyzed have a temperature-sensitive phenotype. A preliminary survey of mutations in other subdomains of RT shows that some of these mutations also destabilize RT. The stability of the RT mutants is enhanced by the addition of a protease inhibitor, suggesting that the viral protease plays an important role in the degradation of the mutant RTs. These results confirm and extend earlier reports of mutations that affect the stability of RT in virions. The data suggest that the stability of a mutant RT in virions could be a major factor in determining the virus titer and, by extension, viral fitness, which could affect whether a mutation in RT is acceptable to the virus.

scholarly journals Complement mediates human immunodeficiency virus type 1 infection of a human T cell line in a CD4- and antibody-independent fashion.

1991 ◽  
Vol 173 (5) ◽  
pp. 1151-1158 ◽  
Author(s):  
V Boyer ◽  
C Desgranges ◽  
M A Trabaud ◽  
E Fischer ◽  
M D Kazatchkine
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Complement Activation ◽  
Human T Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Human T Cell Line

Incubation of the human T cell lymphotropic virus (HTLV)-IIIB and HTLV-RF strains of human immunodeficiency virus type 1 (HIV-1) with normal seronegative human serum under conditions that allow complement activation resulted in enhancement of infection of the MT2 human T cell line cultured in the presence of low amounts of virus. Infection of MT2 cells was assessed by measuring reverse transcriptase activity in supernatants at day 9 of culture. Complement activation by viral suspensions occurred through the alternative pathway. Opsonization of HTLV-RF viral particles with complement was sufficient to allow a productive infection to occur in cells exposed to suboptimal amounts of virus. Infection of MT2 cells with suboptimal amounts of serum-opsonized HIV-1 was suppressed by blocking the C3dg receptor (CR2, CD21) on MT2 cells with monoclonal anti-CR2 antibody and rabbit F(ab')2 anti-mouse immunoglobulin antibodies. Blocking of the gp120-binding site on CD4 under similar experimental conditions had no inhibitory effect on infection of MT2 cells with opsonized virus. Opsonization of HIV-1 with seronegative serum also resulted in a CR2-mediated enhancement of the infection of normal peripheral blood mononuclear cells and T lymphocytes. These results indicate that complement in the absence of antibody may enhance infection of C3 receptor-bearing T cells with HIV-1, and that the interaction of opsonized virus with the CR2 receptor may result by itself in the infection of target T cells in a CD4- and antibody-independent fashion.

scholarly journals Comparative analysis of the fusion efficiency elicited by the envelope glycoprotein V1–V5 regions derived from human immunodeficiency virus type 1 transmitted perinatally

2012 ◽  
Vol 93 (12) ◽  
pp. 2635-2645 ◽  
Author(s):  
Hongyan Guo ◽  
Levon G. Abrahamyan ◽  
Chang Liu ◽  
Mackenzie Waltke ◽  
Yunqi Geng ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Perinatal Transmission ◽  
Viral Fitness ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Fusion Efficiency ◽  
Entry Efficiency

Understanding the properties of viruses preferentially establishing infection during perinatal transmission of human immunodeficiency virus type 1 (HIV-1) is critical for the development of effective measures to prevent transmission. A previous study demonstrated that the newly transmitted viruses (in infants) of chronically infected mother–infant pairs (MIPs) were fitter in terms of growth, which was imparted by their envelope (Env) glycoprotein V1–V5 regions, than those in the corresponding chronically infected mothers. In order to investigate whether the higher fitness of transmitted viruses was conferred by their higher entry efficiency directed by the V1–V5 regions during perinatal transmission, the fusogenicity of Env containing V1–V5 regions derived from transmitted and non-tranmsmitted viruses of five chronically infected MIPs and two acutely infected MIPs was analysed using two different cell–cell fusion assays. The results showed that, in one chronically infected MIP, a higher fusion efficiency was induced by the infant Env V1–V5 compared with that of the corresponding mother. Moreover, the V4–V5 regions played an important role in discriminating the transmitted and non-transmitted viruses in this pair. However, neither a consistent pattern nor significant differences in fusogenicity mediated by the V1–V5 regions between maternal and infant variants was observed in the other MIPs. This study suggests that there is no consistent and significant correlation between viral fitness selection and entry efficiency directed by the V1–V5 regions during perinatal transmission. Other factors such as the route and timing of transmission may also be involved.

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