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Rhesus macaques (Macaca mulatta) immunized with an inactivated whole SIVmac vaccine and muramyl dipeptide (MDP), incomplete Freund's adjuvant (IFA), or aqueous suspension were challenged intravenously with 0.1 TCID50 of cell-free SIVmac. Whereas virus was readily recovered from the peripheral blood lymphocytes of 10 of 10 nonvaccinated controls following this challenge dose, virus was not recovered from the three animals that received the vaccine with MDP nor from one of two animals that received the vaccine with IFA and one of three animals that received the aqueous vaccine. The animals that were protected against challenge were those that had detectable SIV antibody response to the envelop, both the outer glycoprotein (gp120) and the truncated transmembrane glycoprotein (gp31). Protected monkeys tended to have higher titers of syncytial inhibition antibody prior to challenge. An anamnestic response after challenge was observed only in the vaccinated monkeys that became infected. Vaccinated animals that became challenge-infected tended to live longer than infected controls. These results confirm those at two other primate centers and indicate that killed whole SIV vaccines can protect against low challenge doses of SIV and prevent early death in those monkeys that do become infected. The mechanism of this protection remains undetermined. This finding adds optimism to the possibility of an eventual AIDS vaccine.

The human and simian immunodeficiency virus (HIV-1 and SIVmac) transmembrane proteins contain unusually long intracytoplasmic domains (ICD-TM). These domains are suggested to play a role in envelope fusogenicity, interaction with the viral matrix protein during assembly, viral infectivity, binding of intracellular calmodulin, disruption of membranes, and induction of apoptosis. Here we describe a novel mutant virus, SIVmac-M4, containing multiple mutations in the coding region for the ICD-TM of pathogenic molecular clone SIVmac239. Parental SIVmac239-Nef؉ produces high-level persistent viremia and simian AIDS in both juvenile and newborn rhesus macaques. The ICD-TM region of SIVmac-M4 contains three stop codons, a ؉1 frameshift, and mutation of three highly conserved, charged residues in the conserved C-terminal alpha-helix referred to as lentivirus lytic peptide 1 (LLP-1). Overlapping reading frames for tat, rev, and nef are not affected by these changes. In this study, four juvenile macaques received SIVmac-M4 by intravenous injection. Plasma viremia, as measured by branched-DNA (bDNA) assay, reached a peak at 2 weeks postinoculation but dropped to below detectable levels by 12 weeks. At over 1.5 years postinoculation, all four juvenile macaques remain healthy and asymptomatic. In a subsequent experiment, four neonatal rhesus macaques were given SIVmac-M4 intravenously. These animals exhibited high levels of viremia in the acute phase (2 weeks postinoculation) but are showing a relatively low viral load in the chronic phase of infection, with no clinical signs of disease for 1 year. These findings demonstrated that the intracytoplasmic domain of the transmembrane Env (Env-TM) is a locus for attenuation in rhesus macaques.Lentivirus transmembrane proteins (TM) share a conserved structural organization, characterized by an N-terminal hydrophobic fusion peptide, an extracellular domain, a hydrophobic membrane anchor domain, and a C-terminal intracytoplasmic domain (ICD-TM) (21, 41). In human and simian immunodeficiency viruses (HIV-1 and SIVmac), the ICD-TM is unusually long (150 to 200 residues) and contains two conserved amphipathic alpha-helices near the C terminus (38). The ICD-TM region of HIV-1 and SIVmac has been implicated in several virologic functions, notably induction of cytopathic effects (38, 55), interaction with the matrix (MA) protein during virion assembly (10, 17), modulation of fusogenicity (43, 51, 61), regulation of envelope (Env) expression at the cell surface (5, 29, 44), and binding of calmodulin (37,54,57,58), possibly related to induction of apoptosis (37, 40). Several molecular clones of SIVmac and HIV-2 contain stop codons in the ICD-TM; these stop codons were introduced following adaptation to human cell lines (7,19,33). In some cases (i.e., SIVmac142 and SIVmac1A11), these molecular clones were nonpathogenic in rhesus macaques (7, 33). In the case of two other molecular clones, SIVmac239 and SIVmacBK28, single stop codons in TM were found to revert rapidly upon inoculation of rhesus...

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