scholarly journals Level of ICAM-1 Surface Expression on Virus Producer Cells Influences both the Amount of Virion-Bound Host ICAM-1 and Human Immunodeficiency Virus Type 1 Infectivity

1998 ◽  
Vol 72 (11) ◽  
pp. 9329-9336 ◽  
Author(s):  
Jean-Sébastien Paquette ◽  
Jean-François Fortin ◽  
Luc Blanchard ◽  
Michel J. Tremblay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Specific Effect ◽  
Surface Expression ◽  
Target Cells ◽  
Virus Infectivity ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Using virions harvested from 293T cells stably expressing either low or high levels of surface ICAM-1, we determined that the number of virus-embedded host ICAM-1 proteins is positively influenced by the expression level of ICAM-1 on virus producer cells. Moreover, the increase in virion-bound host cell membrane ICAM-1 led to a concomitant enhancement of virus infectivity when a T-cell-tropic strain of human immunodeficiency virus type 1 (HIV-1) was used. The phenomenon was also seen when primary human cells were infected with virions pseudotyped with the envelope protein from a macrophage-tropic HIV-1 isolate, thus ruling out any envelope-specific effect. We also observed that target cells treated with NKI-L16, an anti-LFA-1 antibody known to increase the affinity of LFA-1 for ICAM-1, were markedly more susceptible to infection with HIV-1 particles bearing on their surfaces large numbers of host-derived ICAM-1 proteins. Given that cellular activation of leukocytes is known to modify the conformational state of LFA-1 and induce ICAM-1 surface expression, it is tempting to speculate that activation of virus-infected cells will lead to the production of HIV-1 particles bearing more host ICAM-1 on their surfaces and that such progeny virions will preferentially infect and replicate more efficiently in activated cells which are prevalent in lymphoid organs.

scholarly journals Nuclear Import Defect of Human Immunodeficiency Virus Type 1 DNA Flap Mutants Is Not Dependent on the Viral Strain or Target Cell Type

2006 ◽  
Vol 80 (20) ◽  
pp. 10262-10269 ◽  
Author(s):  
Nathalie Arhel ◽  
Sandie Munier ◽  
Philippe Souque ◽  
Karine Mollier ◽  
Pierre Charneau
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Target Cell ◽  
Nuclear Import ◽  
Target Cells ◽  
Virus Infectivity ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We have previously established, using human immunodeficiency virus type 1 (HIV-1) strain LAI, that the HIV-1 central DNA Flap acts as a cis determinant of viral genome nuclear import. Although the impact of the DNA Flap on nuclear import has already found numerous independent confirmations in the context of lentivirus vectors, it has been claimed that it may be nonessential for infectious virus strains LAI, YU-2 (J. D. Dvorin et al., J. Virol. 76:12087-12096, 2002), HXB2, and NL4-3 (A. Limon et al., J. Virol. 76:12078-12086, 2002). We conducted a detailed analysis of virus infectivity using the provirus clones provided by the authors and analogous target cells. In contrast to published data, our results show that all cPPT mutant viruses exhibit reduced infectivity corresponding to a nuclear import defect irrespective of the viral genetic background or target cell.

scholarly journals Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 49 (12) ◽  
pp. 4911-4919 ◽  
Author(s):  
Julie M. Strizki ◽  
Cecile Tremblay ◽  
Serena Xu ◽  
Lisa Wojcik ◽  
Nicole Wagner ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Calcium Flux ◽  
Ccr5 Antagonist ◽  
Target Cells ◽  
Gene Transcript ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5′-[35S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.

scholarly journals Impaired Processing and Presentation of Cytotoxic-T-Lymphocyte (CTL) Epitopes Are Major Escape Mechanisms from CTL Immune Pressure in Human Immunodeficiency Virus Type 1 Infection

