title: SIV/HIV Nef recombinant virus (SHIVnef) produces simian AIDS in rhesus macaques.
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 lymphoid 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.
authors.affiliation: Department of Medical Pathology, University of California, Davis, California 95616, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Mandell
authors.forename: R A
authors.initials: RA
authors.lastname: Reyes
authors.forename: K
authors.initials: K
authors.lastname: Cho
authors.forename: E T
authors.initials: ET
authors.lastname: Sawai
authors.forename: A L
authors.initials: AL
authors.lastname: Fang
authors.forename: K A
authors.initials: KA
authors.lastname: Schmidt
authors.forename: P A
authors.initials: PA
authors.lastname: Luciw
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015693:Gene Products, nef / Q000235:genetics / Q000502:physiology*; D015497:HIV-1; D006801:Humans; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D017386:Sequence Homology, Amino Acid; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity*; D054311:nef Gene Products, Human Immunodeficiency Virus
chemical_list: D015693:Gene Products, nef; D054311:nef Gene Products, Human Immunodeficiency Virus