Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques

Abstract

A prophylactic vaccine against human immunodeficiency virus (HIV) remains a top priority in biomedical research. Given the failure of conventional immunization protocols to confer robust protection against HIV, new and unconventional approaches may be needed to generate protective anti-HIV immunity. Here we vaccinated rhesus macaques (RMs) with a recombinant (r)DNA prime (without any exogenous adjuvant), followed by a booster with rhesus monkey rhadinovirus (RRV)−a herpesvirus that establishes persistent infection in RMs (Group 1). Both the rDNA and rRRV vectors encoded a near-full-length simian immunodeficiency virus (SIVnfl) genome that assembles noninfectious SIV particles and expresses all nine SIV gene products. This rDNA/rRRV-SIVnfl vaccine regimen induced persistent anti-Env antibodies and CD8+ T-cell responses against the entire SIV proteome. Vaccine efficacy was assessed by repeated, marginal-dose, intrarectal challenges with SIVmac239. Encouragingly, vaccinees in Group 1 acquired SIVmac239 infection at a significantly delayed rate compared to unvaccinated controls (Group 3). In an attempt to improve upon this outcome, a separate group of rDNA/rRRV-SIVnfl-vaccinated RMs (Group 2) was treated with a cytotoxic T-lymphocyte antigen-4 (CTLA-4)-blocking monoclonal antibody during the vaccine phase and then challenged in parallel with Groups 1 and 3. Surprisingly, Group 2 was not significantly protected against SIVmac239 infection. In sum, SIVnfl vaccination can protect RMs against rigorous mucosal challenges with SIVmac239, a feat that until now had only been accomplished by live-attenuated strains of SIV. Further work is needed to identify the minimal requirements for this protection and whether SIVnfl vaccine efficacy can be improved by means other than anti-CTLA-4 adjuvant therapy.

Rhesus Cytomegalovirus-Specific CD8+ Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection

“…Indeed, CTLA-4 blockade facilitates tumor infiltration by CD8 + CTLs in melanoma, the first disease for which CTLA-4 blockade obtained FDA approval (49). The role of CTLA-4 expression by CD8 + CTLs in SIV infection remains unclear, with a number of studies showing inconsistent results regarding the effect of CTLA-4 blockade on SIV-specific CD8 + CTLs (50)(51)(52)(53). All four of the SIVmac239-specific CD8 + CTL populations analyzed in the present study expressed CTLA-4 upon stimulation, to varying degrees.…”

Reappraising the Value of HIV-1 Vaccine Correlates of Protection Analyses

“…Most important of all may be the choice of the challenge virus, particularly whether it is homogeneously neutralization resistant and heterologous. In the highly stringent macaque model of infection by clonal neutralization-resistant SIVmac239, even autologous protection was elusive after multiple immunizations with different replicating vectors carrying near-full-length SIV genome inserts ( 47 – 49 ). In conclusion, when the bar is raised in the NHP model by the use of a clonal, neutralization-resistant, heterologous challenge virus, there is rarely, if ever, a major discrepancy between human trials and NHP experiments.…”

“…In both settings, the general outcome is little or no protection. Furthermore, the negative outcomes in NHP experiments occurred even in the absence of complications such as the immense natural variability in Env and exposure to variable, but sometimes high, doses in human infection ( 47 – 49 ). It is therefore arguable that even the most stringent NHP models sometimes pose lower demands on protection than what is required to prevent human transmission of HIV-1.…”

“…Two further studies illustrate the variable outcomes in NHP experiments. When macaques had been immunized with a DNA prime before a boost with rhesus monkey rhadinovirus, both vectors expressing near-full-length SIVmac316 genomes, they were strongly protected against acquisition of SIVmac239, a clonal, highly neutralization-resistant virus ( 47 ). Promising as that feat was, a more elaborate immunization scheme with multiple sequential viral vectors failed to provide any protection against the same challenge virus ( 49 ).…”

Induction of Transient Virus Replication Facilitates Antigen-Independent Isolation of SIV-Specific Monoclonal Antibodies

“…19 In fact, the live attenuated SIV and the recombinant near full-length SIV rhesus rhadinovirus vaccines are the only vaccine strategies that have effectively provided protection from acquisition after challenge with this pathogenic clone. [20][21][22] Additionally, the infusion of CD4-immunoglobulin (Ig) G2, eCD4 Ig, and 5L7 IgG1 also protected rhesus macaques against SIVmac239. [23][24][25] Adeno-associated virus (AAV)-delivered 5L7 IgG1 prevented infection of a single macaque, presumably through ADCC activity, since 5L7 IgG1 does not detectably neutralize SIVmac239.…”