The role of virus neutralization in primate lentivirus pathogenesis

Abstract

The antiviral neutralizing activity of sera from primate lentivirus-infected human and monkey hosts was studied. In addition, factors affecting the neutralization reaction were investigated. In simian immunodeficiency virus (SIVsm)-infected macaque monkeys, SIVsm variants able to escape neutralization emerged regularly. Long-term survivor monkeys were able to produce neutralizing antibodies against several escape variants showing a broadly cross-reactive neutralizing activity. In contrast, no neutralization escape mutants could be detected in asymptomatic HIV-2-infected monkeys and all subsequent isolates maintained the same biological phenotype as the virus inoculum. The asymptomatic HIV- 2-infected monkeys were subsequently challenged with pathogenic SIVsm.

High-titre neutralizing antibodies against SIVsm were detected in all vaccinated monkeys as early as one month after challenge but were not present in all unvaccinated control monkeys. All four control monkeys developed simian AIDS within two years. Three out of four immunized monkeys were protected against SIVsm-induced disease for five years, while the remaining one showed a delay in disease progression. These results show that a functional humoral immune response appears to be important for protection against SIV-induced immunodeficiency, or may at least delay disease progression. Similarly, in natural HIV-1 infection in humans, increased neutralizing activity with both higher titres and broader specificity compared to fast progressors were observed in HIV-1-infected long term non-progressors and were associated with a low virus load and stable CD4+ T cell count. Thus, the immune response of long term non-progressors remained intact and the neutralizing capacity of the serum was augmented over time and associated with a benign course of infection.

HXB2 chimeric viruses expressing primary envelope gpl20 of HIV-1 molecular clones were compared for both biological phenotype and sensitivity to neutralization in vitro. Chimeric viruses had the same biological phenotype as primary HIV-1 molecular clones but were more sensitive to neutralization by anti-HIV-1-positive human sera. These data show that gpl20 is the major determinant of the HIV-1 biological phenotype in vitro and suggests that the increased sensitivity to neutralization by human sera of chimeric viruses was probably mediated by epitopes within the envelope gp41.

To characterize the effects of the host cell on virus sensitivity to neutralization, progeny virus from HIV-1 molecular clones was adapted for replication in CD4+ T cell lines and tested for neutralization. Short term in vitro passage did not affect the pattern of neutralization. However, extensive adaptation for replication in the H9 and CEM cell lines dramatically increased the sensitivity to neutralization, probably due to higher exposure of certain neutralizing epitopes. These data indicate that the host cell plays an important role in determining the sensitivity to virus neutralization.