This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Münch, J.
Right arrow Articles by Skowronski, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Münch, J.
Right arrow Articles by Skowronski, J.

 Previous Article  |  Next Article 

Journal of Virology, December 2002, p. 12360-12364, Vol. 76, No. 23
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.23.12360-12364.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

T-Cell Receptor:CD3 Down-Regulation Is a Selected In Vivo Function of Simian Immunodeficiency Virus Nef but Is Not Sufficient for Effective Viral Replication in Rhesus Macaques

Jan Münch,1 Ajit Janardhan,2,3 Nicole Stolte,4 Christiane Stahl-Hennig,4 Peter ten Haaft,5 Jonathan L. Heeney,5 Tomek Swigut,3 Frank Kirchhoff,1* and Jacek Skowronski3*

Abteilung Virologie, Universitätsklinikum, 89081 Ulm, Germany,1 Program in Genetics, State University of New York at Stony Brook, Stony Brook, New York 11794,2 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724,3 German Primate Center, 37077 Göttingen, Germany,4 Department of Virology, Biomedical Primate Research Center, 2288 GJ Rijswijk, The Netherlands5

Received 8 April 2002/ Accepted 26 August 2002


arrow
ABSTRACT
 
We investigated the function of severely truncated simian immunodeficiency virus (SIV) Nef proteins (tNef) in vitro and in vivo. These variants emerged in rhesus monkeys infected with SIVmac239 containing a 152-bp deletion in the nef-unique region and have been suggested to enhance SIV virulence (E. T. Sawai, M. S. Hamza, M. Ye, K. E. Shaw, and P. A. Luciw, J. Virol. 74:2038-2045, 2000). We found that the tNef proteins were unable to down-regulate the cell surface expression of major histocompatibility complex class I proteins, CD4, and CD28 and neither stimulated SIV replication nor enhanced virion infectivity. The tNef proteins did efficiently down-regulate T-cell receptor (TCR):CD3 cell surface expression. Nevertheless, the SIVmac239 tnef variants were strongly attenuated in six infected juvenile rhesus macaques. Thus, while the ability of SIV Nef to down-modulate TCR:CD3 cell surface expression apparently confers a selective advantage in vivo, it is insufficient for efficient viral replication in infected macaques. Additional mutations elsewhere in SIVmac239 tnef genomes are required for a virulent phenotype.


arrow
TEXT
 
The 792-bp nef gene of the pathogenic simian immunodeficiency virus mac239 clone (SIVmac239) encodes a myristylated protein of approximately 34 kDa that down-regulates the cell surface expression of CD3, CD4, CD28, and major histocompatibility class I (MHC-I) molecules, enhances viral replication, increases the infectivity of viral particles, and associates with the p21-regulated protein serine kinase PAK2 (10-13, 16, 17, 23-25). These multiple functions of 239wt Nef are genetically separable and require distinct elements located throughout the Nef molecule.

Nef is important for efficient viral replication and the persistence of HIV and SIV in vivo (7, 13-15). Adult or juvenile rhesus macaques inoculated with a variant of the pathogenic SIVmac239 clone containing a deletion of 182 bp in the nef gene (nef{Delta}182) (Fig. 1) usually exhibit low viral loads, and the majority of infected animals do not progress to immunodeficiency (13). These results provided the basis for the design and evaluation of live attenuated SIV vaccines with deletions in accessory genes (6).



View larger version (14K):
[in this window]
[in a new window]
  		FIG. 1. Amino acid sequence alignment of SIVmac239 wild-type and variant Nef proteins. Amino acid sequences surrounding the deleted regions are shown for Nef{Delta}152 and Nef{Delta}182; the truncated Nef proteins that emerged in vivo in macaque 29810-24 (tNef24) or in macaque 27071-46N (tNef46); the tNef proteins modeled on tNef24 and tNef46 used in this work (tNef.1 and tNef.2, respectively); and Nef{Delta}153 and Nef{Delta}183, resulting from repair of frameshift mutations in nef{Delta}152 and nef{Delta}182. Dots represent identical amino acids, dashes represent missing amino acids, and asterisks represent premature in-frame termination codons introduced by frameshift mutations.

