Comparative studies on mucosal and intravenous transmission of simian immunodeficiency virus (SIVsm): the kinetics of evolution to neutralization resistance are related to progression rate of disease

Abstract

The kinetics of appearance of autologous neutralizing antibodies were studied in cynomolgus macaques infected with simian immunodeficiency virus (SIVsm) by the intravenous (IV) route (six monkeys) or the intrarectal (IR) route (ten monkeys). The SIVsm inoculum virus and reisolates obtained at 2 weeks, 3 or 4 months and later than 1 year were tested in a GHOST(3) cell line-based plaque-reduction assay with autologous sera collected at the same sampling times. All monkeys developed a neutralizing-antibody response to the inoculum virus, those infected by the IV route earlier than monkeys infected by the IR route. Animals were divided into progressor (P), slow-progressor (SP) and long-term non-progressor (LTNP) monkeys, based on progression rate. In P monkeys, neutralization escape could be demonstrated by 3 months post-infection. Neutralization-resistant variants also emerged in SP and LTNP monkeys, but were much delayed compared with P monkeys. Evolution of neutralization resistance was also demonstrated by a positive-control serum in the heterologous reaction. Pooled sera from four LTNP monkeys showed a broad neutralizing capacity, including neutralization of escape variants. These results from a large group of infected monkeys showed that SIV evolves to neutralization resistance in the infected host and that the kinetics of this evolution are related to the route of transmission and the progression rate of SIV disease. The results suggest an important role for neutralizing antibodies in controlling viraemia. Although this control is transient in the infected host, neutralization resistance is relative and variant viruses may be neutralized by a broadly cross-neutralizing serum pool. INTRODUCTIONNeutralizing antibodies serve as markers of protective immunity in many virus infections and are the principal component of the humoral immune response against viral pathogens. However, in human immunodeficiency virus types 1 and 2 (HIV-1 and -2) and simian immunodeficiency virus (SIV) infections, the role of neutralizing antibodies has been unclear. We and others have found an association between neutralizing-antibody responses and delayed disease progression in HIV-1 infections (Cao et al., 1995;Montefiori et al., 1996;Pantaleo et al., 1995;Pilgrim et al., 1997;Zhang et al., 1997). In these studies, serum from asymptomatic long-term non-progressors contained antibodies capable of neutralizing both heterologous and autologous virus isolates, whilst serum from fast progressors had no or only weak neutralizing activity. Although autologous HIV-1-neutralizing antibodies could be detected as early as 1 month after infection, not surprisingly, this restricted immune response combined with the high variability of HIV-1 was, in many cases, followed by selection of neutralizationresistant variants (Albert et al., 1990; Arendrup et al., 1992;Richman et al., 2003;Wei et al., 2003). In contrast, no escape from neutralization could be demonstrated in HIV-2-infected individuals (Björling et al., 1993). Similar to HIV-1 infection, in...

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