AIDSWEEKLY Plus, 12 Aug 1996
Daniel J. DeNoon, Senior Editor

Monkeys protected against simian immunodeficiency virus (SIV) infection by a live attenuated SIV vaccine developed cytotoxic lymphocyte (CTL) responses specific for the SIV Nef protein - even though the vaccine lacked a functional nef gene.

It appeared that the initial dose of the live vaccine influenced the animals' susceptibility to challenge. Other monkeys given lower doses of the vaccine became infected and did not exhibit post-challenge anti-Nef CTL.

"Taken together, the results suggest that specific or innate responses that suppress early replication of attenuated virus are critical for superinfection immunity," said Sally A. Sharpe of CAMR, Salisbury, U.K.

Sharpe spoke during a presentation to the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

Sharpe and colleagues inoculated 10 rhesus macaques with the infectious SIV clone C8, a "minimally attenuated" SIV clone with a 12 base-pair deletion in the nef/3'LTR region of its genome.

Five pairs of animals received a single dilution of the C8 clone ranging from 10(-1) to 10(-5).

Previous studies have shown that nef-deleted SIV replicates poorly, does not cause disease in healthy adult animals, and can protect against subsequent challenge with virulent SIV.

Fifteen weeks after inoculation with the C8 SIV clone, the animals were challenged with an intravenous dose of virulent, cell-free macJ5 strain of SIV.

Paradoxically, the animals that received the two highest doses of the attenuated virus had the lowest viral loads two weeks after inoculation. But by six weeks after inoculation, all animals had similar virus load.

The attenuated virus elicited SIV-specific antibodies in all 10 inoculated animals, but the level of this response at the time of challenge did not correlate with protection.

Three of nine monkeys tested had pre-challenge Nef- specific CTL responses, but these became undetectable by the time of challenge.

"Superinfection resistance was seen only in animals that had been infected with high doses of attenuated virus," Sharpe reported. "Two animals completely resisted challenge and in a third challenge virus was detectable by PCR only at 4 weeks after challenge."

Three of the protected animals were tested for anti-Nef CTL after challenge; all three were positive. None of three unprotected animals developed post-challenge anti-Nef CTL.

"High doses of attenuated SIVmac are required to induce early superinfection resistance in rhesus macaques," Sharpe and colleagues wrote in their presentation abstract. "The dynamics of virus appearance in peripheral blood mononuclear cells was altered with high doses of attenuated virus. Prechallenge immune responses measured did not correlate with protection."

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