Preadaptation of Simian Immunodeficiency Virus SIVsmm Facilitated Env-Mediated Counteraction of Human Tetherin by Human Immunodeficiency Virus Type 2

ABSTRACTThe host restriction factor tetherin inhibits virion release from infected cells and poses a significant barrier to successful zoonotic transmission of primate lentiviruses to humans. While most simian immunodeficiency viruses (SIV), including the direct precursors of human immunodeficiency virus type 1 (HIV-1) and HIV-2, use their Nef protein to counteract tetherin in their natural hosts, they fail to antagonize the human tetherin ortholog. Pandemic HIV-1 group M and epidemic group O strains overcame this hurdle by adapting their Vpu and Nef proteins, respectively, whereas HIV-2 group A uses its envelope (Env) glycoprotein to counteract human tetherin. Whether or how the remaining eight groups of HIV-2 antagonize this antiviral factor has remained unclear. Here, we show that Nef proteins from diverse groups of HIV-2 do not or only modestly antagonize human tetherin, while their ability to downmodulate CD3 and CD4 is highly conserved. Experiments in transfected cell lines and infected primary cells revealed that not only Env proteins of epidemic HIV-2 group A but also those of a circulating recombinant form (CRF01_AB) and rare groups F and I decrease surface expression of human tetherin and significantly enhance progeny virus release. Intriguingly, we found that many SIVsmm Envs also counteract human as well as smm tetherin. Thus, Env-mediated tetherin antagonism in different groups of HIV-2 presumably stems from a preadaptation of their SIVsmm precursors to humans. In summary, we identified a phenotypic trait of SIVsmm that may have facilitated its successful zoonotic transmission to humans and the emergence of HIV-2.IMPORTANCEHIV-2 groups A to I resulted from nine independent cross-species transmission events of SIVsmm to humans and differ considerably in their prevalence and geographic spread. Thus, detailed characterization of these viruses offers a valuable means to elucidate immune evasion mechanisms and human-specific adaptations determining viral spread. In a systematic comparison of rare and epidemic HIV-2 groups and their simian SIVsmm counterparts, we found that the ability of Nef to downmodulate the primary viral entry receptor CD4 and the T cell receptor CD3 is conserved, while effects on CD28, CD74, and major histocompatibility complex class I surface expression vary considerably. Furthermore, we show that not only the Env proteins of HIV-2 groups A, AB, F, and I but also those of some SIVsmm isolates antagonize human tetherin. This finding helps to explain why SIVsmm has been able to cross the species barrier to humans on at least nine independent occasions.

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Exploring the potential of group II introns to inactivate human immunodeficiency virus type 1

Journal of General Virology ◽

10.1099/vir.0.2008/004333-0 ◽

2008 ◽

Vol 89 (10) ◽

pp. 2605-2610 ◽

Cited By ~ 5

Author(s):

Reza Nazari ◽

Sadhna Joshi

Keyword(s):

Human Immunodeficiency Virus ◽

Virus Replication ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Group Ii Intron ◽

Progeny Virus ◽

Immunodeficiency Virus ◽

Group Ii ◽

Hiv 1

This study examined whether insertion of a mobile group II intron into infectious human immunodeficiency virus type 1 (HIV-1) provirus DNA could inhibit virus replication. Introns targeted against two sites within the integrase-coding region were used. The intron-inserted HIV-1 provirus DNA clones were isolated and tested for virus replication. Similar amounts of HIV-1 RNA, Gag protein and progeny virus were produced from HIV-1 provirus DNA and intron-inserted HIV-1 provirus DNA. However, when the progeny virus was tested for its infectivity, although the group II intron-inserted HIV-1 RNA was packaged and reverse-transcribed, the dsDNA failed to integrate, as expected in the absence of a functional integrase, and virus replication was aborted. These results demonstrate that group II introns can confer ‘complete’ inhibition of HIV-1 replication at the intended step and should be further exploited for HIV-1 gene therapy and other targeted genetic repairs.

