Selection of the R17Y substitution in SIVmac239 Nef coincided with a dramatic increase in plasma viremia and rapid progression to death

Three rhesus macaques were infected with an SIVmac239 variant containing su bstitutions of 73/74PA-->ED and 204D-->R in Nef that disrupted the ability of Nef to downregulate CD4 surface expression. One of these animals, Mm8155 , rapidly progressed to AIDS and died 21 weeks postinfection. During the fi nal 5 weeks of infection, the levels of viral RNA and of p27 antigenemia we re about 100-fold higher than usually observed in SIVmac239 infection. Post mortem examination revealed giant cell disease of the lymph nodes and the g astrointestinal tract, opportunistic infections, and a severe chronic enter itis. The majority of proviruses in spleen, kidney, and lymph nodes, and al most 100% of the viral RNA sequences, contained mutations of CGA-->TAT in c odon 17 of nef, predicting a change of 17R-->Y. The appearance of this subs titution, which has recently been shown to confer the phenotype of the acut ely pathogenic SIVpbj14, coincided with the dramatic increase in viral load and rapid progression to fatal disease. In comparison, reversions of 204R- ->D and changes of 72-74NED-->DKD, which restored the ability of Nef to dow nregulate CD4, were already selected earlier in infection. Similarly to SIV pbj14, virus reisolated at late time points from Mm8155 replicated efficien tly in unstimulated monkey lymphocytes. The Y17 substitution was not detect ed in 14 additional SIVmac239-infected macaques at the time of AIDS-related death or in the two slowly progressing animals initially infected with the same Nef variant. Although infection of macaques with SIV is commonly used as an animal model for HIV-1 infection in humans, this is only the second example for the emergence of an acutely lethal SIVmac Nef variant. (C) 1999 Academic Press.