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The Effect of nef-Deleted SIV Administration on Disease Progression in SIVInfected Rhesus Macaques

Saipiroon M Tam, Subhagya Wadekar, Jared L Clever, Audrey Gutierrez, Victor Lira, Esther Fatehi, Victor Martin, Sateesh Apte and Koen KA Van Rompay

The effect of a live nef-deleted SIVmac 239 construct (SIVΔ nef) was evaluated in rhesus macaques infected with wild-type SIVmac 239 . Rhesus macaques were inoculated by intravenous administration of 100 tissue culture infectious doses 50% (TCID 50 ) of SIVmac 239 . All animals had detectable viremia at 1 week post-inoculation (pi), with peak viremia (6 to 100 million copies viral RNA/ml plasma) two to three weeks pi. From week 4 to week 8 pi, virus levels ranged from ~ 10 4 to ~ 10 6 copies/ml, which is the expected range for SIVmac 239 . MHC type 1 Phenotyping and week 4 viral load data were used to stratify the animals into 3 groups, which all received 2 consecutive intravenous injections of Placebo or SIV Δnef at weeks 8 and 10 pi. The control group received Placebo vehicle (RPMI1640 medium). The Low Dose group received 4e5 TCID 50 units/dose of SIV Δnef, while the log- fold High Dose group received 4e6 TCID 50 units/dose. Animals were monitored daily for clinical signs. At defined regular time points, weight and body temperatures were recorded and blood and urine samples were collected for viral load analysis, clinical haematology, clinical chemistry, urinalysis and immunological assay. No obvious differences were observed in any parameters between the three experimental groups.We conclude that SIV Δnef injection in rhesus macaques infected with wild-type SIV did not increase the progression to disease compared to Placebo control.

We also investigated whether intradermal injection of rhesus macaques with nef-deleted SIV is a suitable route to induce infection with this live-attenuated SIV. Two animals that received a high-dose intradermal injection of SIVΔnef became infected and had a pattern of viremia that is indistinguishable from historical data for animals inoculated intravenously with this virus. These findings confirm the attenuated phenotype of SIVΔnef.