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Costimulation of Naive CD8+ Lymphocytes Induces CD4 Expression and Allows Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.72.11.9054-9060.1998 ◽

1998 ◽

Vol 72 (11) ◽

pp. 9054-9060 ◽

Cited By ~ 95

Author(s):

Scott G. Kitchen ◽

Yael D. Korin ◽

Michael D. Roth ◽

Alan Landay ◽

Jerome A. Zack

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Surface Expression ◽

Cell Surface Expression ◽

Rapid Disease Progression ◽

Cd8 Cells ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection requires cell surface expression of CD4. Costimulation of CD8+/CD4− T lymphocytes by anti-CD3 and anti-CD28 antibodies or by allogeneic dendritic cells induced expression of CD4 and rendered these CD8 cells susceptible to HIV-1 infection. Naive CD45RA+ cells responded with greater expression of CD4 than did CD45RO+ cells. CD8+lymphocytes derived from fetal or newborn sources exhibited a greater tendency to express CD4, consistent with their naive states. This mechanism of infection suggests HIV-induced perturbation of the CD8 arm of the immune response and could explain the generally rapid disease progression seen in HIV-infected children.

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Effect of Calcium-Modulating Cyclophilin Ligand on Human Immunodeficiency Virus Type 1 Particle Release and Cell Surface Expression of Tetherin

Journal of Virology ◽

10.1128/jvi.01786-09 ◽

2009 ◽

Vol 83 (24) ◽

pp. 13032-13036 ◽

Cited By ~ 3

Author(s):

Mariana G. Bego ◽

Mathieu Dubé ◽

Johanne Mercier ◽

Éric A. Cohen

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Surface ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Surface Expression ◽

Cell Surface Expression ◽

Particle Release ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpu enhances virus particle release by counteracting a host factor that retains virions at the surfaces of infected cells. It was recently demonstrated that cellular protein BST-2/CD317/Tetherin restricts HIV-1 release in a Vpu-dependent manner. Calcium-modulating cyclophilin ligand (CAML) was also proposed to be involved in this process. We investigated whether CAML is involved in cell surface expression of Tetherin. Here, we show that CAML overexpression in permissive Cos-7 cells or CAML depletion in restrictive HeLa cells has no effect on HIV-1 release or on Tetherin surface expression, indicating that CAML is not required for Tetherin-mediated restriction of HIV-1 release.

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CXCR-4 Is Expressed by Primary Macrophages and Supports CCR5-Independent Infection by Dual-Tropic but Not T-Tropic Isolates of Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.72.1.772-777.1998 ◽

1998 ◽

Vol 72 (1) ◽

pp. 772-777 ◽

Cited By ~ 129

Author(s):

Yanjie Yi ◽

Shalini Rana ◽

Julie D. Turner ◽

Nathan Gaddis ◽

Ronald G. Collman

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Chemokine Receptors ◽

Surface Expression ◽

Reverse Transcription Pcr ◽

Immunodeficiency Virus ◽

Inactivating Mutation ◽

Hiv 1

ABSTRACT Primary macrophages are infected by macrophage (M)-tropic but not T-cell line (T)-tropic human immunodeficiency virus type 1 (HIV-1) strains, and CCR5 and CXCR-4 are the principal cofactors utilized for CD4-mediated entry by M-tropic and T-tropic isolates, respectively. Macrophages from individuals homozygous for an inactivating mutation of CCR5 are resistant to prototype M-tropic strains that depend on CCR5 but are permissive for a dual-tropic isolate, 89.6, that can use both CCR5 and CXCR-4, as well as CCR2b, CCR3, and CCR8. Here we show that 89.6 entry into CCR5-deficient macrophages is blocked by an anti-CXCR-4 antibody and by the CXCR-4-specific chemokine SDF but not by the ligands to CCR2b or CCR3. Reverse transcription-PCR demonstrated expression of CXCR-4 but not CCR3 or CCR8 in macrophages, while CCR2b was variable. Macrophage surface expression of CXCR-4 was confirmed by immunofluorescence staining and flow cytometry. Thus, CXCR-4 is expressed by primary macrophages and functions as a cofactor for entry by dual-tropic but not T-tropic HIV-1 isolates, and macrophage resistance to T-tropic strains does not result from a lack of the T-tropic entry cofactor CXCR-4. Since CXCR-4 on macrophages can be used by some but not other isolates, these results indicate that HIV-1 strains differ in how they utilize chemokine receptors as cofactors for entry and that the ability of a chemokine receptor to mediate HIV-1 entry differs, depending on the cell type in which it is expressed.

