Mamu-B*17 ⁺ Rhesus Macaques Vaccinated with env , vif , and nef Manifest Early Control of SIVmac239 Replication

Abstract

Certain major histocompatibility complex class I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). These cases of "elite" control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. In this study, we examined how vaccination impacts SIV replication in RMs expressing the MHC-I allele Approximately 21% of and 50% of RMs control chronic-phase viremia after SIVmac239 infection. Because CD8 T cells targeting Mamu-B*08-restricted SIV epitopes have been implicated in virologic suppression in RMs, we investigated whether this might also be true for RMs. Two groups of RMs were vaccinated with genes encoding Mamu-B*17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (group 1) or together with (group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the group 1 vaccine regimen had little effect on viral replication compared to group 3, suggesting that unlike RMs, preexisting SIV-specific CD8 T cells alone do not facilitate long-term virologic suppression in RMs. Remarkably, however, 5/8 group 2 vaccinees controlled viremia to<15 viral RNA copies/ml soon after infection. No serological neutralizing activity against SIVmac239 was detected in group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light on the unique mechanism of elite control in RMs and implicate vaccine-induced, nonneutralizing anti-Env antibodies in the containment of immunodeficiency virus infection. A better understanding of the immune correlates of protection against HIV might facilitate the development of a prophylactic vaccine. Therefore, we investigated simian immunodeficiency virus (SIV) infection outcomes in rhesus macaques expressing the major histocompatibility complex class I allele Approximately 21% of macaques spontaneously controlled chronic phase viremia after SIV infection, an effect that may involve CD8 T cells targeting Mamu-B*17-restricted SIV epitopes. We vaccinated macaques with genes encoding immunodominant epitopes in Vif and Nef alone (group 1) or together with (group 2). Although neither vaccine regimen prevented SIV infection, 5/8 group 2 vaccinees controlled viremia to below detection limits shortly after infection. This outcome, which was not observed in group 1, was associated with vaccine-induced, nonneutralizing Env-binding antibodies. Together, these findings suggest a limited contribution of Vif- and Nef-specific CD8 T cells for virologic control in macaques and implicate anti-Env antibodies in containment of SIV infection.

A Recombinant Rhesus Monkey Rhadinovirus Deleted of Glycoprotein L Establishes Persistent Infection of Rhesus Macaques and Elicits Conventional T Cell Responses

“…RRV has been used as a vaccine vector in the SIV macaque model of HIV infection (19)(20)(21)(22). Recombinant RRV (rRRV) encoding SIV antigens alone or in combination with other vaccine strategies was able to elicit potent and durable T cell responses (19)(20)(21) and antibody responses to vectored SIV antigens (23).…”

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

“…All procedures were performed in accordance with protocols approved by the University of Wisconsin Graduate School Animal Care and Use Committee. Detailed descriptions of caretaking procedures (i.e., housing, feeding, environmental enrichment, and medical care) and efforts to minimize animal suffering (i.e., anesthesia and euthanasia) can be found in the "Research Animals and Ethics Statement" sections in the Materials and Methods of our previously published studies (30)(31)(32)(33). MHC class I genotyping was conducted by the WNPRC.…”

“…As described in our previous studies, RMs were subjected to repeated intrarectal challenges with SIVmac239, once every 2 weeks (30)(31)(32)(33). Depending on the study, each challenge dose contained either 4.8 × 10 5 (31-33) or 6.52 × 10 6 viral RNA (vRNA) copies (30).…”

“…For all other studies, the same dose was used for all challenges. Viral loads were determined by extracting total RNA from EDTA-anticoagulated plasma and using this RNA as template for a two-step reversetranscription PCR with Gag-specific primers and a Gag-specific fluorescent probe, as previously described (30)(31)(32)(33)36). Viral loads for each animal are shown in Figure 1.…”

“…(30)(31)(32)(33). All animals were housed at the Wisconsin National Primate Research Center (WNPRC) and cared for in compliance with the guidelines of the Weatherall report(34) and the National Research Council's Guide for the Use and Care of Laboratory Animals…”