2004 ◽  
Vol 78 (3) ◽  
pp. 1324-1332 ◽  
Author(s):  
Yoshiyuki Yokomaku ◽  
Hideka Miura ◽  
Hiroko Tomiyama ◽  
Ai Kawana-Tachikawa ◽  
Masafumi Takiguchi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Target Cells ◽  
Ctl Epitopes ◽  
Field Isolates ◽  
Ctl Epitope ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Investigating escape mechanisms of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTLs) is essential for understanding the pathogenesis of HIV-1 infection and developing effective vaccines. To study the processing and presentation of known CTL epitopes, we prepared Epstein-Barr virus-transformed B cells that endogenously express the gag gene of six field isolates by adopting an env/nef-deletion HIV-1 vector pseudotyped with vesicular stomatitis virus G protein and then tested them for the recognition by Gag epitope-specific CTL lines or clones. We observed that two field variants, SLFNTVAVL and SVYNTVATL, of an A*0201-restricted Gag CTL epitope SLYNTVATL, and three field variants, KYRLKHLVW, QYRLKHIVW, and RYRLKHLVW, of an A24-restricted Gag CTL epitope KYKLKHIVW escaped from being killed by the CTL lines, despite the fact that they were recognized when the synthetic peptides corresponding to these variant sequences were exogenously loaded onto the target cells. Thus, their escape is likely due to the changes that occur during the processing and presentation of epitopes in the infected cells. Mutations responsible for this mode of escape were located within the epitope regions rather than the flanking regions, and such mutations did not influence the virus replication. The results suggest that the impaired antigen processing and presentation often occur in HIV-1 field isolates and thus are one of the major mechanisms that enable HIV-1 to escape from CTL recognition. We emphasize the importance of testing HIV-1 variants in an endogenous expression system.

scholarly journals Interaction between the Cytoplasmic Domain of ICAM-1 and Pr55Gag Leads to Acquisition of Host ICAM-1 by Human Immunodeficiency Virus Type 1

2004 ◽  
Vol 78 (21) ◽  
pp. 11916-11925 ◽  
Author(s):  
Yannick Beauséjour ◽  
Michel J. Tremblay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Adhesion Molecule ◽  
Cytoplasmic Domain ◽  
Virus Infectivity ◽  
Immunodeficiency Virus ◽  
Selective Incorporation ◽  
Hiv 1

ABSTRACT We have examined the molecular basis for the selective incorporation of the adhesion molecule ICAM-1 within human immunodeficiency virus type 1 (HIV-1). The process of ICAM-1 incorporation was investigated by using different ICAM-1 constructs in combination with virus capture and immunoprecipitation studies, Western blot and confocal microscopy analyses, and infectivity assays. Experiments conducted with viruses bearing a truncated version of ICAM-1 revealed that the cytoplasmic domain of ICAM-1 governs insertion of this adhesion molecule into HIV-1. Further experiments suggested that there is an association between ICAM-1 and the virus-encoded Pr55Gag polyprotein. This study represents the first demonstration that structural Gag polyproteins play a key role in the uptake of a host-derived cell surface by the virus entity. Taken together, our results indicate that interactions between viral and cellular proteins are responsible for the selective uptake of host ICAM-1 by HIV-1. This observation describes a new strategy by which HIV-1 can modulate its replicative cycle, considering that insertion of ICAM-1 within nascent virions has been shown to increase virus infectivity.

scholarly journals LFA-1 Is a Key Determinant for Preferential Infection of Memory CD4+ T Cells by Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 79 (21) ◽  
pp. 13714-13724 ◽  
Author(s):  
Mélanie R. Tardif ◽  
Michel J. Tremblay
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Virus Infectivity ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Memory CD4+ T cells are considered a stable latent reservoir for human immunodeficiency virus type 1 (HIV-1) and a barrier to eradication of this retroviral infection in patients under therapy. It has been shown that memory CD4+ T cells are preferentially infected with HIV-1, but the exact mechanism(s) responsible for this higher susceptibility remains obscure. Previous findings indicate that incorporation of host-derived intercellular adhesion molecule 1 (ICAM-1) in HIV-1 increases virus infectivity. To measure the putative involvement of virus-anchored ICAM-1 in the preferential infection of memory cells by HIV-1, quiescent and activated naive and memory T-cell subsets were exposed to isogenic virions either lacking or bearing ICAM-1. Memory CD4+ T cells were found to be more susceptible than naive CD4+ T cells to infection with ICAM-1-bearing virions, as exemplified by a more important virus replication, an increase in integrated viral DNA copies, and a more efficient entry process. Interactions between virus-associated host ICAM-1 and cell surface LFA-1 under a cluster formation seem to be responsible for the preferential HIV-1 infection of the memory cell subset. Altogether, these data shed light on a potential mechanism by which HIV-1 preferentially targets long-lived memory CD4+ T cells.

