Fatal immunopathogenesis by SIV/HIV-1 (SHIV) containing a variant form of the HIV-1SF33 env gene in juvenile and newborn rhesus macaques.
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 approximately 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.
Luciw
P A
PA
Department of Medical Pathology, University of California, Davis, California 95616, USA. paluciw@ucdavis.edu
Mandell
C P
CP
Himathongkham
S
S
Li
J
J
Low
T A
TA
Schmidt
K A
KA
Shaw
K E
KE
Cheng-Mayer
C
C
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000821:virology*; D000595:Amino Acid Sequence; D000818:Animals; D018791:CD4 Lymphocyte Count; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D015752:Genes, env; D014644:Genetic Variation; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction / Q000379:methods; D011995:Recombination, Genetic; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D019562:Viral Load
D004279:DNA, Viral