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Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants.

ABSTRACT: Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics throughout Africa and Asia, causing infectious arthritis and reportedly linked with fatal infections in newborns and elderly. Previous studies in animal models indicate that humoral immunity can protect against CHIKV infection, but despite the potential efficacy of B-cell-driven intervention strategies, there are no virus-specific vaccines or therapies currently available. In addition, CHIKV has been reported to elicit long-lasting virus-specific IgM in humans, and to establish long-term persistence in non-human primates, suggesting that the virus might evade immune defenses to establish chronic infections in man. However, the mechanisms of immune evasion potentially employed by CHIKV remain uncharacterized. We previously described two human monoclonal antibodies that potently neutralize CHIKV infection. In the current report, we have characterized CHIKV mutants that escape antibody-dependent neutralization to identify the CHIKV E2 domain B and fusion loop "groove" as the primary determinants of CHIKV interaction with these antibodies. Furthermore, for the first time, we have also demonstrated direct CHIKV cell-to-cell transmission, as a mechanism that involves the E2 domain A and that is associated with viral resistance to antibody-dependent neutralization. Identification of CHIKV sub-domains that are associated with human protective immunity, will pave the way for the development of CHIKV-specific sub-domain vaccination strategies. Moreover, the clear demonstration of CHIKV cell-to-cell transmission and its possible role in the establishment of CHIKV persistence, will also inform the development of future anti-viral interventions. These data shed new light on CHIKV-host interactions that will help to combat human CHIKV infection and inform future studies of CHIKV pathogenesis.

SUBMITTER: Lee CY

PROVIDER: S-EPMC3228792 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:The avian influenza A H5N1 virus occasionally infects humans, with high mortality rates. Although all current human infections are from avian-to-human transmission, it has been shown that H5N1 can be evolved to transmit between mammals, and is therefore a pandemic threat. For H5N1 surveillance, it is of interest to identify the avian isolates most likely to infect humans. In this study, we develop a method to identify mutations significantly associated with avian to human transmission. METHOD:Using protein sequences for the surface glycoprotein hemagglutinin from avian and human H5N1 isolates in China, Egypt, and Indonesia from the years 1996-2011, we used Principle Component Analysis and a Maximum Likelihood Multinomial method to identify mutations associated with avian to human transmission. In each geographic region, transmission bias residues were identified using two signatures: a) significantly different amino-acid frequencies in human isolates compared to avian isolates from the same year, and b) significantly low probability of neutral evolution of the human isolates from the avian viral pool of the previous year. RESULTS:In each geographic region, we find specific transmission bias mutations associated with human infections. These mutations are located in antigenic regions and receptor binding, glycosylation and polybasic cleavage sites of HA. We show that human isolates derive from a limited, subset of the avian pool characterized by geography specific mutations. In Egypt, two of three PCA clusters have very few human isolates but are highly enriched in mutations associated with a vaccine escape mutant H5N1 avian sub-clade that is known to be resistant to the Mexican H5N2 vaccine Furthermore, at these transmission bias associated residues, the mutations characteristic of these two clusters are distinct from those associated with the cluster enriched in human isolates, suggesting that vaccine resistant avian strains are unable to infect humans. Our results are relevant for surveillance and vaccination strategies for human H5N1 infections.

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Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants.

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