Vaccination of Rhesus Macaques with RecombinantMycobacterium bovisBacillus Calmette-Guérin Env V3 Elicits Neutralizing Antibody-Mediated Protection against Simian-Human Immunodeficiency Virus with a Homologous but Not a Heterologous V3 Motif

Abstract

Although the correlates of vaccine-induced protection against human immunodeficiency virus type 1 (HIV-1) are not fully known, it is presumed that neutralizing antibodies (NAb) play a role in controlling virus infection. In this study, we examined immune responses elicited in rhesus macaques following vaccination with recombinant Mycobacterium bovis bacillus Calmette-Guérin expressing an HIV-1 Env V3 antigen (rBCG Env V3). We also determined the effect of vaccination on protection against challenge with either a simian-human immunodeficiency virus (SHIV-MN) or a highly pathogenic SHIV strain (SHIV-89.6PD). Immunization with rBCG Env V3 elicited significant levels of NAb for the 24 weeks tested that were predominantly HIV-1 type specific. Sera from the immunized macaques neutralized primary HIV-1 isolates in vitro, including HIV-1 BZ167/X4 , HIV-1 SF2/X4 , HIV-1 CI2/X4 , and, to a lesser extent, HIV-1 MNp/X4 , all of which contain a V3 sequence homologous to that of rBCG Env V3. In contrast, neutralization was not observed against HIV-1 SF33/X4 , which has a heterologous V3 sequence, nor was it found against primary HIV-1 R5 isolates from either clade A or B. Furthermore, the viral load in the vaccinated macaques was significantly reduced following low-dose challenge with SHIV-MN, and early plasma viremia was markedly decreased after high-dose SHIV-MN challenge. In contrast, replication of pathogenic SHIV-89.6PD was not affected by vaccination in any of the macaques. Thus, we have shown that immunization with an rBCG Env V3 vaccine elicits a strong, type-specific V3 NAb response in rhesus macaques. While this response was not sufficient to provide protection against a pathogenic SHIV challenge, it was able to significantly reduce the viral load in macaques following challenge with a nonpathogenic SHIV. These observations suggest that rBCG vectors have the potential to deliver an appropriate virus immunogen for desirable immune elicitations.

Priming-Boosting Vaccination with Recombinant Mycobacterium bovis Bacillus Calmette-Guérin and a Nonreplicating Vaccinia Virus Recombinant Leads to Long-Lasting and Effective Immunity

“…In order to fully take advantage of the potential benefits of traditional live vectors in HIV-1 vaccine development, we studied the Mycobacterium bovis bacillus Calmette-Guérin (BCG) substrain Tokyo 172 (6) and the replication-deficient vaccinia virus vaccine strain DIs (22,50), both of which have been shown to be nonpathogenic when inoculated into immunodeficient animals (41,51,53) as live recombinant vaccine vehicles (1,(17)(18)(19)(46)(47)(48). As further evidence of the potential of the live vectors for use in HIV/AIDS vaccines, we noted that a recombinant M. bovis BCG vector candidate vaccine for HIV-1-induced positive immune responses in animals (17,46). Moreover, we found that recombinant vaccinia virus DIs encoding the simian immunodeficiency virus (SIV) gene was effective at eliciting anti-SIV immunity in mice when administered as a booster antigen after priming with SIV DNA (47).…”

Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate

“…However, the biological activity of Ab responsible for protection in vivo is unknown. Although neutralizing Ab activity often correlates with protection (3,5,8,9), nonneutralizing Abs also prevent or modulate SIV and SHIV infections, and the fact that Ab neutralizes cell-free virus in vitro does not necessarily implicate neutralization as the critical Ab function in vivo.…”

Induction of Positive Cellular and Humoral Immune Responses by a Prime-Boost Vaccine Encoded with Simian Immunodeficiency Virusgag/pol

“…SIV Gag-and SHIV Env-specific IgG Ab end-point titers of the macaques' sera were measured by ELISA as previously described (23,27,30 The SHIV Env-specific neutralization Ab responses induced by challenge with SHIV were analyzed as previously described (28). In brief, 10 g/ml purified macaque IgG was incubated with 100 50% tissue culture infectious doses (TCID 50 ) of SHIV-C2/1, then cultured in M8166 cells.…”

“…The macaques were fed and cared for in accordance with the standard operating procedure approved by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The study was performed in the P3 facility under guidelines established by the laboratory biosafety manual of the World Health Organization (28).…”