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Paragraph: In fact, in persistently infected individuals anti-HCV/E2 cross-nAbs are generally elicited at low titer and in a late stage of the infection, leading to a poor control of viremia, whereas quasispecies-specific neutralizing or high titer non-nAbs are elicited earlier [53, [58] [59] [60] [61] [62] . Moreover, the in vivo use of anti-HCV polyclonal immunoglobulin preparations in both chimpanzees and humans has been disappointing, and clinical studies have shown that these preparations fail to prevent recurrent infections in patients after liver transplantation [63] . At this regard, a recent paper has suggested that the effect of some of these nAbs, directed against functionally important residues involved in the viral binding to CD81 (within epitope I, encompassing aminoacid residues 412-426), could be hindered by the presence of non-nAbs binding residues within epitope II on HCV/E2 (aminoacid residues 434-446) [58] . In particular, blocking of these interfering epitope II-specific Abs not only raised the neutralizing titer of serum containing both epitope I-and epitope II-specific Abs, but also uncovered a broader cross-genotype neutralizing response [58] . However, the role (and the existence itself) of these interfering Abs in influencing HCV infection is still controversial. Some authors recently corroborated the data of Zhang et al. by in vitro neutralization assays using serum-derived HCV of genotype 4a and polyclonal Abs derived from immunized goats with different conserved peptides spanning aminoacid residues 412-419, 430-447 and 517-531 of HCV/E2 glycoprotein [64] . In particular, this group found an interfering activity exerted by the weakly neutralizing 430-447-elicited Abs on the neutralizing activity of both the 412-419 and the 517-531-elicited Abs [64] . Interestingly, according to the putative model for E2 folding, all the three aforementioned regions would lie next to each other on the glycoprotein [48] . Therefore, this structural prediction possibly supports the interfering effect of epitope II-directed Abs. However, while this predicted structure is currently the best model available, these conclusions cannot be absolutely ascertained. For this purpose, the availability of E1-E2 crystal will certainly accelerate the fine elucidation of the spatial proximities of neutralizing and interfering mAbs on the E1-E2 structure and, consequently, structure-based vaccine progress. Moreover, it is noteworthy that individuals with Abs that target the region of E2 encompassing epitope I frequently harbor Abs that recognize the region containing epitope II, thus confirming the co-immunogenicity of these epitopes [58] . Finally, it has been shown both a low prevalence (less than 2.5%) and a low titer of epitope I-reactive Abs in sera from both chronic and acute resolved infections thus supporting the hypothesis of a conformational masking by adjacent regions such as that containing epitope II [65] . In fact, Zhang et al. originally put forward the idea that once epitope II is bound to an Ab, the site of epitope I becomes masked and can no longer be recognized by specific nAbs. Indeed, depletion of Abs to epitope II in plasma from a chronically infected HCV patient and vaccinated chimpanzees recovered an otherwise undetectable cross-genotype neutralizing activity [58] . Another possibility is that the initial binding of interfering Abs to the region containing epitope II may induce conformational changes on E2 that inhibit the binding by epitope I-directed Abs, as recently suggested by Lapierre et al. for other anti-HCV/E2 Abs [66] . Conversely, these conclusions were not supported in a recent study by Tarr et al. using murine (AP33) and rat (2/69a) mAbs, as well as human immunoglobulin fractions affinity-purified on linear peptides representing distinct HCV/E2 domains clustering within the regions 412-426 and 434-446 [67] . Although confirming the previously reported co-immunogenicity of these two regions, the authors failed to demonstrate any inhibition between these two groups of Abs. Considering their results, the authors indeed suggested that interference by non-nAbs, at least to the region encompassing residues 434-446, is not a possible mechanism for HCV persistence in chronically infected individuals, as it had been originally proposed by Zhang et al. In accordance with the findings of Tarr and colleagues, Keck et al. described anti-HCV/E2 human mAbs binding conformation-sensitive epitopes encompassing also some residues within the 434-446 interfering region [56] . These mAbs are broadly neutralizing and do not lead to viral escape mutants, demonstrating the functional importance of their epitopes. The authors conclude that not all Abs directed against epitope II are interfering, but they also speculate that the interfering activity could be limited to Abs recognizing linear epitopes within it [56] . Recently, we have