SIV/HIV nef Recombinant Virus (SHIVnef) Produces Simian AIDS in Rhesus Macaques

Authors: Mandell C.P.¹; Reyes R.A.^{1, 2}; Cho K.¹; Sawai E.T.¹; Fang A.L.^{1, 2}; Schmidt K.A.¹; Luciw P.A.^{1, 2}

Source: Virology, Volume 265, Number 2, December 1999 , pp. 235-251(17)

Buy & download fulltext article:

Price: $52.63 plus tax (Refund Policy)

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. Copyright 1999 Academic Press.

Language: English

Document Type: Research article

Affiliations: 1: Department of Medical Pathology 2: Department of Medical Pathology, Center for Comparative Medicine, University of California, Davis, California, 95616

Publication date: 1999-12-01

SIV/HIV nef Recombinant Virus (SHIVnef) Produces Simian AIDS in Rhesus Macaques

Buy & download fulltext article:

Tools

Key

Text size:

Useful pages