scholarly journals Genetic Recombination of Human Immunodeficiency Virus Type 1 in One Round of Viral Replication: Effects of Genetic Distance, Target Cells, Accessory Genes, and Lack of High Negative Interference in Crossover Events

2005 ◽  
Vol 79 (3) ◽  
pp. 1666-1677 ◽  
Author(s):  
Terence D. Rhodes ◽  
Olga Nikolaitchik ◽  
Jianbo Chen ◽  
Douglas Powell ◽  
Wei-Shau Hu
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Recombination Rate ◽  
Target Cells ◽  
Recombination Rates ◽  
Negative Interference ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Recombination is a major mechanism that generates variation in populations of human immunodeficiency virus type 1 (HIV-1). Mutations that confer replication advantages, such as drug resistance, often cluster within regions of the HIV-1 genome. To explore how efficiently HIV-1 can assort markers separated by short distances, we developed a flow cytometry-based system to study recombination. Two HIV-1-based vectors were generated, one encoding the mouse heat-stable antigen gene and green fluorescent protein gene (GFP), and the other encoding the mouse Thy-1 gene and GFP. We generated derivatives of both vectors that contained nonfunctional GFP inactivated by different mutations. Recombination in the region between the two inactivating mutations during reverse transcription could yield a functional GFP. With this system, we determined that the recombination rates of markers separated by 588, 300, 288, and 103 bp in one round of viral replication are 56, 38, 31, and 12%, respectively, of the theoretical maximum measurable recombination rate. Statistical analyses revealed that at these intervals, recombination rates and marker distances have a near-linear relationship that is part of an overall quadratic fit. Additionally, we examined the segregation of three markers within 600 bp and concluded that HIV-1 crossover events do not exhibit high negative interference. We also examined the effects of target cells and viral accessory proteins on recombination rate. Similar recombination rates were observed when human primary CD4+ T cells and a human T-cell line were used as target cells. We also found equivalent recombination rates in the presence and absence of accessory genes vif, vpr, vpu, and nef. These results illustrate the power of recombination in generating viral population variation and predict the rapid assortment of mutations in the HIV-1 genome in infected individuals.

scholarly journals Structural Requirements for Recognition of the Human Immunodeficiency Virus Type 1 Core during Host Restriction in Owl Monkey Cells

2005 ◽  
Vol 79 (2) ◽  
pp. 869-875 ◽  
Author(s):  
Brett M. Forshey ◽  
Jiong Shi ◽  
Christopher Aiken
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Target Cells ◽  
Host Restriction ◽  
Amino Terminal ◽  
Immunodeficiency Virus ◽  
Owl Monkey ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection of simian cells is restricted at an early postentry step by host factors whose mechanism of action is unclear. These factors target the viral capsid protein (CA) and attenuate reverse transcription, suggesting that they bind to the HIV-1 core and interfere with its uncoating. To identify the relevant binding determinants in the capsid, we tested the capacity of viruses containing Gag cleavage site mutations and amino acid substitutions in CA to inhibit restriction of a wild type HIV-1 reporter virus in owl monkey cells. The results demonstrated that a stable, polymeric capsid and a correctly folded amino-terminal CA subunit interface are essential for saturation of host restriction in target cells by HIV-1 cores. We conclude that the owl monkey cellular restriction machinery recognizes a polymeric array of CA molecules, most likely via direct engagement of the HIV-1 capsid in target cells prior to uncoating.

scholarly journals The DNA Deaminase Activity of Human APOBEC3G Is Required for Ty1, MusD, and Human Immunodeficiency Virus Type 1 Restriction

2008 ◽  
Vol 82 (6) ◽  
pp. 2652-2660 ◽  
Author(s):  
April J. Schumacher ◽  
Guylaine Haché ◽  
Donna A. MacDuff ◽  
William L. Brown ◽  
Reuben S. Harris
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Virus Infectivity ◽  
Repair System ◽  
Cytosine Deamination ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Human Apobec3g