partly confirmed the observations of Zhang et al. using a panel of anti-HCV/E2 mAbs: the well characterized mouse anti-HCV/E2 mAb AP33, whose epitope encompasses epitope I (aminoacid residues 412-423), and a weakly neutralizing human anti-HCV/E2 mAb (named e509), whose epitope encompasses epitope II [68] . In particular, we found that e509 is able to interfere with the neutralizing activity of AP33 on genotype 1a virus (strain H77). Instead, we found that e509 does not minimally interfere with the activity of two other broadly cross-neutralizing human anti-HCV/E2 mAbs, named e20 and e137 [49, 69] . Interestingly, we found that both e20 and e137 bind also residues within epitope II, at a higher affinity compared to e509, thus displacing it from the interfering epitope and, therefore, keeping unaltered their neutralizing activity. Thus, in our opinion, the described divergent observations reported above may depend on the different Ab specificities present in the polyclonal preparations used and, probably, also on the different HCV genotypes infecting the studied patients [68] . Moreover, the different strategies adopted in isolating epitope I-and epitope II-directed Abs followed in the studies above could explain the different data obtained. In fact, immunoglobulins purified on peptides representing distinct HCV/E2 regions [67] are obviously directed against linear epitopes; these preparations are certainly different from mAbs cloned using a full-length HCV/E2 glycoprotein, which are more probably directed against conformational epitopes including also residues outside the investigated linear regions [54] . To summarize, in the HCV field several works support the existence of interfering Ab populations and hypothesize their possible role in HCV persistence, as demonstrated using human plasma-derived immunoglobulin preparations, human mAbs, and sera of animals vaccinated with recombinant HCV/E2 peptides. The possible mechanism leading to the interference is still controversial, but both direct steric hindrance and induced antigen conformational changes have been hypothesized. On the other hand, other papers do not confirm these findings, suggesting that the putative interfering epitope II may be targeted by Abs endowed with a broadly neutralizing activity. Our recent paper, using well characterized mAbs [68] , shows that the interfering Abs do exist but that their overall effect may be biased by the presence of nAbs with different binding features and by the infecting HCV genotype. Future works investigating the in vivo role of these interfering Ab subpopulations in HCV persistence will certainly be very useful. The influenza viruses circulate worldwide in animal reservoirs, especially water fowl, potentially affecting humans of any age group. Influenza viruses are classified into types A, B or C based on antigenic differences of their nucleoprotein and matrix protein . The most clinically relevant and variable type is influenza A which is divided in several subtypes, according to the antigenic characteristic of the two envelope glycoproteins, and causes epidemic and pandemic infections [70] . The yearly recurring influenza epidemics are associated with significant morbidity and mortality, particularly among risk groups (such as elderly people or those with chronic medical conditions, pregnant women and children) [71] ; the global spread of pandemic influenza viruses can cause millions of deaths [72] . Within the enveloped influenza virion eight segments of negative single-stranded RNA are protected by the nucleocapsid protein, forming the ribonucleoprotein (RNP). The first six RNA segments each code for a single protein: PB2, PB1, and PA (all constituting the RNA-dependent RNA polymerase), the hemagglutinin (HA), the nucleoprotein (NP), the neuraminidase (NA). The last two segments each code for two different proteins: the matrix proteins (M1 and M2) and the non-structural proteins (NS1 and NS2). Three different proteins (HA, NA and M2) are present on the viral envelope. The HA glycoprotein is the most abundant and it is the major target of the humoral immune response. Together with the NA transmembrane glycoprotein, HA is capable of eliciting a subtype-specific immune responses which is fully protective within, but only partially protective across different subtypes [73] . HA is synthesized as inactive precursor that transits into its active form upon cleavage by host cell proteases, and which is present on the viral membrane as homotrimers. HA trimers bind to 2,6-linked sialic acid molecules on cell membrane proteins or lipids through domains located in the globular head of each monomer. Subsequently, the viral envelope fuses by clathrin-dependent and -independent mechanisms with the endocytic vesicle membrane through the HA fusion peptide located in the stem region of each monomer. As a consequence, viral components are released into the host cell and can subvert the synthetic capabilities of