Recently, it was found that uncloned SIVmac239 variants expressing truncated Nef (tNef) proteins of about 25 kDa are pathogenic in infected rhesus macaques (20). These variants emerged in animals infected with recombinant SIVmac239 viruses containing a missense mutation of the Nef initiator methionine, combined with either a 152-bp deletion in the nef-unique region or an insertion of the interleukin-2 (IL-2) cDNA in place of the 152-bp deletion, both of which introduced frameshifts into the nef open reading frame (ORF) (Fig. 1). In the reverted tnef alleles, the nef ATG initiation codon was restored and frameshift mutations were repaired to restore contiguous, albeit truncated, nef ORFs (tnef24 and tnef46) (Fig. 1) (20). The tNef proteins lack an approximately 50-amino-acid-long region overlapping the highly conserved core of the Nef protein. This deletion spans elements mediating functional interactions of Nef with clathrin adaptor complexes that are required for the down-regulation of CD4 and CD28, as well as elements required for Nef to associate with PAK2 activity (4, 16, 18). Therefore, it was surprising that the tNef proteins were linked to a pathogenic phenotype.

The emergence of variant viruses containing a restored tnef ORF indicated that the severely truncated tNef proteins (tNef24 and tNef46) contained some residual function. To identify this function, we constructed truncated 239nef alleles, tnef.1 and tnef.2, corresponding to those previously recovered from the progressing animals 29810-24 and 27021-46N, respectively (20). The mutant tnef.1 and tnef.2 alleles were generated by splice overlap extension PCR and cloned into both a bicistronic vector coexpressing GFP (pCGCG.tNef.1 and pCGCG.tNef.2) and a proviral SIVmac239 construct essentially as described previously (12, 19). Flow cytometry analysis of Jurkat T cells transiently transfected with the bicistronic vectors (9, 11, 12) revealed that, in contrast to 239wt Nef, the tNef.1 and tNef.2 proteins did not decrease the cell surface expression of CD4, CD28, and MHC-I molecules (Fig. 2) (data not shown). However, both tNef forms down-regulated the cell surface expression of the T-cell receptor (TCR):CD3 complex as efficiently as 239wt Nef (Fig. 2) (data not shown). Down-modulation of TCR:CD3 is a conserved function of SIVmac239 and HIV-2 Nef proteins (2, 10, 21).



View larger version (92K):
[in this window]
[in a new window]
  		FIG. 2. The SIVmac239 tNef.1 protein retains the ability to down-regulate TCR:CD3 cell surface expression. Jurkat T cells were transiently transfected with a control plasmid expressing green fluorescent protein (GFP) alone (left panels) or with plasmids coexpressing GFP and 239nef*, 239wt Nef (middle panels), or tNef.1 (right panels). 239nef* contains a premature in-frame TAA stop signal at the 93rd codon of nef (13). Expression of CD4, MHC-I, CD28, CD3, and GFP was analyzed by two-color flow cytometry as described previously (9, 11, 12). Similar results were obtained in two independent experiments.

To test the ability of the tNefs to stimulate SIV replication and particle infectivity, virus stocks were generated in 239T cells transiently transfected with the respective wild-type and mutant proviral genomes (8). As expected (16), no significant differences in the replication kinetics of SIVmac239 viruses containing the 239wt nef, tnef.1, and tnef.2 alleles were observed in CEMx174 cells (Fig. 3A). Western blot analysis revealed that CEMx174 cells infected with the SIVmac239 variants expressed tNef proteins of the expected size of about 25 kDa (data not shown). Infection of rhesus macaque peripheral blood mononuclear cells (rhPBMC) (Fig. 3B) and the herpesvirus saimiri-transformed macaque T-cell line 221 (Fig. 3C) (1) demonstrated that, in contrast to the 239wt nef allele, the tnef.1 and tnef.2 alleles were unable to stimulate SIVmac239 replication. Additionally, the tNef proteins did not increase virion infectivity (Fig. 3D).



