Live, attenuated simian immunodeficiency virus vaccines elicit potent resistance against a challenge with a human immunodeficiency virus type 1 chimeric virus

Abstract

Three rhesus macaques, previously immunized with SIV⌬3 or SIV⌬2, each an attenuated derivative of SIV mac239 , and two naive monkeys were challenged with 30,000 50% tissue culture infective doses of SHIV, an SIV/human immunodeficiency virus type 1 (HIV-1) chimeric virus bearing the dual-tropic envelope of HIV-1 DH12. By several criteria, including virus isolation, serological assays, and PCR (both DNA and reverse transcriptase), SHIV levels were reduced to barely detectable levels in the circulating blood of vaccinated animals. The resistant SIV-vaccinated macaques had no preexisting neutralizing antibodies directed against SHIV, nor did they produce neutralizing antibodies at any time over a 14-month observation period following SHIV challenge. Interestingly, SIV sequences, derived from the vaccine, could be amplified from numerous tissue samples collected at the conclusion of the experiment, 60 weeks postchallenge, but SHIV-specific sequences (viz., HIV-1 env) could not. These results demonstrate that live attenuated SIV vaccines provide strong long-term protection even against challenge strains with highly divergent envelope sequences.

SIVrcm infection of macaques

“…None of the macaques appeared to completely clear the infection, since SIVrcm provirus was found in rhesus after four months and cynomolgus after six months. Proviral load at four months in rhesus is similar to that seen in non-pathogenic SHIV infections in macaques and non-pathogenic HIV-1 infections in chimpanzees [4,5]. The in vivo passage had no obvious effect on outcome in this limited experiment.…”

Cytotoxic T Lymphocyte–based Control of Simian Immunodeficiency Virus Replication in a Preclinical AIDS Vaccine Trial

“…The magnitude of the total prechallenge Gag-specific CD8 ϩ T cell or CD4 ϩ T cell responses did not appear to correlate with the level of control. We examined plasma-neutralizing activities against SIVmac239 as described previously (31), but found no neutralizing activities in any of the controls or the vaccinees at weeks 5 or 12 after challenge (not depicted), indicating that neutralizing antibodies were not essential for the control of SIV replication observed in this experiment.…”

“…Locus-specific RT-PCR products were subjected to second round PCR to obtain 725-bp-long DNA fragments encoding Mamu-A/B extracellular domains using Mamu-A/B universal forward (5A: 5 Ј -ATGGCGCCCCGAACCCTC-3 Ј ) and reverse (4R: 5 Ј -CCAGGTCAGTGTGATCTCCG-3 Ј ) primers. The product was analyzed by RSCA conformation analysis essentially as described previously (31). In brief, the second round PCR products and "a reference strand," a fragment derived from the same PCR condition except for using 5 Ј Cy5-labeled forward primer and a certain cloned DNA template (its sequence is available upon request), were mixed together in a reaction tube, heat denatured, and then cooled down to form heteroduplex DNA.…”

Enhanced safety and efficacy of live attenuated SIV vaccines by prevaccination with recombinant vaccines

“…However, the safety of attenuated live vaccine is a major concern. Although SIV Dnef and SIV D3 appeared to be completely attenuated in the first trials [7,8,22], it has since been shown to be pathogenic to neonatal macaques and lethal in some adult macaques [4,5,24]. We have been exploring the possibility of combining current models of vaccines to improve the safety and efficacy of live attenuated vaccines.…”