This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alexander, L. Articles by Desrosiers, R. C. Search for Related Content PubMed PubMed Citation Articles by Alexander, L. Articles by Desrosiers, R. C.

Determinants of Increased Replicative Capacity of Serially Passaged Simian Immunodeficiency Virus with nef Deleted in Rhesus Monkeys

Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut,¹ Chemgenomics, Inc., Medford, Massachusetts 02155,² New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772,³ AIDS Vaccine Program, SAIC Frederick, National Cancer Institute, Frederick, Maryland 21702⁴

Received 9 September 2002/ Accepted 26 February 2003

Most rhesus macaques infected with simian immunodeficiency virus SIVmac239 with nef deleted (either nef or nefvprUS [3]) control viral replication and do not progress to AIDS. Some monkeys, however, develop moderate viral load set points and progress to AIDS. When simian immunodeficiency viruses (SIVs) recovered from two such animals (one nef and the other 3) were serially passaged in rhesus monkeys, the SIVs derived from both lineages were found to consistently induce moderate viral loads and disease progression. Analysis of viral sequences in the serially passaged derivatives revealed interesting changes in three regions: (i) an unusually high number of predicted amino acid changes (12 to 14) in the cytoplasmic domain of gp41, most of which were in regions that are usually conserved; these changes were observed in both lineages; (ii) an extreme shortening of nef sequences in the region of overlap with U3; these changes were observed in both lineages; and (iii) duplication of the NF-B binding site in one lineage only. Neither the polymorphic gp41 changes alone nor the U3 deletion alone appeared to be responsible for increased replicative capacity because recombinant SIVmac239nef, engineered to contain either of these changes, induced moderate viral loads in only one of six monkeys. However, five of six monkeys infected with recombinant SIVmac239nef containing both TM and U3 changes did develop persisting moderate viral loads. These genetic changes did not increase lymphoid cell-activating properties in the monkey interleukin-2-dependent T-cell line 221, but the gp41 changes did increase the fusogenic activity of the SIV envelope two- to threefold. These results delineate sequence changes in SIV that can compensate for the loss of the nef gene to partially restore replicative and pathogenic potential in rhesus monkeys.

This article has been cited by other articles:

• Koenen, P. G. F., Hofhuis, F. M., Oosterwegel, M. A., Tesselaar, K. (2007). T Cell Activation and Proliferation Characteristic for HIV-Nef Transgenic Mice Is Lymphopenia Induced. J. Immunol. 178: 5762-5768 [Abstract] [Full Text]  
• Crotti, A., Neri, F., Corti, D., Ghezzi, S., Heltai, S., Baur, A., Poli, G., Santagostino, E., Vicenzi, E. (2006). Nef Alleles from Human Immunodeficiency Virus Type 1-Infected Long-Term-Nonprogressor Hemophiliacs with or without Late Disease Progression Are Defective in Enhancing Virus Replication and CD4 Down-Regulation. J. Virol. 80: 10663-10674 [Abstract] [Full Text]  
• Song, R. J., Chenine, A.-L., Rasmussen, R. A., Ruprecht, C. R., Mirshahidi, S., Grisson, R. D., Xu, W., Whitney, J. B., Goins, L. M., Ong, H., Li, P.-L., Shai-Kobiler, E., Wang, T., McCann, C. M., Zhang, H., Wood, C., Kankasa, C., Secor, W. E., McClure, H. M., Strobert, E., Else, J. G., Ruprecht, R. M. (2006). Molecularly Cloned SHIV-1157ipd3N4: a Highly Replication- Competent, Mucosally Transmissible R5 Simian-Human Immunodeficiency Virus Encoding HIV Clade C env.. J. Virol. 80: 8729-8738 [Abstract] [Full Text]  
• 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]  
• Churchill, M. J., Rhodes, D. I., Learmont, J. C., Sullivan, J. S., Wesselingh, S. L., Cooke, I. R. C., Deacon, N. J., Gorry, P. R. (2006). Longitudinal Analysis of Human Immunodeficiency Virus Type 1 nef/Long Terminal Repeat Sequences in a Cohort of Long-Term Survivors Infected from a Single Source. J. Virol. 80: 1047-1052 [Abstract] [Full Text]  
• Amara, R. R., Patel, K., Niedziela, G., Nigam, P., Sharma, S., Staprans, S. I., Montefiori, D. C., Chenareddi, L., Herndon, J. G., Robinson, H. L., McClure, H. M., Novembre, F. J. (2005). A Combination DNA and Attenuated Simian Immunodeficiency Virus Vaccine Strategy Provides Enhanced Protection from Simian/Human Immunodeficiency Virus-Induced Disease. J. Virol. 79: 15356-15367 [Abstract] [Full Text]  
• Evans, D. T., Bricker, J. E., Sanford, H. B., Lang, S., Carville, A., Richardson, B. A., Piatak, M. Jr., Lifson, J. D., Mansfield, K. G., Desrosiers, R. C. (2005). Immunization of Macaques with Single-Cycle Simian Immunodeficiency Virus (SIV) Stimulates Diverse Virus-Specific Immune Responses and Reduces Viral Loads after Challenge with SIVmac239. J. Virol. 79: 7707-7720 [Abstract] [Full Text]  
• Kim, E.-Y., Busch, M., Abel, K., Fritts, L., Bustamante, P., Stanton, J., Lu, D., Wu, S., Glowczwskie, J., Rourke, T., Bogdan, D., Piatak, M. Jr., Lifson, J. D., Desrosiers, R. C., Wolinsky, S., Miller, C. J. (2005). Retroviral Recombination In Vivo: Viral Replication Patterns and Genetic Structure of Simian Immunodeficiency Virus (SIV) Populations in Rhesus Macaques after Simultaneous or Sequential Intravaginal Inoculation with SIVmac239{Delta}vpx/{Delta}vpr and SIVmac239{Delta}nef. J. Virol. 79: 4886-4895 [Abstract] [Full Text]  
• Pham, H. M., Arganaraz, E. R., Groschel, B., Trono, D., Lama, J. (2004). Lentiviral Vectors Interfering with Virus-Induced CD4 Down-Modulation Potently Block Human Immunodeficiency Virus Type 1 Replication in Primary Lymphocytes. J. Virol. 78: 13072-13081 [Abstract] [Full Text]  
• Swigut, T., Alexander, L., Morgan, J., Lifson, J., Mansfield, K. G., Lang, S., Johnson, R. P., Skowronski, J., Desrosiers, R. (2004). Impact of Nef-Mediated Downregulation of Major Histocompatibility Complex Class I on Immune Response to Simian Immunodeficiency Virus. J. Virol. 78: 13335-13344 [Abstract] [Full Text]  
• Blancou, P., Chenciner, N., Fang, R. H. T., Monceaux, V., Cumont, M.-C., Guetard, D., Hurtrel, B., Wain-Hobson, S. (2004). Simian Immunodeficiency Virus Promoter Exchange Results in a Highly Attenuated Strain That Protects against Uncloned Challenge Virus. J. Virol. 78: 1080-1092 [Abstract] [Full Text]