View larger version (16K):
[in this window]
[in a new window]
  		FIG. 3. Infectivity and replication of the SIVmac239 tnef.1 and tnef.2 variants. Stocks of SIVmac239 containing wild type (wt), prematurely terminated (239nef*), or tnef.1 and tnef.2 variants were generated in 293T cells. Replication of the wild-type and variant viruses in CEMx174 cells (A), rhPBMCs (B), and 221 cells in the absence of IL-2 (C) is shown. Cells were infected with aliquots of virus stocks containing 5 ng of p27. PBMCs were infected immediately after isolation and stimulated 3 days later as described previously (16, 19). The amount of p27 antigen was determined by an SIV/HIV-2 enzyme-linked immunosorbent assay (ELISA) obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Reverse transcriptase (RT) activity was determined with a phosphorimager by photon-stimulated light emission (P.S.L.). The infectivity of wild-type and variant SIV to P4-CCR5 cells (5) infected with virus stocks containing 50 ng of p27 was determined as described previously (19), and is shown in panel D. All results are representative of three to five experiments performed with several independently produced virus stocks.

Of the six in vitro Nef activities investigated, the only one retained by the tNef proteins was the ability to down-regulate TCR:CD3. Therefore, the previous suggestion that the severely truncated tNef proteins were capable of significantly increasing SIV virulence in rhesus macaques was surprising (20). However, in this study, virus was recovered from the progressing animal, 26939-105N, near necropsy, leaving the possibility that mutations elsewhere in the viral genome might have contributed to the virulent phenotype.

To address this possibility, six juvenile rhesus macaques were inoculated intravenously with SIVmac239 tnef.1 virus stock containing 5 ng of p27 produced from transiently transfected 293T cells as described previously (8). The animals were healthy and seronegative for SIV, D-type retroviruses, and STLV-1 at the time of infection. Sera and PBMCs were collected from the infected rhesus monkeys at regular intervals. Serological, virological, and immunological analyses of the clinical samples were performed as described before (22, 23, 26). As shown in Fig. 4, following initial spikes in the acute phase, the viral RNA copy numbers and cell associated viral loads were low in all six animals infected with SIVmac239 tnef.1 compared to those infected with wild-type SIVmac239. In agreement with the observed attenuated in vivo replication of SIVmac239 tnef.1, the total CD4+ T cells and CD4+ CD29+ memory T cells were essentially unchanged in the infected animals (Fig. 5), all of whom remained healthy throughout the 40-week observation period. Thus, the SIVmac239 tnef.1 allele was severely attenuated, and the infections were well controlled in all animals.



View larger version (21K):
[in this window]
[in a new window]
  		FIG. 4. Replication of the SIVmac239 tnef.1 variant is attenuated in vivo. The cell-associated viral load (A) and the viral RNA load (B) in Mm10287 ({blacktriangleup}), Mm10295 ({triangleup}), Mm10302 ({blacklozenge}), Mm10663 ({diamond}), Mm10672 (•), and Mm10677 ({circ}) infected with the SIVmac239 tnef.1 variant are shown. For comparison, average values obtained from four rhesus macaques infected with SIVmac239 NU ({square}) and eight who received wild-type SIVmac239 ({blacksquare}) are also shown. The detection limit for viral RNA of approximately 40 copies per ml (26) is indicated by a dotted line.



View larger version (22K):
[in this window]
[in a new window]
  		FIG. 5. CD4+ T-cell counts in macaques infected with SIVmac239 tnef.1 variant. The total number of CD4+ T cells (A) and CD4+ CD29+ memory T cells (B) in the peripheral blood of six animals inoculated with SIVmac239 tnef.1 over time are shown. Symbols and animal codes are as indicated in the legend to Fig. 4.

