Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine

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 Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus.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.

Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older

“…Although the proportion of CD4 3+ T cells appeared to be greater in HZ/su recipients <70 years, the proportion of CD4 3+ T cells was over 50% in all age groups at 2 and 3 years after 2 doses of HZ/su. In human trials, CD4 + T-cell polyfunctionality correlated with protection induced by many vaccines, including human immunodeficiency virus (HIV), tuberculosis (BCG vaccine), malaria, and melanoma [ 31–33 , S1]. The correlation of CD4 + T-cell polyfunctionality with protection has similarly been observed in animal models of vaccines for simian immunodeficiency virus and herpes simplex virus [ 31–35 ].…”

“…In human trials, CD4 + T-cell polyfunctionality correlated with protection induced by many vaccines, including human immunodeficiency virus (HIV), tuberculosis (BCG vaccine), malaria, and melanoma [ 31–33 , S1]. The correlation of CD4 + T-cell polyfunctionality with protection has similarly been observed in animal models of vaccines for simian immunodeficiency virus and herpes simplex virus [ 31–35 ]. In vaccine trials against metastatic melanoma, T-cell polyfunctionality correlated with long-term survival [ 36 ].…”

Variable Baseline Papio cynocephalus Endogenous Retrovirus (PcEV) Expression Is Upregulated in Acutely SIV-Infected Macaques and Correlated to STAT1 Expression in the Spleen

“…Low levels of PcEV RNA are present in the plasma of some SIV+ macaques. Viral RNA copies/ml plasma RNA in naïve and SIV+ macaques: SIVmac239 (48), SIVmacC8 (35), SIVmac251 (49), and SIVsmE660 (50). Absence of DNA contamination was confirmed in all experiments by simultaneous RT-qPCR without the RT enzyme and only results from the corresponding RT+ reactions are shown.…”

“…Plasma and cells were derived from acutely SIV-infected Indian RM and CM challenged with different SIV isolates in historical studies of SIV pathogenesis and vaccination (35, 48, 50, 84). Total RNA was extracted from 140 μL to 1 mL plasmas using QiaAmp (Qiagen Ltd) according to the manufacturer's instruction.…”

“…Animal procedures were performed in strict accordance with UK Home Office guidelines under a license granted by the Secretary of State for the Home Office which approved the work described. These previous experiments have been published (35, 48, 81–83, 85) along with full details of experimental design, procedures and ethical approval.…”