We have previously identified and characterized cross-reactive neutralizing human monoclonal antibodies (crnhmAbs) against HIV-1, SARS CoV and henipaviruses (Hendra and Nipah). To find possible causes of the infrequent and difficult elicitation of HIV-1-specific crnhmAbs we examined comparatively the extent and dynamics of the antibody somatic mutational diversification (ASMD). The ASMD was calculated as the number of amino acid mutations compared to germline sequences per VH gene. MAbs were selected from phage libraries generated from an HIV-1-infected patient with known time of infection. MAbs were also isolated at different time points from an individual who recovered from SARS CoV infection.

 

 The ASMD of all known HIV-1-specific crnhmAbs was significantly higher (~ 3-30-fold, range 16-32) than that for crnhmAbs against the SARS CoV and henipaviruses (Nipah and Hendra) (range 1-6). The ASMD rate of two newly selected antibodies from an acutely HIV-1-infected patient was about two mutations per month. The ASMD rate for a panel of SARS CoV-specific antibodies was about one mutation per month. Using a linear interpolation based on these data it was estimated that elicitation of known HIV-1-specific crnhmAbs could require ~ 3 years. An illustrative mathematical model for the ASMD rate based on an exponential dependence of time on the number of mutations suggested even longer times unless the somatic diversification is initiated from an antibody that is already appropriately diversified. Elicitation of HIV-1-specific crnhmAbs may require extensive ASMD in contrast to the SARS CoV and henipaviruses. We hypothesize that the infrequent occurrence (absence) of crnhmAbs in HIV-1-infected (immunized) individuals is caused in part by a lack or limited availability of B cell receptors that are able to rapidly mature to cross-reactive neutralizing antibodies. Thus, appropriate immunization protocols of long duration should be developed using the knowledge gained from the exploration of the antibody maturation pathways in humans