Abstract
In order to evaluate the role of persisting virus replication during occult phase immunisation in the live attenuated SIV vaccine model, a novel SIVmac239Δnef variant (SIVrtTA) genetically engineered to replicate in the presence of doxycycline was evaluated for its ability to protect against wild-type SIVmac239. Indian rhesus macaques were vaccinated either with SIVrtTA or with SIVmac239Δnef. Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus. Unvaccinated challenge controls exhibited ~107 peak plasma viral RNA copies/ml persisting beyond the acute phase. Six vaccinates, four SIVmac239Δnef and two SIVrtTA vaccinates exhibited complete protection, defined by lack of wild-type viraemia post-challenge and virus-specific PCR analysis of tissues recovered post-mortem, whereas six SIVrtTA vaccinates were protected from high levels of viraemia. Critically, the complete protection in two SIVrtTA vaccinates was associated with enhanced SIVrtTA replication in the immediate post-acute vaccination period but was independent of doxycycline status at the time of challenge. Mutations were identified in the LTR promoter region and rtTA gene that do not affect doxycycline-control but were associated with enhanced post-acute phase replication in protected vaccinates. High frequencies of total circulating CD8+T effector memory cells and a higher total frequency of SIV-specific CD8+ mono and polyfunctional T cells on the day of wild-type challenge were associated with complete protection but these parameters were not predictive of outcome when assessed 130 days after challenge. Moreover, challenge virus-specific Nef CD8+ polyfunctional T cell responses and antigen were detected in tissues post mortem in completely-protected macaques indicating post-challenge control of infection. Within the parameters of the study design, on-going occult-phase replication may not be absolutely required for protective immunity.
Highlights
Following disappearance of vaccine virus from the peripheral circulation replication persists in lymphoid tissue
Protection appeared independent of doxycycline status at the time of virulent virus challenge suggesting that occult replication may not be absolutely necessary for persistence of immunity; stronger protection was observed in monkeys vaccinated with SIVrtTA where vaccine replication persisted for longer after peak viraemia
Some evidence of very low level breakthrough of vaccine virus replication was seen and protection was weaker than that obtained with SIVmac239Δnef
Summary
Live attenuated SIV has proven to be a highly effective vaccination strategy in non-human primate (NHP) models of HIV/AIDS [1,2], in many cases protecting macaques from detectable superinfection following re-challenge with both homologous and heterologous wild-type SIV administered systemically and mucosally [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23]. A detailed comparative study of different attenuated virus strains derived from SIVmac239 concluded that protection was associated with the induction of an effector memory T cell (TEM) response and protection of the T follicular helper (TFH) cell subset in lymphoid tissue [10]. This association, is not definitively established as the mechanism of protection
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