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Enhanced Inhibition of Human Immunodeficiency Virus Type 1 by Met-Stromal-Derived Factor 1β Correlates with Down-Modulation of CXCR4

Journal of Virology ◽

10.1128/jvi.73.6.4582-4589.1999 ◽

1999 ◽

Vol 73 (6) ◽

pp. 4582-4589 ◽

Cited By ~ 46

Author(s):

Otto O. Yang ◽

Stephen L. Swanberg ◽

Zhijian Lu ◽

Michelle Dziejman ◽

John McCoy ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Biological Activities ◽

Surface Expression ◽

Calcium Flux ◽

Methionine Residue ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT CXCR4 is a chemokine receptor used by some strains of HIV-1 as an entry coreceptor in association with cell surface CD4 on human cells. In human immunodeficiency virus type 1 (HIV-1)-infected individuals, the appearance of viral isolates with a tropism for CXCR4 (T tropic) has been correlated with late disease progression. The presumed natural ligands for CXCR4 are SDF-1α and SDF-1β, which are proposed to play a role in blocking T-tropic HIV-1 cell entry. Here, we demonstrate that addition of an N-terminal methionine residue to SDF-1β (Met-SDF-1β) results in a dramatically enhanced functional activity compared to that of native SDF-1β. Equivalent concentrations of Met-SDF-1β are markedly more inhibitory for T-tropic HIV-1 replication than SDF-1β. A comparison of the biological activities of these two forms of SDF-1β reveals that Met-SDF-1β induces a more pronounced intracellular calcium flux yet binds with slightly lower affinity to CXCR4 than SDF-1β. Down-modulation of CXCR4 is similar after exposure of cells to either chemokine form for 2 h. However, after a 48-h incubation, the surface expression of CXCR4 is much lower for cells treated with Met-SDF-1β. The enhanced blocking of T-tropic HIV-1 by Met-SDF-1β appears to be related to prolonged CXCR4 down-modulation.

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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

Journal of Virology ◽

10.1128/jvi.72.11.9329-9336.1998 ◽

1998 ◽

Vol 72 (11) ◽

pp. 9329-9336 ◽

Cited By ~ 47

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.

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Human Immunodeficiency Virus Type 2 Produces a Defect in CD3-γ Gene Transcripts Similar to That Observed for Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.73.6.5207-5213.1999 ◽

1999 ◽

Vol 73 (6) ◽

pp. 5207-5213 ◽

Cited By ~ 6

Author(s):

Iris Segura ◽

Christine Delmelle-Wibaut ◽

Michel Janssens ◽

Yvette Cleuter ◽

Anne van den Broeke ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Interleukin 2 ◽

Surface Expression ◽

Molecular Defect ◽

Immunodeficiency Virus ◽

Gene Transcripts ◽

Hiv 1

ABSTRACT T cells are central players in the immune response to infectious disease, with the specificity of their responses controlled by the T-cell receptor (TCR)/CD3 complex on the cell surface. Impairment of TCR/CD3-directed CD4+ T-cell immune responses is frequently observed in individuals infected with human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Virus replication is also regulated by T-cell activation factors, with HIV-1 and HIV-2 responding to different TCR/CD3-directed cellular pathways. We previously demonstrated that HIV-1 infection of the human interleukin-2-dependent CD4+T-cell line WE17/10 abrogates TCR/CD3 function and surface expression by a specific loss of CD3-γ gene transcripts. In this study, we show that HIV-2 provokes the same molecular defect in CD3-γ gene transcripts, resulting in a similar but delayed progressive loss of TCR/CD3 surface expression after infection.

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The effect of cyclosporine A on infection of susceptible cells by human immunodeficiency virus type 1

Blood ◽

10.1182/blood.v72.6.1904.1904 ◽

1988 ◽

Vol 72 (6) ◽

pp. 1904-1910 ◽

Cited By ~ 49

Author(s):

MA Wainberg ◽

A Dascal ◽

N Blain ◽

L Fitz-Gibbon ◽

F Boulerice ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Cyclosporine A ◽

