Envelope sequence variation, neutralizing antibodies, and primate lentivirus persistence

Studies in ungulate lentivirus systems clearly indicate that neutralization escape variants emerge over time in chronically infected animals. Studies in the EIAV system, in particular, have provided strong evidence that the humoral branch of the immune system is at least one selective force acting on an array of viral variants. In previous studies with the ungulate lentiviruses, molecularly cloned virus was never used, and plaque-purified virus was only sometimes used; the genetic determinants responsible for antigenic variation and immune selection were not determined. While molecular clones are available for HIV-1, immune selection studies have been hampered in this system by the fact that HIV-1 is infectious only for chimpanzees, which do not develop disease and are available in only limited numbers. Experiments on immune selection in humans are generally complicated by lack of knowledge on the time of infection and the genetic make-up of the infecting virus. Our studies on SIV immune selection summarized in this review provide definitive evidence that neutralization-resistant variants emerge in an individual during persistent infection by primate lentiviruses. By cloning viral envelope genes from rhesus monkeys over time and obtaining sequential serum samples from them, we have been able to study not only the evolution of envelope sequences but also the emergence of neutralization-resistant variants. Reciprocal neutralization studies were performed using parental and variant specific sera, and immune selection was demonstrated using molecularly cloned virus of defined sequence. During the course of persistent infection with SIV and HIV, there is clear selective pressure for change in discrete variable regions of envelope. The host neutralizing antibody response appears to be at least one of the selective forces driving sequence change in envelope since one result of the sequence variation is the emergence of neutralization escape mutants. This indicates that neutralizing antibodies do serve to limit HIV and SIV replication during the lengthy asymptomatic stage of infection. The coincidence of neutralization domains of HIV and/or SIV with variable regions V1, V2, V3, V4, V5, and V6 suggests a direct relationship between neutralization domains and the emergence of sequence variants. However, different selective forces may be responsible all or in part for driving sequence changes in some variable domains (summarized in Table 2). For example, alterations in cell and/or tissue tropism may be responsible at least in part for driving change in V3 and the cytotoxic T-lymphocyte response may be responsible for driving change in the signal peptide (V0; Henderson et al. 1992; Wei and Cresswell 1992).(ABSTRACT TRUNCATED AT 400 WORDS)