Intact but truncated tnef ORFs were independently restored in several animals infected with SIVmac239 variants containing the 152-bp deletion (20), yet this was never observed in macaques infected with an SIVmac239 variant containing a 182-bp deletion (13, 14). Both deletions start at nucleotide position 172 of the nef ORF (13, 20). However, in contrast to the 152-bp deletion, the 182-bp deletion removes nucleotides encoding amino acids 111 to 120 of the Nef protein (see Fig. 1). This suggested that amino acids 111 to 120 might be required to down-regulate TCR:CD3 cell surface expression. To address this possibility, the frameshift mutations introduced by the 152- and 182-bp deletions were repaired by removing an additional single nucleotide in the respective nef ORFs. The resulting nef variants (nef{Delta}153 and nef{Delta}183, see Fig. 1) were expressed transiently in Jurkat T cells. As shown in Fig. 6, Nef{Delta}153 down-modulated the cell surface expression of TCR:CD3. In contrast, Nef{Delta}183 was not able to down-modulate TCR:CD3 (Fig. 6), and was also defective in all other in vitro assays of Nef functions tested (data not shown). Thus, a selective pressure for TCR:CD3 down-regulation may explain why the truncated Nef proteins emerged only in animals infected with SIVmac239 containing the 152-bp deletion in the nef-unique region. This event was not possible in animals infected with SIVmac239 containing the 182-bp deletion because it removed amino acids required for TCR:CD3 downregulation.



View larger version (37K):
[in this window]
[in a new window]
  		FIG. 6. Differential abilities of Nef{Delta}153 and Nef{Delta}183 to down-regulate cell surface TCR:CD3 expression. The effects of Nef{Delta}153 and Nef{Delta}183 on TCR:CD3 cell surface levels upon transient expression in Jurkat T cells, determined by two-color flow cytometry as described in the legend to Fig. 1, are shown.

In summary, there are two novel implications of this work. First, it is evident that TCR:CD3 down-regulation by SIVmac239 Nef is associated with a selective advantage for the virus in vivo. However, this function alone is insufficient for high viral loads and rapid disease induction by SIVmac239 in infected rhesus macaques. This is consistent with recent evidence suggesting that a combination of several independent Nef functions allows SIVmac239 and HIV-1 to replicate efficiently in the infected host (3, 5, 12, 19). Second, our data imply that changes elsewhere in the viral genome are required for a pathogenic phenotype of SIVmac239 expressing the tNef proteins. It will be important to determine the nature of such alterations in the SIVmac genome that can compensate for the loss of other Nef functions.


arrow
ACKNOWLEDGMENTS
 
We thank Mandy Krumbiegel and Nathaly Finze for excellent technical assistance and Ingrid Bennett for critical reading of the manuscript. We also thank Thomas Mertens and Bernhard Fleckenstein for constant support and encouragement.

This work was supported by grants from the Wilhelm-Sander Foundation and the Deutsche Forschungsgemeinschaft (to F.K.), as well as the Public Health Service (AI-42561 to J.S.).


arrow
FOOTNOTES
 
* Mailing address for Frank Kirchhoff: Abteilung Virologie-Universit@auml;tsklinikum, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Phone: 49 (731) 50023344. Fax: 49 (731) 50023389. E-mail: frank.kirchhoff{at}medizin.uni-ulm.de. Back

Corresponding author. Mailing address for Jacek Skowronski: Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724. Phone: (516) 367-8407. Fax: (516) 367-8454. E-mail: skowrons{at}cshl.org. Back


