Abstract
Vaccination with live attenuated simian immunodeficiency virus (SIV) in non-human primate species provides a means of characterizing the protective processes of retroviral superinfection and may lead to novel advances of human immunodeficiency virus (HIV)/AIDS vaccine design. The minimally attenuated SIVmacC8 vaccine has been demonstrated to elicit early potent protection against pathogenic rechallenge with genetically diverse viral isolates in cynomolgus macaques (Macaca fascicularis). In this study, we have characterized further the biological breadth of this vaccine protection by assessing the ability of both the nef-disrupted SIVmacC8 and its nef-intact counterpart SIVmacJ5 viruses to prevent superinfection with the macrophage/neurotropic SIVmac239/17E-Fr (SIVmac17E-Fr) isolate. Inoculation with either SIVmacC8 or SIVmacJ5 and subsequent detailed characterization of the viral replication kinetics revealed a wide range of virus–host outcomes. Both nef-disrupted and nef-intact immunizing viruses were able to prevent establishment of SIVmac17E-Fr in peripheral blood and secondary lymphoid tissues. Differences in virus kinetics, indicative of an active process, identified uncontrolled replication in one macaque which although able to prevent SIVmac17E-Fr superinfection led to extensive neuropathological complications. The ability to prevent a biologically heterologous, CD4-independent/CCR5+ viral isolate and the macrophage-tropic SIVmac316 strain from establishing infection supports the hypothesis that direct target cell blocking is unlikely to be a central feature of live lentivirus vaccination. These data provide further evidence to demonstrate that inoculation of a live retroviral vaccine can deliver broad spectrum protection against both macrophage-tropic as well as lymphocytotropic viruses. These data add to our knowledge of live attenuated SIV vaccines but further highlight potential safety concerns of vaccinating with a live retrovirus.
Highlights
Human immunodeficiency virus (HIV), the causative agent of AIDS, infects approximately 35 million people worldwide with an estimated 2.3 million new cases in 2012 (UNAIDS, 2013)
At day 84, post SIVmac17E-Fr challenge viral RNA levels were *103 simian immunodeficiency virus (SIV) RNA copies ml21. Both macaques seroconverted to SIV Gag and Envelope antigens by 84 days p.i
SIVmac17E-Fr was detected in X73 in PBMCs; all controls (X69–X73) signalled SIVmac17E-Fr positive in Mesenteric lymph nodes (MLN) and peripheral lymph nodes (PLN), but no signals for challenge virus were detected in any macaques immunized with SIVmacC8 or SIVmacJ5
Summary
Human immunodeficiency virus (HIV), the causative agent of AIDS, infects approximately 35 million people worldwide with an estimated 2.3 million new cases in 2012 (UNAIDS, 2013). In cynomolgus macaques (CM; Macaca fascicularis), prior exposure to the nef-disrupted live attenuated virus SIVmac251/C8 (SIVmacC8; Rud et al, 1994) confers potent and durable protection against subsequent infection with wild-type SIV, delivered either as cell-free or cell-associated virus (Almond et al, 1995) and against heterologous as well as homologous viral challenge (Berry et al, 2008, 2011). SIVmacC8 is ostensibly T-cell tropic, targeting CCR5+/CD4+ lymphocytes early in the infection process (Canto -Nogues et al, 2001; Ferguson et al, 2014) and multiple lymphoid tissues resulting in the establishment of persistent virus infection in a highly dynamic process. The implications of the findings from these studies are presented in the context of understanding the broader issues of vaccine protection delivered by a live retrovirus
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