Envelope Glycoprotein Determinants of Neutralization Resistance in a Simian-Human Immunodeficiency Virus (SHIV-HXBc2P 3.2) Derived by Passage in Monkeys

Abstract

The simian-human immunodeficiency virus SHIV-HXBc2 contains the envelope glycoproteins of a laboratoryadapted, neutralization-sensitive human immunodeficiency virus type 1 variant, HXBc2. Serial in vivo passage of the nonpathogenic SHIV-HXBc2 generated SHIV KU-1, which causes rapid CD4 ؉ T-cell depletion and an AIDS-like illness in monkeys. A molecularly cloned pathogenic SHIV, SHIV-HXBc2P 3.2, was derived from the SHIV KU-1 isolate and differs from the parental SHIV-HXBc2 by only 12 envelope glycoprotein amino acid residues. Relative to SHIV-HXBc2, SHIV-HXBc2P 3.2 was resistant to neutralization by all of the antibodies tested with the exception of the 2G12 antibody. The sequence changes responsible for neutralization resistance were located in variable regions of the gp120 exterior envelope glycoprotein and in the gp41 transmembrane envelope glycoprotein. The 2G12 antibody, which neutralized SHIV-HXBc2 and SHIV-HXBc2P 3.2 equally, bound the HXBc2 and HXBc2P 3.2 envelope glycoproteins on the cell surface comparably. The ability of the other tested antibodies to achieve saturation was less for the HXBc2P 3.2 envelope glycoproteins than for the HXBc2 envelope glycoproteins, even though the affinity of the antibodies for the two envelope glycoproteins was similar. Thus, a highly neutralization-sensitive SHIV, by modifying both gp120 and gp41 glycoproteins, apparently achieves a neutralization-resistant state by decreasing the saturability of its envelope glycoproteins by antibodies.

Protection of Rhesus Monkeys against Infection with Minimally Pathogenic Simian-Human Immunodeficiency Virus: Correlations with Neutralizing Antibodies and Cytotoxic T Cells

“…The neutralizing antibodies induced did not cross-react with SHIV 89.6p or SHIV SF162p3 , although they did neutralize HIV-1 89.6 and HIV-1 SF162 . The alteration of the neutralization properties of SHIV consequent to adaptation to monkeys is likely to be relevant to the use of these viruses as models for human infections (31,61,62). In this study, we demonstrate for the first time that active immunization to induce neutralizing antibodies protected rhesus monkeys from experimental challenge from moderately pathogenic, heterologous SHIV against which the neutralizing response was cross-reactive.…”

Efficacy of DNA and Fowlpox Virus Priming/Boosting Vaccines for Simian/Human Immunodeficiency Virus

“…In contrast to SHIV 89 were not rapidly (Յ8 weeks) generated following challenge, which is also in contrast to SHIV 89.6P challenge studies. The slow generation of neutralizing antibody to SHIV mn229 is consistent with the long (30 to 70 weeks) initial in vivo passage of SHIV HXB2 through two pigtail macaques, the heterologous nature of the neutralization determinants in the vaccines, and the previously described resistance to neutralizing antibody of pathogenic SHIVs derived from SHIV HXB2 (1,12,13,21,35,36,41). The late generation of neutralizing antibody (11 weeks postchallenge) did not completely control SHIV mn229 viremia in these animals, potentially due to evolution of neutralizing antibody escape variants over time, as described in humans with HIV-1 infection (30,40).…”

Equine Infectious Anemia Virus Envelope Evolution In Vivo during Persistent Infection Progressively Increases Resistance to In Vitro Serum Antibody Neutralization as a Dominant Phenotype

“…This seminal paper has been followed by several other published studies demonstrating a temporal relationship between envelope sequence changes and increases in neutralization resistance for viruses that evolve in monkeys during the course of persistent SIV infection (3,4,27). Similarly, the evolution from neutralization-sensitive to -resistant envelope phenotypes has been documented in persistent infections of monkeys with SHIV constructs containing the HIV-1 envelope (6,24,30,33). Experiments on immune selection and changes in neutralization phenotypes in HIV-1-infected patients are generally complicated by the lack of knowledge of the infecting viral strain and time of infection and by the low levels of in vitro serum antibody neutralization characteristic of primary HIV-1 neutralization.…”