ABSTRACT Human APOBEC3G and several other APOBEC3 proteins have been shown to inhibit the replication of a variety of retrotransposons and retroviruses. All of these enzymes can deaminate cytosines within single-strand DNA, but the overall importance of this conserved activity in retroelement restriction has been questioned by reports of deaminase-independent mechanisms. Here, three distinct retroelements, a yeast retrotransposon, Ty1, a murine endogenous retrovirus, MusD, and a lentivirus, human immunodeficiency virus type 1 (HIV-1), were used to evaluate the relative contributions of deaminase-dependent and -independent mechanisms. Although human APOBEC3G can restrict the replication of all three of these retroelements, APOBEC3G lacking the catalytic glutamate (E259Q) was clearly defective. This phenotype was particularly clear in experiments with low levels of APOBEC3G expression. In contrast, purposeful overexpression of APOBEC3G-E259Q was able to cause modest to severe reductions in the replication of Ty1, MusD, and HIV-1(ΔVif). The importance of these observations was highlighted by data showing that CEM-SS T-cell lines expressing near-physiologic levels of APOBEC3G-E259Q failed to inhibit the replication of HIV-1(ΔVif), whereas similar levels of wild-type APOBEC3G fully suppressed virus infectivity. Despite the requirement for DNA deamination, uracil DNA glycosylase did not modulate APOBEC3G-dependent restriction of Ty1 or HIV-1(ΔVif), further supporting prior studies indicating that the major uracil excision repair system of cells is not involved. In conclusion, the absolute requirement for the catalytic glutamate of APOBEC3G in Ty1, MusD, and HIV-1 restriction strongly indicates that DNA cytosine deamination is an essential part of the mechanism.

scholarly journals How Many Human Immunodeficiency Virus Type 1-Infected Target Cells Can a Cytotoxic T-Lymphocyte Kill?

2005 ◽  
Vol 79 (21) ◽  
pp. 13579-13586 ◽  
Author(s):  
W. David Wick ◽  
Otto O. Yang ◽  
Lawrence Corey ◽  
Steven G. Self
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Target Cells ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT The antiviral role of CD8+ cytotoxic T lymphocytes (CTLs) in human immunodeficiency virus type 1 (HIV-1) infection is poorly understood. Specifically, the degree to which CTLs reduce viral replication by killing HIV-1-infected cells in vivo is not known. Here we employ mathematical models of the infection process and CTL action to estimate the rate that CTLs can kill HIV-1-infected cells from in vitro and in vivo data. Our estimates, which are surprisingly consistent considering the disparities between the two experimental systems, demonstrate that on average CTLs can kill from 0.7 to 3 infected target cells per day, with the variability in this figure due to epitope specificity or other factors. These results are compatible with the observed decline in viremia after primary infection being primarily a consequence of CTL activity and have interesting implications for vaccine design.

scholarly journals Persistent Infection with Primate Foamy Virus Type 1 Increases Human Immunodeficiency Virus Type 1 Cell Binding via a Bet-Independent Mechanism

2004 ◽  
Vol 78 (20) ◽  
pp. 11405-11410 ◽  
Author(s):  
Cecile Schiffer ◽  
Charles-Henri Lecellier ◽  
Abdelkrim Mannioui ◽  
Nathalie Felix ◽  
Elisabeth Nelson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Foamy Virus ◽  
Virus Transmission ◽  
Target Cells ◽  
Virus Attachment ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We report that human T cells persistently infected with primate foamy virus type 1 (PFV-1) display an increased capacity to bind human immunodeficiency virus type 1 (HIV-1), resulting in increased cell permissiveness to HIV-1 infection and enhanced cell-to-cell virus transmission. This phenomenon is independent of HIV-1 receptor, CD4, and it is not related to PFV-1 Bet protein expression. Increased virus attachment is specifically inhibited by heparin, indicating that it should be mediated by interactions with heparan sulfate glycosaminoglycans expressed on the target cells. Given that both viruses infect similar animal species, the issue of whether coinfection with primate foamy viruses interferes with the natural course of lentivirus infections in nonhuman primates should be considered.

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