SIV/HIV nef recombinant virus (SHIVnef) produces simian AIDS in rhesus macaques

Carol P. Mandell, Richard A. Reyes, Kiho Cho, Earl T. Sawai, Adrienne L. Fang, Kim A. Schmidt, Paul A Luciw

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Abstract

The simian immunodeficiency virus (SIV) nef gene is an important determinant of viral load and acquired immunodeficiency syndrome (AIDS) in macaques. A role(s) for the HIV-1 nef gene in infection and pathogenesis was investigated by constructing recombinant viruses in which the nef gene of the pathogenic molecular clone SIVmac239 nef was replaced with either HIV-1SF2nef or HIV-1SF33nef. These chimeras, designated SHIV-2nef and SHIV-33nef, expressed HIV-1 Nef protein and replicated efficiently in cultures of rhesus macaque lymphcid cells, in two SHIV-2nef-infected juvenile rhesus macaques and in one of two SHIV-33nef-infected juvenile macaques, virus loads remained at low levels in both peripheral blood and lymph nodes in acute and chronic phases of infection (for >83 weeks). In striking contrast, the second SHIV- 33nef-infected macaque showed high virus loads during the chronic stage of infection (after 24 weeks). CD4+ T-cell numbers declined dramatically in this latter animal, which developed simian AIDS (SAIDS) at 47-53 weeks after inoculation; virus was recovered at necropsy at 53 weeks and designated SHIV- 33Anef. Sequence analysis of the HIV-1SF33 nef gene in SHIV-33Anef revealed four consistent amino acid changes acquired during passage in vivo. Interestingly, one of these consensus mutations generated a tyr-x-x-leu (Y-X- X-L) motif in the HIV-1SF33 Nef protein. This motif is characteristic of certain endocytic targeting sequences and also resembles a src-homology region-2 (SH-2) motif found in many cellular signaling proteins. Four additional macaques infected with SHIV-33Anef contained high virus loads, and three of these animals progressed to fatal SAIDS. Several of the consensus amino acid changes in Nef, including Y-X-X-L motif, were retained in these recipient animals exhibiting high virus load and disease. In summary, these findings indicate that the SHIV-33Anef chimera is pathogenic in rhesus macaques and that this approach, i.e., construction of chimeric viruses, will be important for analyzing the function(s) of HIV-1 nef genes in immunodeficiency in vivo, testing antiviral therapies aimed at inhibiting AIDS, and investigating adaptation of this HIV-1 accessory gene to the macaque host.

Original languageEnglish (US)
Pages (from-to)235-251
Number of pages17
JournalVirology
Volume265
Issue number2
DOIs
StatePublished - Dec 20 1999

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

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    Mandell, C. P., Reyes, R. A., Cho, K., Sawai, E. T., Fang, A. L., Schmidt, K. A., & Luciw, P. A. (1999). SIV/HIV nef recombinant virus (SHIVnef) produces simian AIDS in rhesus macaques. Virology, 265(2), 235-251. https://doi.org/10.1006/viro.1999.0051