arrow
REFERENCES
 
    1
  1. Alexander, L., Z. Du, M. Rosenzweig, J. U. Jung, and R. C. Desrosiers. 1997. A role for natural simian immunodeficiency virus and human immunodeficiency virus type 1 Nef alleles in lymphocyte activation. J. Virol. 71:6094-6099.[Abstract]
    2. 2
  2. Bell, I., C. Ashman, J. Maughan, E. Hooker, F. Cook, and T. A. Reinhart. 1998. Association of simian immunodeficiency virus Nef with the T-cell receptor (TCR) zeta chain leads to TCR down-modulation. J. Gen. Virol. 79:2717-2727.[Abstract]
    3. 3
  3. Carl, S., A. J. Iafrate, S. M. Lang, C. Stahl-Hennig, E. M. Kuhn, D. Fuchs, K. Mätz-Rensing, P. ten Haaft, J. L. Heeney, J. Skowronski, and F. Kirchhoff. 1999. The acidic region and conserved putative protein kinase C phosphorylation site in Nef are important for SIV replication in rhesus macaques. Virology 257:138-155.[CrossRef][Medline]
    4. 4
  4. Carl, S., T. C. Greenough, M. Krumbiegel, M. Greenberg, J. Skowronski, J. L. Sullivan, and F. Kirchhoff. 2001. Modulation of different human immunodeficiency virus type 1 Nef functions during progression to AIDS. J. Virol. 75:3657-3665.[Abstract/Free Full Text]
    5. 5
  5. Charneau, P., G. Mirambeau, P. Roux, S. Paulous, H. Buc, and F. Clavel. 1994. HIV-1 reverse transcription. A termination step at the center of the genome. J. Mol. Biol. 241:651-662.[CrossRef][Medline]
    6. 6
  6. Daniel, M. D., F. Kirchhoff, S. C. Czajak, P. K. Sehgal, and R. C. Desrosiers. 1992. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 258:1938-1941.[Abstract/Free Full Text]
    7. 7
  7. Deacon, N. J., A. Tsykin, A. Solomon, K. Smith, M. Ludford-Menting, D. J. Hooker, D. A. McPhee, A. L. Greenway, A. Ellett, and C. Chatfield. 1995. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270:988-991.[Abstract/Free Full Text]
    8. 8
  8. Deng, H., R. Liu, W. Ellmeier, S. Choe, D. Unutmaz, M. Burkhart, P. Di Marzio, S. Marmon, R. E. Sutton, C. M. Hill, C. B. Davis, S. C. Peiper, T. J. Schall, D. R. Littman, and N. R. Landau. 1996. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381:661-666.[CrossRef][Medline]
    9. 9
  9. Greenberg, M. E., A. J. Iafrate, and J. Skowronski. 1998. The SH3 domain-binding surface and an acidic motif in HIV-1 Nef regulate trafficking of class I MHC complexes. EMBO J. 17:2777-2789.[CrossRef][Medline]
    10. 10
  10. Howe, A. Y. M., J. U. Jung, and R. C. Desrosiers. 1998. Zeta chain of the T-cell receptor interacts with nef of simian immunodeficiency virus and human immunodeficiency virus type 2. J. Virol. 72:9827-9834.[Abstract/Free Full Text]
    11. 11
  11. Iafrate, A. J., S. Bronson, and J. Skowronski. 1997. Separable functions of Nef disrupt two aspects of T cell receptor machinery: CD4 expression and CD3 signaling. EMBO J. 16:673-684.[CrossRef][Medline]
    12. 12
  12. Iafrate, A. J., S. Carl, S. Bronson, C. Stahl-Hennig, T. Swigut, J. Skowronski, and F. Kirchhoff. 2000. Disrupting surfaces of Nef required for down-regulation of CD4 and for enhancement of virion infectivity attenuates simian immunodeficiency virus replication in vivo. J. Virol. 74:9836-9844.[Abstract/Free Full Text]
    13. 13
  13. Kestler, H. W., III, D. J. Ringler, K. Mori, D. L. Panicali, P. K. Sehgal, M. D. Daniel, and R. C. Desrosiers. 1991. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65:651-662.[CrossRef][Medline]
    14. 14
