Early Potent Protection against Heterologous SIVsmE660 Challenge Following Live Attenuated SIV Vaccination in Mauritian Cynomolgus Macaques

Abstract

BackgroundLive attenuated simian immunodeficiency virus (SIV) vaccines represent the most effective means of vaccinating macaques against pathogenic SIV challenge. However, thus far, protection has been demonstrated to be more effective against homologous than heterologous strains. Immune correlates of vaccine-induced protection have also been difficult to identify, particularly those measurable in the peripheral circulation.Methodology/Principal FindingsHere we describe potent protection in 6 out of 8 Mauritian-derived cynomolgus macaques (MCM) against heterologous virus challenge with the pathogenic, uncloned SIVsmE660 viral stock following vaccination with live attenuated SIVmac251/C8. MCM provided a characterised host genetic background with limited Major Histocompatibility Complex (MHC) and TRIM5α allelic diversity. Early protection, observed as soon as 3 weeks post-vaccination, was comparable to that of 20 weeks vaccination. Recrudescence of vaccine virus was most pronounced in breakthrough cases where simultaneous identification of vaccine and challenge viruses by virus-specific PCR was indicative of active co-infection. Persistence of the vaccine virus in a range of lymphoid tissues was typified by a consistent level of SIV RNA positive cells in protected vaccinates. However, no association between MHC class I /II haplotype or TRIM5α polymorphism and study outcome was identified.Conclusion/SignificanceThis SIV vaccine study, conducted in MHC-characterised MCM, demonstrated potent protection against the pathogenic, heterologous SIVsmE660 challenge stock after only 3 weeks vaccination. This level of protection against this viral stock by intravenous challenge has not been hitherto observed. The mechanism(s) of protection by vaccination with live attenuated SIV must account for the heterologous and early protection data described in this study, including those which relate to the innate immune system.

Distinct Evolutionary Pressures Underlie Diversity in Simian Immunodeficiency Virus and Human Immunodeficiency Virus Lineages

“…1); SIVmac239 is a clone isolated after additional macaque passages of SIVmac251 (11,30,63). For a heterologous challenge to resemble the distances observed in the HIV circulating population, more distant viruses must be used as vaccine/challenge pairs (for instance, SIVmac239/ SIVmac251 vaccination followed by SIVmacE660 challenge [7,50,66,92]). SIVmacE660 is phylogenetically distinct from the SIVmac251/239 lineage (Fig.…”

A critical analysis of the cynomolgus macaque, Macaca fascicularis, as a model to test HIV-1/SIV vaccine efficacy

“…Even though MHC haplotype did not affect viral loads in SIV sm E660 challenge experiment [30] and neither was there a strong impact of the TRIM5␣ genotype on viral acquisition or replication [16], but when challenged with SIV mac 251, animals positive for MHC haplotype H6 had lower viral loads during the chronic phase, whereas animals positive for haplotype H5 failed to control viraemia [31]. Similarly, MHC heterozygotes confer significant advantage when MHC-identical cynomolgus macaques were challenged with a clonal SIV mac 239 virus.…”

“…The most common live attenuated vaccine, SIV-C8, offered significant protection when challenged with SIV sm E660 [16,30] but performed poorly against SIV mac 32H/L28, a derivative of SIV mac 251 [16,88]. About 75% of the whole virus-vaccinated animals were protected against SIV sm challenge [89].…”

Early Biodistribution and Persistence of a Protective Live Attenuated SIV Vaccine Elicits Localised Innate Responses in Multiple Lymphoid Tissues

“…In our studies conducted in the Mauritian cynomolgus macaque (MCM, Macaca fascicularis ) model with the attenuated nef -disrupted C8 variant of SIVmac251/32H (SIVmacC8), we have been able to demonstrate that protection against wild-type strains can be generated as early as 21 days after vaccination [17], [18], [7], [8], including against heterologous viral challenge [7]. As efficient vaccine replication in vivo appears to be a crucial prerequisite to long-term protection and early vaccine virus replication leads to changes in lymphocyte populations in gut-associated lymphoid tissue [25], we sought to understand the viral kinetics in vivo at multiple localised sites of infection and how localisation and dissemination of the SIVmacC8 virus influences innate responses associated with vaccination/infection.…”