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 lentivurses. 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 ahd 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). Continued experimentation, particularly in the SIV system, will be needed for a more detailed understanding of the selective forces driving change in variable regions and for identification of variable domains most responsible for escape from neutralization. Although the V3 loop is often referred to as the PND of HIV-1, there is no clear evidence to suggest that V3 epitopes predominate over conformational epitopes as targets of neutralizing antibody responses during the natural course of HIV-1 infection in humans. It is not yet known to what extent neutralizing antibodies in patients sera are directed at linear versus conformational epitopes, variable versus conserved, or V3 versus other domains. Attempts to identify neutralization epitopes in the SIV system indicate that conformational determinants may be more important than linear determinants. Studies with cloned SIV variants and neutralizing monoclonal antibodies also indicate that conformational or discontinuous epitopes are important targets of neutralizing antibodies to SIV(mac). Sequence changes that accumulate in gp120 during persistent infection in vivo dramatically influence recognition by neutralizing antibodies. Our experiments have defined specific, naturally occurring sequence changes in the fourth variable region of SIV that result in loss of recognition by at least one class of neutralizing antibody. Continued study of this defined system will hopefully allow a clearer understanding of the role of antigenic variation and immune selection in viral persistence and the pathogenesis of AIDS.
|Original language||English (US)|
|Number of pages||35|
|Journal||Current topics in microbiology and immunology|
|State||Published - Jan 1 1994|
ASJC Scopus subject areas
- Immunology and Allergy
- Microbiology (medical)