  14. Kirchhoff, F., H. W. Kestler III, and R. C. Desrosiers. 1994. Upstream U3 sequences in simian immunodeficiency virus are selectively deleted in vivo in the absence of an intact nef gene. J. Virol. 68:2031-2037.[Abstract/Free Full Text]
    15. 15
  15. Kirchhoff, F., T. C. Greenough, D. B. Brettler, J. L. Sullivan, and R. C. Desrosiers. 1995. Absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N. Engl. J. Med. 332:228-232.[Free Full Text]
    16. 16
  16. Lang, S. M., A. J. Iafrate, C. Stahl-Hennig, E. M. Kuhn, T. Nißlein, M. Haupt, G. Hunsmann, J. Skowronski, and F. Kirchhoff. 1997. Association of simian immunodeficiency virus Nef with cellular serine/threonine kinases is dispensable for the development of AIDS in rhesus macaques. Nat. Med. 3:860-865.[CrossRef][Medline]
    17. 17
  17. Lock, M., M. E. Greenberg, A. J. Iafrate, T. Swigut, J. Münch, F. Kirchhoff, N. Shohdy, and J. Skowronski. 1999. Two elements target SIV Nef to the AP-2 clathrin adaptor complex, but only one is required for the induction of CD4 endocytosis. EMBO J. 18:2722-2733.[CrossRef][Medline]
    18. 18
  18. Manninen, A., M. Hipakka, M. Vihinen, W. Lu, B. J. Mayer, and K. Saksela. 1998. SH3-domain binding of HIV-1 Nef is required for association with a PAK-related kinase. Virology 250:273-282.[CrossRef][Medline]
    19. 19
  19. Münch, J., N. Stolte, D. Fuchs, C. Stahl-Hennig, and F. Kirchhoff. 2001. Efficient class I major histocompatibility complex down-regulation by simian immunodeficiency virus Nef is associated with a strong selective advantage in infected rhesus macaques. J. Virol. 75:10532-10536.[Abstract/Free Full Text]
    20. 20
  20. Sawai, E. T., M. S. Hamza, M. Ye, K. E. Shaw, and P. A. Luciw. 2000. Pathogenic conversion of live attenuated simian immunodeficiency virus vaccines is associated with expression of truncated Nef. J. Virol.74:2038-2045.[Abstract/Free Full Text]
    21. 21
  21. Schaefer, T. M., I. Bell, B. A. Fallert, and T. A. Reinhart. 2000. The T-cell receptor {zeta} chain contains two homologous domains with which simian immunodeficiency virus Nef interacts and mediates down-modulation. J Virol.74:3273-3283.[Abstract/Free Full Text]
    22. 22
  22. Stahl-Hennig, C., O. Herchenröder, S. Nick, M. Evers, M. Stille-Siegener, K.-D. Jentsch, F. Kirchhoff, T. Tolle, T. J. Gatesmann, W. Lüke, and G. Hunsmann. 1990. Experimental infection of macaques with HIV-2BEN a novel HIV-2 isolate. AIDS 4:611-617.[Medline]
    23. 23
  23. Stahl-Hennig, C., G. Voss, S. Nick, H. Petry, D. Fuchs, H. Wachter, C. Coulibaly, W. Lüke, and G. Hunsmann. 1992. Immunization with Tween-ether-treated SIV adsorbed onto aluminium hydoxide protects monkeys against experimental SIV infection. Virology 186:588-596.[CrossRef][Medline]
    24. 24
  24. Swigut, T., A. J. Iafrate, J. Münch, F. Kirchhoff, and J. Skowronski. 2000. Simian and human immunodeficiency virus Nef proteins use different surfaces to down-regulate class I major histocompatibility antigen expression. J. Virol. 74:5691-5701.[Abstract/Free Full Text]
    25. 25
  25. Swigut, T., N. Shody, and J. Skowronski. 2001. Mechanism for down-regulation of CD28 by Nef. EMBO J. 20:1593-1604.[CrossRef][Medline]
    26. 26
  26. Ten Haaft, P., B. Verstrepen, K. Überla, B. Rosenwirth, and J. Heeney. 1998. A pathogenic threshold of virus load defined in simian immunodeficiency virus- or simian-human immunodeficiency virus-infected macaques. J. Virol. 72:10281-10285.[Abstract/Free Full Text]

