Cervico-Vaginal Inflammatory Cytokine and Chemokine Responses to Two Different SIV Immunogens.

Studies have shown that vaccine vectors and route of immunization can differentially activate different arms of the immune system. However, the effects of different HIV vaccine immunogens on mucosal inflammation have not yet been studied. Because mucosal sites are the primary route of HIV infection, we evaluated the cervico-vaginal inflammatory cytokine and chemokine levels of Mauritian cynomolgus macaques following immunization and boost using two different SIV vaccine immunogens. The PCS vaccine delivers 12 20-amino acid peptides overlapping the 12 protease cleavage sites, and the Gag/Env vaccine delivers the full Gag and full Env proteins of simian immunodeficiency virus. We showed that the PCS vaccine prime and boosts induced short-lived, lower level increases of a few pro-inflammatory/chemotactic cytokines. In the PCS-vaccine group only the levels of MCP-1 were significantly increased above the baseline (P = 0.0078, Week 6; P = 0.0078, Week 17; P = 0.0234; Week 51) following multiple boosts. In contrast, immunizations with the Gag/Env vaccine persistently increased the levels of multiple cytokines/chemokines. In the Gag/Env group, higher than baseline levels were consistently observed for IL-8 (P = 0.0078, Week 16; P = 0.0078, Week 17; P = 0.0156, Week 52), IL-1ß (P = 0.0234, Week 16; P = 0.0156, Week 17; P = 0.0156, Week 52), and MIP-1α (P = 0.0313, Week 16; P = 0.0156, Week 17; P = 0.0313, Week 52). Over time, repeated boosts altered the relative levels of these cytokines between the Gag/Env and PCS vaccine group. 18 weeks after final boost with a higher dosage, IP-10 levels (P = 0.0313) in the Gag/Env group remained higher than baseline. Thus, the influence of vaccine immunogens on mucosal inflammation needs to be considered when developing and evaluating candidate HIV vaccines.

Rescuing the negative impact of human endogenous retrovirus envelope protein on oligodendroglial differentiation and myelination.

Remyelination in the adult CNS depends on activation, differentiation, and functional integration of resident oligodendroglial precursor cells (OPCs) and constitutes the only spontaneous neuroregenerative process able to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis. The proteins encoded by p57kip2- and by human endogenous retrovirus type W (pHERV-W) envelope genes were previously identified as negative regulators of OPC maturation. We here focused on the activity of the ENV protein and investigated how it can be neutralized for an improved myelin repair. We could demonstrate that myelination in vitro is severely affected by this protein but that application of an anti-ENV neutralizing antibody, currently investigated in clinical trials, can rescue the generation of internodes. We then compared p57kip2 and ENV dependent inhibitory mechanisms and found that a dominant negative version of the p57kip2 protein can equally save OPCs from myelination failure in response to ENV-mediated TLR4 activation. Additional experiments addressing p57kip2's underlying mode of action revealed a direct interaction with ATP6v1d, a central component of a vascular ATPase. Its pharmacological blocking was then shown to exert an analogous myelination rescue effect in presence of the ENV protein. Therefore, our study provides mechanistic insights into oligodendroglial inhibition processes and presents three different means to counteract the anti-myelination effect of the ENV protein. These observations are therefore of interest in light of understanding the complexity of the numerous oligodendroglial inhibitors and might promote the establishment of novel regenerative therapies.

Retroviral envelope proteins: Involvement in neuropathogenesis.

The primary disease caused by infection with the exogenous human retroviruses, human immunodeficiency virus 1 (HIV-1) or human T-cell lymphotropic virus 1 (HTLV-1), may overlay manifestations of additional autoimmune pathogenesis. Currently, a role for human endogenous retroviruses (HERVs) is also emerging in some autoimmune/immune-mediated diseases, particularly in multiple sclerosis (MS). Both exogenous and endogenous retroviruses have the potential to elicit the processes leading to autoimmune disease. The pathogenicity of the retroviral envelope protein (Env) is a key player with notable importance in neuroimmune diseases. An essential prerequisite of retroviral infection is the interactions between Env (the retroviral adhesion) proteins on the virion and specific surface receptors on the host cell. These interactions facilitate fusion of the viral envelope and cellular membranes. Additional fusiogenic activities mediated by Env may be beneficial (establishment of the syncytiotrophoblast induced by a HERV-encoded Env) or detrimental to the host (syncytia formation, induction of apoptosis), and Envs are further implied in the direct induction of proinflammatory cytokines, the regulation of autophagy, and pathways of cell death. The pathogenic potential of retroviral Env is therefore not limited to the pathogenetics of infection but also comprise the pathogenic/toxic capacity of the Env protein itself.

Potentiation of N-methyl-D-aspartate-mediated brain injury by a human immunodeficiency virus-1-derived peptide in perinatal rodents.

In this study, we tested the hypothesis that human immunodeficiency virus (HIV)-1-derived peptides augment the neurotoxicity of excitatory amino acid agonists in vivo in postnatal day (PND) 7 rats. Stereotaxic intracerebral injections of the excitatory amino acid agonist N-methyl-D-aspartate (NMDA), alone or coinjected with an HIV-derived recombinant fusion peptide envelope gag (env-gag) were performed in PND-7 rats [group I: 5 nmol NMDA, n = 20; group II: 5 nmol NMDA + low-dose (1 or 50 ng) env-gag, n = 27; group III: 5 nmol NMDA + high-dose (100 ng) env-gag, n = 20], and brain injury was evaluated on PND 12. Based on histopathology scoring and measurements of hippocampal cross-sectional areas in the injected and contralateral hemispheres, coinjection of 100 ng of env-gag with 5 nmol of NMDA markedly increased the severity of resulting injury (p < 0.002, comparing histopathology scores; p < 0.003, comparing interhemispheric differences in hippocampal areas). These data suggest that in the developing nervous system HIV neurotoxicity may result, at least in part, from overactivation of excitatory amino acid receptors, and that perinatal rodent models may provide clinically relevant insights about the pathophysiology of HIV-mediated brain injury.