CpG di-nucleotide Odds Ratio Measures Drive Unsupervised Clustering to Characterize the Andes Hantavirus

Hantaviruses belong to the Bunyaviridae family with small mammals hosting them. Humans are infected either by inhaling virus-containing aerosols or through contact with animal droppings. Even if rodents host the pathogenic species and humans are dead-end hosts, they still get accidentally infected. The Andes Orthohantavirus (ANDV) seems to be the only species with documented person-to-person transmission. Hemorrhagic fever with renal syndrome (HFRS) and Hantavirus cardiopulmonary syndrome (HCPS) are both serious syndromes associated with hantavirus infections. For both syndromes, the mortality rate is near 40%. Decades of studies have already highlighted the CpG repression in RNA viruses, and both the estimation of the CpG odds ratio and the correlation with their genome polarity were dominant factors in figuring out the CpG bias. We conducted the differential analysis of the CpG odds ratio for all the orthohantaviruses on the full segmented genomes (L, M, S). The results suggested the statistical significance of the three groups. The “Small” genomes were more informative from the CpG odd ratio point of view. We calculated the CpG odds ratio for all the Orthohantaviruses within these segments and furthermore estimated the correlation coefficient with the relative coding sequences (CDS). Preliminary results first confirmed the CpG odds ratio as the lowest among all the nucleotides. Second, the Andes virus was highlighted as the one with the highest CpG odds ratio within CDS. The use of these two measures as features for unsupervised clustering algorithms has allowed us to identify four different sub-groups within the Orthohantaviridae family. The evidence is that the Andes Hantavirus exhibits a peculiar CpG odds ratio distribution, probably linked to its unique characteristic of passing from person to person.

Unsupervised Clustering characterizes the CPG dinucleotides distribution of the Andes hantavirus

Hantaviruses belong to the family of Bunyaviridae, and small mammals host them. Humans are infected either by inhaling virus-containing aerosols or through contact with animal droppings. Even if rodents host the pathogenic species and humans are dead-end hosts, they get accidentally infected. Andes Orthohantavirusus (ANDV) seems to be the only species with documented person-to-person transmission. Hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) are both serious syndromes associated with hantavirus infections. For both syndromes, the mortality rate is near 40%. Decades of studies already highlighted the CpG repression in RNA viruses, and both the estimation of the CpG odds ratio and the correlation with their genome polarity were dominant factors to figure out the CpG bias. We conducted the differential analysis of the CpG odds ratio for all the orthohantaviruses on the full segmented genomes (L, M, S). The results suggested the statistical significance of the three groups. The “Small” genomes resulted in the more informative from the CpG odd ratio point of view. We calculated the CpG odds ratio for all the Orthohantaviruses within these segments, and besides, we estimated the correlation coefficient with the relative coding sequences (CDS). Preliminary results firstly confirmed the CpG odds ratio as the lowest among all the nucleotides. Second, highlighted the Andes virus as that whose CpG odds ratio within CDS is highest. The use of these two measures as features for unsupervised clustering algorithms has brought to the identification of four different sub-groups inside of the Orthohantaviridae family. The evidence is that the Andes Hantavirus exhibits a peculiar CpG odds ratio distribution, probably linked to its unique prerogative to pass from human-to-human.

Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, we screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV–glycoprotein (GP) Abs. ANDV-GP–specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. We examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV-induced HCPS.