Journal of Virology, December 2002, p. 12360-12364, Vol. 76, No. 23
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.23.12360-12364.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Brenner, M., Munch, J., Schindler, M., Wildum, S., Stolte, N., Stahl-Hennig, C., Fuchs, D., Matz-Rensing, K., Franz, M., Heeney, J., Ten Haaft, P., Swigut, T., Hrecka, K., Skowronski, J., Kirchhoff, F. (2006). Importance of the N-Distal AP-2 Binding Element in Nef for Simian Immunodeficiency Virus Replication and Pathogenicity in Rhesus Macaques. J. Virol. 80: 4469-4481 [Abstract] [Full Text]  
  • Munch, J., Schindler, M., Wildum, S., Rucker, E., Bailer, N., Knoop, V., Novembre, F. J., Kirchhoff, F. (2005). Primary Sooty Mangabey Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 2 nef Alleles Modulate Cell Surface Expression of Various Human Receptors and Enhance Viral Infectivity and Replication. J. Virol. 79: 10547-10560 [Abstract] [Full Text]  
  • Vigerust, D. J., Egan, B. S., Shepherd, V. L. (2005). HIV-1 Nef mediates post-translational down-regulation and redistribution of the mannose receptor. J. Leukoc. Biol. 77: 522-534 [Abstract] [Full Text]  
  • Schindler, M., Munch, J., Brenner, M., Stahl-Hennig, C., Skowronski, J., Kirchhoff, F. (2004). Comprehensive Analysis of Nef Functions Selected in Simian Immunodeficiency Virus-Infected Macaques. J. Virol. 78: 10588-10597 [Abstract] [Full Text]  
  • Kirchhoff, F., Schindler, M., Bailer, N., Renkema, G. H., Saksela, K., Knoop, V., Muller-Trutwin, M. C., Santiago, M. L., Bibollet-Ruche, F., Dittmar, M. T., Heeney, J. L., Hahn, B. H., Munch, J. (2004). Nef Proteins from Simian Immunodeficiency Virus-Infected Chimpanzees Interact with p21-Activated Kinase 2 and Modulate Cell Surface Expression of Various Human Receptors. J. Virol. 78: 6864-6874 [Abstract] [Full Text]  
  • Eckstein, A K, Quadbeck, B, Tews, S, Mann, K, Kruger, C, Mohr, C H, Steuhl, K-P, Esser, J, Gieseler, R K (2004). Thyroid associated ophthalmopathy: evidence for CD4+ {gamma}{delta} T cells; de novo differentiation of RFD7+ macrophages, but not of RFD1+ dendritic cells; and loss of {gamma}{delta} and {alpha}{beta} T cell receptor expression. Br J Ophthalmol 88: 803-808 [Abstract] [Full Text]  
  • Schindler, M., Wurfl, S., Benaroch, P., Greenough, T. C., Daniels, R., Easterbrook, P., Brenner, M., Munch, J., Kirchhoff, F. (2003). Down-Modulation of Mature Major Histocompatibility Complex Class II and Up-Regulation of Invariant Chain Cell Surface Expression Are Well-Conserved Functions of Human and Simian Immunodeficiency Virus nef Alleles. J. Virol. 77: 10548-10556 [Abstract] [Full Text]  
  • Grivel, J.-C., Santoro, F., Chen, S., Faga, G., Malnati, M. S., Ito, Y., Margolis, L., Lusso, P. (2003). Pathogenic Effects of Human Herpesvirus 6 in Human Lymphoid Tissue Ex Vivo. J. Virol. 77: 8280-8289 [Abstract] [Full Text]  
  • Swigut, T., Greenberg, M., Skowronski, J. (2003). Cooperative Interactions of Simian Immunodeficiency Virus Nef, AP-2, and CD3-{zeta} Mediate the Selective Induction of T-Cell Receptor-CD3 Endocytosis. J. Virol. 77: 8116-8126 [Abstract] [Full Text]  

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Münch, J.
Right arrow Articles by Skowronski, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Münch, J.
Right arrow Articles by Skowronski, J.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»