the host cell for production and release of progeny particles [74] . The humoral immunity plays an important role in the host defense against influenza virus infection as most of Abs neutralize influenza viruses and, hence, limit infection [75] [76] [77] [78] . In fact, a large body of experimental works suggests that occlusion of the receptor-binding site on HA by Abs is the main mechanism of influenza viral neutralization. Less common, but more broadly nAbs may neutralize influenza virus by inhibiting fusion of the viral envelope with the endocytic-vesicle membrane [50, [79] [80] [81] [82] [83] . Aminoacid changes on HA, more frequent on the immunodominant globular head, have complex effects on viral neutralization by Abs, usually allowing the mutated variants to escape from previously generated nAbs [84] . Classical studies using neutralizing mouse mAbs identified five distinct antigenic sites (A-E) on the HA1 globular head region in the three-dimensional structure of the H3 HA molecule (A/Hong Kong/1/68) [85] [86] [87] as well as in H1 [88] and H2 subtypes [89] . During the first few days of an infection, the nAb titer is often low, while the titer of non-nAbs is higher and may play a role in the outcome of an infection, as recently observed for influenza A/2009 H1N1 pandemic virus infected patients by To et al. [90] . In particular, this group found that the amount, as well as the avidity, of non-nAbs were higher for patients with severe disease than for those with mild disease. The authors concluded that an exaggerated non-nAb response during the early stage of infection was associated with severe disease [90] . Moreover, the authors speculated that non-nAbs present in patients' sera during the early stage of infection were likely to be either preexisting or the result of a secondary heterosubtypic humoral immune response against more conserved epitopes on several influenza proteins [91] . This early humoral response can be elicited within a few days after infection, because of immune priming by previous exposure to shared viral epitopes. In fact, the matrix proteins and nucleoprotein have conserved aminoacid sequences, and therefore Abs against these proteins from previous seasonal influenza virus infection or vaccination could be induced [92] . Indeed, upon infection with influenza virus, memory B-cells can proliferate rapidly and generate a large amount of these high avidity non-nAbs, especially in patients with severe disease. This is consistent with the observation that the number of peripheral blood B-cells is higher in patients with severe disease than in those with mild disease during the early stage of infection. The mechanism of Ab neutralization interference has been indirectly speculated also by Ndifon et al., who observed that some aminoacid changes on HA actually increase the efficiency of neutralization of escape variants by previously generated Abs, even if not directly influencing their binding [93] . In detail, this group suggested that the increase in neutralizing activity after HA mutation could be the resultant of a lesser steric interference between Abs. Specifically, if there is a steric competition for binding to HA by Abs with different neutralization efficiency, then a mutation that reduces the binding of Abs with low neutralizing activity could increase the overall viral neutralization. Indeed, similarly to what has been speculated for HCV, Abs that bind to HA epitopes located at a distance from the receptor-binding site may therefore fail to occupy this site efficiently, thereby leading to a decreased viral neutralization. Moreover, it has been shown that Abs that bind to a certain HA epitope can prevent further binding of Abs to other epitopes of the same HA protein, and even to epitopes found on adjacent HA proteins. The above observations suggest that Abs that bind to low-neutralization efficiency epitopes of HA might interfere with the binding of nAbs to close high-neutralization efficiency epitopes, thereby impeding the neutralization of influenza viruses. Considering the HA structure, the binding of the interfering Abs would lie at the level of epitope C and E located far from the receptor-binding site on the globular head of the HA. However, the binding of these Abs may influence the binding of nAbs to epitopes A, B and D, located closer to the receptorbinding site [93] . At this regard changes to epitope A, B and D could be highly favored by natural selection, whereas changes to epitopes C and E could be disadvantageous to influenza viruses [93] . Similarly to HCV, but with a sounder confirm due to the availability of the crystal structure, these speculations raise the intriguing possibility that the influenza viruses may have evolved by favoring the preferential elicitation of Abs recognizing epitopes with a low-neutralization profile.

Question: How are type A, B, and C viruses determined?
antigenic differences of their nucleoprotein and matrix protein