Most rhesus macaques infected with the CCR5-tropic SHIV _AD8 generate cross-reactive antibodies that neutralize multiple HIV-1 strains

Abstract

The induction of broadly reacting neutralizing antibodies has been a major goal of HIV vaccine research. Characterization of a pathogenic CCR5 (R5)-tropic SIV/HIV chimeric virus (SHIV) molecular clone (SHIV AD8-EO ) revealed that eight of eight infected animals developed cross-reactive neutralizing antibodies (NAbs) directed against an envelope glycoprotein derived from the heterologous HIV-1 DH12 strain. A panel of plasmas, collected from monkeys inoculated with either molecularly cloned or uncloned SHIV AD8 stocks, exhibited cross-neutralization against multiple tier 1 and tier 2 HIV-1 clade B isolates. One SHIV AD8 -infected animal also developed NAbs against clades A and C HIV-1 strains. In this particular infected macaque, the cross-reacting anti–HIV-1 NAbs produced between weeks 7 and 13 were directed against a neutralization-sensitive virus strain, whereas neutralizing activities emerging at weeks 41–51 targeted more neutralization-resistant HIV-1 isolates. These results indicate that the SHIV AD8 macaque model represents a potentially valuable experimental system for investigating B-cell maturation and the induction of cross-reactive NAbs directed against multiple HIV-1 strains.

Generation of Rhesus Macaque-Tropic HIV-1 Clones That Are Resistant to Major Anti-HIV-1 Restriction Factors

“…Although MN4/LSDQgtu is a CXCR4-tropic virus, it has clear potential for the establishment of a model system. MN4/LSDQgtu can be changed to a pathogenic CCR5-tropic virus through in vitro and in vivo approaches, as well documented by previous SHIV studies (68)(69)(70). It is also possible to generate entirely new CCR5-tropic HIV-1mt clones other than MN4/LSDQgtu derivatives on the basis of the key findings for Gag-CA and Vpu-TM in this study.…”

Single-amino acid mutation 66SR in Gag-matrix enhances viral single-cycle infectivity of R5-tropic HIV-1rmt

“…5, while 62QR+5gtu grew significantly more poorly than 5gtu, 66SR+ 5gtu exhibited slightly more retarded growth kinetics relative to 5gtu. To see if this result is applicable to the other R5 -tropic viruses, and to confirm a generalization of above observation, we generated two other R5 -tropic HIV-1rmt clones carrying an env gene from a simian immunodeficiency virus/HIV-1 chimeric virus clone (SHIVAD8 -EH) (17) or from an HIV-1 clinical isolate. We then performed the M1.3S infection experiments as above.…”

Generation of a neutralization-resistant CCR5 tropic simian/human immunodeficiency virus (SHIV-MK38) molecular clone, a derivative of SHIV-89.6

“…In this study, we showed that the neutralization-resistant R5 tropic SHIV-MK38#818 molecular clone derived from SHIV-KS661 can cause stably persistent infection with high viral load via intrarectal inoculation despite the immune responses that occurred in the host. Currently, SHIV AD8 , categorized as a tier 2 neutralization-resistant phenotype, is widely used as a SHIV challenge virus for a variety of vaccine developments (Nishimura et al, 2010;Shingai et al, 2012Shingai et al, 2013;Gardner et al, 2015;Francica et al, 2015). However, use of SHIV AD8 as the only challenge virus is very risky for precise evaluation in vaccine candidates and anti-HIV-1 neutralizing antibodies.…”