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INTRODUCTION Even with intimate exposure to a virus, some people fail to become infected. Variable transmission partly depends on the dose and duration of exposure but is also governed by the immune status of the host, such as the presence of specific protective antibodies or T cells. However, for some infections, the reasons for erratic transmission are largely unknown. For example, respiratory syncytial virus (RSV) can repeatedly reinfect individuals throughout their lives despite the presence of specific immunity. Additionally, antibodies and T cells have limited efficacy against newly emergent pathogens with pandemic potential. However, the intrinsic and innate mechanisms underlying protection when people are exposed to these viruses are poorly understood. RATIONALE We reasoned that the prior state of the respiratory mucosa’s innate defenses may contribute to the variable outcome of RSV inoculation. By performing experimental challenge of adult volunteers, we were able to measure variations in the status of the nasal mucosa before inoculation and in mucosal responses during the presymptomatic phase of infection. Neither of these phases is easily observable during natural spontaneous transmission. Our observations could then be validated using specific interventional studies in a well-established mouse model of RSV infection. RESULTS After nasal administration of RSV, 57% of inoculated volunteers became infected. The uptake of infection was poorly explained by specific B or T cell immunity. However, transcriptomic profiling of the nasal tissue before inoculation demonstrated a neutrophilic inflammatory signal in those destined to develop symptomatic infection, and this was associated with suppression of an early interleukin-17 (IL-17)–dominated immune response during the presymptomatic period. This was followed by symptomatic infection associated with the expression of proinflammatory cytokines. By contrast, those who resisted infection showed a transient boost in mucosal markers of innate immune activation for several days after viral administration and no subsequent viral replication. In mice, chemokine-induced neutrophil recruitment to the airway before viral exposure transiently enhanced viral replication immediately after inoculation. As with human subjects, this was associated with decreased expression of some innate mediators in the respiratory tract, which was then followed by enhanced disease driven by CD8+ T cells. CONCLUSION Although reinfection with a respiratory virus can be partially explained by the waning of antibody titers and T cell numbers, neutrophilic inflammation in the airway at the time of pathogen exposure also predisposes individuals to symptomatic infection. After exposure, the response of the mucosa diverges: A mild and transient increase in nasal inflammatory mediators is accompanied by termination of viral infection, whereas failure to mount this response is followed by viral success. The state of innate immune preparedness of the respiratory mucosa is thus a major determinant of susceptibility to viral challenge. Our results show the importance of understanding the mucosal microenvironment in studies of respiratory infection and highlight targets for local intervention, which may enhance protection against a range of respiratory pathogens.

Escape from T cell–mediated immune responses affects the ongoing evolution of rapidly evolving viruses such as HIV. By applying statistical approaches that account for phylogenetic relationships among viral sequences, we show that viral lineage effects rather than immune escape often explain apparent human leukocyte antigen (HLA)–mediated immune-escape mutations defined by older analysis methods. Phylogenetically informed methods identified immune-susceptible locations with greatly improved accuracy, and the associations we identified with these methods were experimentally validated. This approach has practical implications for understanding the impact of host immunity on pathogen evolution and for defining relevant variants for inclusion in vaccine antigens.

The review by B. Gaschen et al . (”Diversity considerations in HIV-1 vaccine selection,” 28 June, p. [2354][1]) describes two computational methods (consensus and ancestral state) being considered for developing vaccine antigens against HIV. These methods attempt to minimize the amount of