We also demonstrate that this competitive exclusion is reduced in infections initialized with multiple strains. == Model == A schematic of the stochastic simulation model for the evolution of virus and antibody populations is shown inFig. Here, using a computational model, we show that broad antibodies could in fact emerge earlier and be less mutated, but that they may be prevented from doing so as a result of competitive exclusion by the autologous antibody response. We further find that this competitive exclusion is usually weaker in infections founded by multiple distinct strains, with broadly neutralizing antibodies emerging earlier than in infections founded by a single strain. Our computational model simulates coevolving multitype virus and antibody populations. Broadly neutralizing antibodies may therefore be easier for the adaptive CCG-1423 immune system to generate than previously thought. If less mutated broad antibodies exist, it may be possible to elicit them with a vaccine made up of a mixture of diverse virus strains. A major challenge to developing an HIV type 1 (HIV-1) vaccine is the difficulty of eliciting an immune response that can neutralize the large diversity of viral strains circulating in the human population. The discovery of broad and potent neutralizing monoclonal antibodies against HIV-1 in humans has renewed hopes for an effective HIV vaccine (14). Termed broadly neutralizing antibodies (BnAbs), they are found some years into chronic contamination and typically neutralize a large fraction of a diverse panel of HIV-1 strains in vitro CCG-1423 (5). The B-cell lineages that produce these antibodies constitute on the order of 0.1% of the hosts B-cell population (68), and their presence does not seem to reduce viral load or decrease transmission in the individuals in which they are found (9). However, passive Rabbit polyclonal to SelectinE immunization with BnAbs has been shown to block infections of simian immunodeficiency virus (SIV) and simian-HIV-1 in nonhuman primates (10; see ref.11for a review). In addition, passive infusion with BnAbs leads to rapid, although transient, suppression of viral load in macaques chronically infected with simian-HIV-1 (12,13). These studies suggest that if a vaccine can elicit BnAbs to a sufficiently high level before exposure to HIV-1, the transmitted virus may be neutralized before it becomes established in the host. Attempts to elicit BnAbs have so far been unsuccessful (13,1416). One reason is the antibodies are highly mutated relative to their germline ancestor (Fig. 1A), and it CCG-1423 is a challenge to develop a vaccine that can induce antibodies mutated to such an extent (3). However, several recent lines of research indicate that high levels of mutation may not be necessary for breadth. First, the extent of mutation is usually correlated with the length of contamination (Fig. 1B), and as all broad antibodies to date have been found late into chronic contamination, the high level of mutation may be a result of the passage of time. This is supported by a study that found high levels of somatic mutation in antibodies associated with chronic infections, regardless of whether the antibodies were broadly neutralizing (17). Second, B cells with long heavy chain complementarity determining region 3 loops, a property associated with neutralizing breadth, have been found to exist in the naive B-cell population (18). This suggests the potential for broad HIV-1 antibodies to be generated with few somatic mutations. Last, cross-clade neutralizing responses have been found in HIV-1-infected infants as early as 1115 mo postinfection (19). That an infant immune response is usually capable of producing antibodies de novo that neutralize HIV-1 strains distinct from the founder strain within a relatively short period further supports the idea that B cells need not undergo substantial amounts of affinity maturation and mutation to produce BnAbs. == Fig. 1. == Levels of somatic mutation in HIV-1 antibodies. (A) Number of mutations in the heavy chain variable gene (VH) in antibodies developed against pandemic H1N1 influenza (pH1N1; blue, data from ref.40) compared with BnAbs against HIV-1 (green, data from ref.4). (B) The number of mutations on VHfor antibodies in the CH103 BnAb lineage in a patient over three years (data from ref.8). The length.