Fatal immunopathogenesis by SIV/HIV-1 (SHIV) containing a variant form of the HIV-1SF33 env gene in juvenile and newborn rhesus macaques

Paul A Luciw, Carol P. Mandell, Sunee Himathongkham, Jinling Li, Tesi A. Low, Kim A. Schmidt, Karen E S Shaw, Cecilia Cheng-Mayer

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Abstract

SIV/HIV-1 (SHIV) chimeric clones, constructed by substituting portions of the pathogenic molecular clone SIVmac239 with counterpart portions from HIV-1 clones, provide a means to analyze functions of selected HIV-1 genes in vivo in nonhuman primates. Our studies focused on SHIVSF33, which contains the vpu, tat, rev, and env genes of the cytopathic, T-cell line tropic clone HIV-1SF33 (subtype-B); this clone has a premature stop codon in the vpu gene. In three juvenile macaques inoculated intravenously with SHIVSF33, low-level persistent infection was established; no disease was observed for a period of >2 years. However, at ~ 16 months p.i., one of four SHIVSF33-infected juvenile macaques exhibited an increase in virus load, depletion of CD4+ T cells in peripheral blood and lymph nodes, and other symptoms of simian AIDS (SAIDS). Virus recovered from this animal in the symptomatic stage was designated SHIVSF33A (A, adapted); this virus displayed multiple amino acid sequence changes throughout the HIV-1 env gene compared with the input SHIVSF33 clone. Additionally, a mutation in all clones from SHIVSF33A restored the open reading frame for the vpu gene. In vitro evaluations in tissue-culture systems revealed that SHIVSF33A replicated to higher levels and exhibited greater cytopathicity than SHIVSF33. Furthermore cloned env genes for SHIVSF33A were more fusogenic in a cell-fusion assay compared with the env gene of the SHIVSF33. Intravenous inoculation of SHIVSF33A into juvenile and newborn macaques resulted in a rapid decline in CD4+ T cells to very low levels and development of a fatal AIDS-like disease. A cell-free preparation of this pathogenic chimeric virus also established persistent infection when applied to oral mucosal membranes of juvenile macaques and produced a fatal AIDS-like disease. These studies on pathogenic SHIVSF33A establish the basis for further investigations on the role of the HIV-1 env gene in virus adaptation and in mechanism(s) of immunodeficiency in primates; moreover, the chimeric virus SHIVSF33A can play a role in elucidating mucosal membrane transmission and development of antiviral vaccines in newborns as well as juvenile and adult macaques.

Original languageEnglish (US)
Pages (from-to)112-127
Number of pages16
JournalVirology
Volume263
Issue number1
DOIs
StatePublished - Oct 10 1999

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env Genes
Macaca mulatta
HIV-1
Macaca
Clone Cells
vpu Genes
HIV
Viruses
T-Lymphocytes
Primates
Simian Acquired Immunodeficiency Syndrome
rev Genes
Acquired Immunodeficiency Syndrome
tat Genes
Membranes
Cell Fusion
Nonsense Codon
Infection
Open Reading Frames
Antiviral Agents

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

Fatal immunopathogenesis by SIV/HIV-1 (SHIV) containing a variant form of the HIV-1SF33 env gene in juvenile and newborn rhesus macaques. / Luciw, Paul A; Mandell, Carol P.; Himathongkham, Sunee; Li, Jinling; Low, Tesi A.; Schmidt, Kim A.; Shaw, Karen E S; Cheng-Mayer, Cecilia.

In: Virology, Vol. 263, No. 1, 10.10.1999, p. 112-127.

Research output: Contribution to journalArticle

Luciw, PA, Mandell, CP, Himathongkham, S, Li, J, Low, TA, Schmidt, KA, Shaw, KES & Cheng-Mayer, C 1999, 'Fatal immunopathogenesis by SIV/HIV-1 (SHIV) containing a variant form of the HIV-1SF33 env gene in juvenile and newborn rhesus macaques', Virology, vol. 263, no. 1, pp. 112-127. https://doi.org/10.1006/viro.1999.9908
Luciw, Paul A ; Mandell, Carol P. ; Himathongkham, Sunee ; Li, Jinling ; Low, Tesi A. ; Schmidt, Kim A. ; Shaw, Karen E S ; Cheng-Mayer, Cecilia. / Fatal immunopathogenesis by SIV/HIV-1 (SHIV) containing a variant form of the HIV-1SF33 env gene in juvenile and newborn rhesus macaques. In: Virology. 1999 ; Vol. 263, No. 1. pp. 112-127.
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abstract = "SIV/HIV-1 (SHIV) chimeric clones, constructed by substituting portions of the pathogenic molecular clone SIVmac239 with counterpart portions from HIV-1 clones, provide a means to analyze functions of selected HIV-1 genes in vivo in nonhuman primates. Our studies focused on SHIVSF33, which contains the vpu, tat, rev, and env genes of the cytopathic, T-cell line tropic clone HIV-1SF33 (subtype-B); this clone has a premature stop codon in the vpu gene. In three juvenile macaques inoculated intravenously with SHIVSF33, low-level persistent infection was established; no disease was observed for a period of >2 years. However, at ~ 16 months p.i., one of four SHIVSF33-infected juvenile macaques exhibited an increase in virus load, depletion of CD4+ T cells in peripheral blood and lymph nodes, and other symptoms of simian AIDS (SAIDS). Virus recovered from this animal in the symptomatic stage was designated SHIVSF33A (A, adapted); this virus displayed multiple amino acid sequence changes throughout the HIV-1 env gene compared with the input SHIVSF33 clone. Additionally, a mutation in all clones from SHIVSF33A restored the open reading frame for the vpu gene. In vitro evaluations in tissue-culture systems revealed that SHIVSF33A replicated to higher levels and exhibited greater cytopathicity than SHIVSF33. Furthermore cloned env genes for SHIVSF33A were more fusogenic in a cell-fusion assay compared with the env gene of the SHIVSF33. Intravenous inoculation of SHIVSF33A into juvenile and newborn macaques resulted in a rapid decline in CD4+ T cells to very low levels and development of a fatal AIDS-like disease. A cell-free preparation of this pathogenic chimeric virus also established persistent infection when applied to oral mucosal membranes of juvenile macaques and produced a fatal AIDS-like disease. These studies on pathogenic SHIVSF33A establish the basis for further investigations on the role of the HIV-1 env gene in virus adaptation and in mechanism(s) of immunodeficiency in primates; moreover, the chimeric virus SHIVSF33A can play a role in elucidating mucosal membrane transmission and development of antiviral vaccines in newborns as well as juvenile and adult macaques.",
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