Peripheral Blood ◽

Inhibitory Effect ◽

Progeny Virus ◽

Immunodeficiency Virus ◽

Hiv 1

Abstract The effect of cyclosporine A (CyA) on the ability of the human immunodeficiency virus type 1 (HIV-1) to infect the H-9 T-cell leukemic line, as well as interleukin-2 (IL-2)-grown human peripheral blood- derived lymphocytes, has been studied. Pretreatment of H-9 cells and human lymphocytes with CyA over 24 hours completely prevented viral infection over a 21-day period, whereas the addition of drug at two hours postinfection with HIV-1 had a significant inhibitory effect on viral replication and expression of the virus-specific antigens p17 and p24. However, if CyA was added at later times to these lymphocytic cells, this inhibitory effect was lost. Indeed, the removal of CyA from cultures that had been treated from two hours after infection led to the rapid production of progeny virus. HIV-1 was able to infect peripheral blood lymphocytes obtained from each of four kidney allograft recipients on long-term CyA antirejection therapy, as long as drug was not included in the culture medium. In addition, we asked what effect pretreatment with CyA of cells of the U-937 monocytic line and primary cultures of human monocytes/macrophages might have on infection by HIV-1. CyA had no demonstrable effect on the ability of HIV-1 to infect cells of either type.

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The effect of cyclosporine A on infection of susceptible cells by human immunodeficiency virus type 1

Blood ◽

10.1182/blood.v72.6.1904.bloodjournal7261904 ◽

1988 ◽

Vol 72 (6) ◽

pp. 1904-1910

Author(s):

MA Wainberg ◽

A Dascal ◽

N Blain ◽

L Fitz-Gibbon ◽

F Boulerice ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Cyclosporine A ◽

Peripheral Blood ◽

Inhibitory Effect ◽

Progeny Virus ◽

Immunodeficiency Virus ◽

Hiv 1

The effect of cyclosporine A (CyA) on the ability of the human immunodeficiency virus type 1 (HIV-1) to infect the H-9 T-cell leukemic line, as well as interleukin-2 (IL-2)-grown human peripheral blood- derived lymphocytes, has been studied. Pretreatment of H-9 cells and human lymphocytes with CyA over 24 hours completely prevented viral infection over a 21-day period, whereas the addition of drug at two hours postinfection with HIV-1 had a significant inhibitory effect on viral replication and expression of the virus-specific antigens p17 and p24. However, if CyA was added at later times to these lymphocytic cells, this inhibitory effect was lost. Indeed, the removal of CyA from cultures that had been treated from two hours after infection led to the rapid production of progeny virus. HIV-1 was able to infect peripheral blood lymphocytes obtained from each of four kidney allograft recipients on long-term CyA antirejection therapy, as long as drug was not included in the culture medium. In addition, we asked what effect pretreatment with CyA of cells of the U-937 monocytic line and primary cultures of human monocytes/macrophages might have on infection by HIV-1. CyA had no demonstrable effect on the ability of HIV-1 to infect cells of either type.

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Second-Site Reversion of a Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutant That Restores Enzyme Function and Replication Capacity

Journal of Virology ◽

10.1128/jvi.73.8.6293-6298.1999 ◽

1999 ◽

Vol 73 (8) ◽

pp. 6293-6298 ◽

Cited By ~ 17

Author(s):

Isabel Olivares ◽

Víctor Sánchez-Merino ◽

Miguel A. Martínez ◽

Esteban Domingo ◽

Cecilio López-Galíndez ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Progeny Virus ◽

Replication Capacity ◽

Nucleotide Sequence Analysis ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Nonconservative substitutions for Tyr-115 in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) lead to enzymes displaying lower affinity for deoxynucleoside triphosphates (dNTPs) (A. M. Martı́n-Hernández, E. Domingo, and L. Menéndez-Arias, EMBO J. 15:4434–4442, 1996). Several mutations at this position (Y115W, Y115L, Y115A, and Y115D) were introduced in an infectious HIV-1 clone, and the replicative capacity of the mutant viruses was monitored. Y115W was the only mutant able to replicate in MT-4 cells, albeit very poorly. Nucleotide sequence analysis of the progeny virus recovered from supernatants of four independent transfection experiments showed that the Y115W mutation was maintained. However, in all cases an additional substitution in the primer grip of the RT (M230I) emerged when the virus increased its replication capacity. Using recombinant HIV-1 RT, we demonstrate that M230I mitigates the polymerase activity defect of the Y115W mutant, by increasing the dNTP binding affinity of the enzyme. The second-site suppressor effects observed were mediated by mutations in the 66-kDa subunit of the RT, as demonstrated with chimeric heterodimers. Examination of available crystal structures of HIV-1 RT suggests a possible mechanism for restoration of enzyme activity by the second-site revertant.

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