Attenuation of V- or C-Defective Measles Viruses: Infection Control by the Inflammatory and Interferon Responses of Rhesus Monkeys

Abstract

Patients recruited in virus-based cancer clinical trials and immunocompromised individuals in need of vaccination would profit from viral strains with defined attenuation mechanisms. We generated measles virus (MV) strains defective for the expression of either the V protein, a modulator of the innate immune response, or the C protein, which has multiple functions. The virulence of these strains was compared with that of the parental wild-type MV in a natural host, Macaca mulatta. Skin rash, viremia, and the strength of the innate and adaptive immune responses were characterized in groups of six animals. Replication of V-or C-proteindefective viruses was short-lived and reached lower levels in peripheral blood mononuclear cells and lymphatic organs compared to the wild-type virus; none of the mutants reverted to the wild type. The neutralizing antibody titers and MV-specific T-cell responses were equivalent in monkeys infected with the viral strains tested, documenting strong adaptive immune responses. In contrast, the inflammatory response was better controlled by wild-type MV, as revealed by inhibition of interleukin-6 and tumor necrosis factor alpha transcription. The interferon response was also better controlled by the wild-type virus than by the defective viruses. Since V-and C-defective MVs induce strong adaptive immune responses while spreading less efficiently, they may be developed as vaccines for immunocompromised individuals. Moreover, MV unable to interact with single innate immunity proteins may be developed for preferential replication in tumors with specific contexts of vulnerability.Certain safe and effective live attenuated vaccines were generated simply by repeated passage of virulent strains on heterologous cells, resulting in multiple mutations and sometimes gene deletions (30,43). Nevertheless, vaccine strains with defined mechanisms and levels of attenuation would be preferable for new applications of viruses for cancer therapy (18,22) and the vaccination of immunocompromised hosts (37). Many viruses express proteins that control the antiviral response, and viruses without these proteins are promising candidates for specific vector and vaccine applications. Measles virus (MV) host control proteins include V protein, whose mechanisms of innate immunity modulation are well understood, and C protein, whose mechanisms of action are less well defined. Both V and C proteins are dispensable for replication in cultivated cells (35,41).The V protein shares the amino-terminal domain of the P protein, but its 68 carboxyl-terminal highly conserved amino acids forming a zinc-binding domain (31) are translated from a different open reading frame (ORF) accessed by the cotranscriptional insertion of a pseudotemplate G residue (9). MV V functions as an interferon (IFN) antagonist through its interaction with both MDA5 and the STAT proteins (3,7,8,10,27,29,47). V can also interfere with signaling by interleukin-6 (IL-6) (29). Interference with the IFN response facilitates virus replication by blocking the i...

Lymphotropism and host responses during acute wild-type canine distemper virus infections in a highly susceptible natural host

“…Of note, a similar disparity has been found in studies on wild-type MVs of mild clinical virulence in rhesus monkeys, displaying slow kinetics of IL-4 mRNA levels in PBMCs (Devaux et al, 2008). As events in the immune induction of B-cell responses occur in lymph nodes, the local IL-4 response could give a different picture from that for PBMCs.…”

“…The latter study based on blood leukocytes further identified early cytokine expression in animals within the first 7 days of eventually non-lethal infections (Svitek & von Messling, 2007). Also, analogous experiments with MV in monkeys have shown that wild-type viruses appear to control the early innate and antiviral responses in studies focusing on PBMCs during weeks 1 and 2 after infection (Devaux et al, 2008).…”

“…This disengagement of the host innate immune system has been shown to be associated with the morbillivirus V protein, which interferes with STAT protein and cytokine signal transduction and is required to control the inflammatory and IFN responses in vivo (Devaux et al, 2008;Nakatsu et al, 2008;von Messling et al, 2006). Also, the C protein appears to be involved via different actions (Fontana et al, 2008a;Nakatsu et al, 2008;Takeuchi et al, 2005).…”

“…Thus, accumulating evidence strongly links immunosuppression and lymphopenia not only to direct effects following infection and subsequent destruction of signalling lymphocytic activating molecule (SLAM)-positive immune cells and precursor cells in the acute phase of the infections, but also to indirect effects modulating the host innate and adaptive immune systems (Cruz et al, 2006;Devaux et al, 2008;Heaney et al, 2005;Karp et al, 1996;Schlender et al, 1996;Tatsuo et al, 2001;von Messling et al, 2006). The relative impact on virulence of the different mechanisms modulating the immune system in vivo is, however, not yet clarified.…”

Nipah virus infection: current scenario

“…The P gene of Henipaviruses encodes at least three nonstructural proteins (C, V, and W) in addition to the P protein [33,34]; however, P protein is the only essential gene product for genome replication. The additional gene products are usually not required for virus replication in vitro, though they often serve as virulence factors in vivo [20,21].…”