Developing a vaccine for HIV may be aided by a complete understanding of those rare cases where some HIV-infected individuals control replication of the virus1–3. The majority of these elite controllers (ECs) express HLA-B*57 or HLA-B*273. These alleles remain by far the most robust associations with low concentrations of plasma virus4,5, yet the mechanism of control in these individuals is not entirely clear. Here we vaccinated Indian rhesus macaques that express Mamu-B*08, an animal model for HLA-B*27-mediated elite control6, with three Mamu-B*08-restricted CD8+ T cell epitopes and demonstrate that these vaccinated animals controlled replication of the highly pathogenic SIVmac239 clonal virus. High frequencies of CD8+ T cells against these Vif and Nef epitopes in the blood, lymph nodes and colon, were associated with viral control. Moreover, the frequency of the Nef RL10-specific response correlated significantly with reduced acute phase viremia. Finally, two of the eight vaccinees lost control of viral replication in the chronic phase, concomitant with escape in all three targeted epitopes, further implicating these three CD8+ T cell responses in control of viral replication. Our findings indicate that narrowly targeted vaccine-induced virus-specific CD8+ T cell responses can control replication of the AIDS virus.
Here we describe a novel vaccine vector for expressing human immunodeficiency virus (HIV) antigens. We show that recombinant attenuated yellow fever vaccine virus 17D expressing simian immunodeficiency virus SIVmac239 Gag sequences can be used as a vector to generate SIV-specific CD8؉ T-cell responses in the rhesus macaque. Priming with recombinant BCG expressing SIV antigens increased the frequency of these SIVspecific CD8؉ T-cell responses after recombinant YF17D boosting. These recombinant YF17D-induced SIVspecific CD8؉ T cells secreted several cytokines, were largely effector memory T cells, and suppressed viral replication in CD4 ؉ T cells.
Certain major histocompatibility complex class I (MHC-I) alleles (e.g., HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed "elite controllers" [ECs]).Likewise, Mamu-B*08 expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infected Mamu-B*08؉ animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control in Mamu-B*08 ؉ macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8 ؉ T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8 ؉ T-cell response would facilitate the development of elite control in Mamu-B*08 ؉ animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinated Mamu-B*08؉ animals with nef inserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8 ؉ T cells. These vaccine-induced effector memory CD8 ؉ T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8 ؉ T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control in Mamu-B*08 ؉ macaques.
IMPORTANCESince elite control of chronic-phase viremia is a classic example of an effective immune response against HIV/SIV, elucidating the basis of this phenomenon may provide useful insights into how to elicit such responses by vaccination. We have previously established that vaccine-induced CD8 ؉ T-cell responses against three immunodominant epitopes can increase the incidence of elite control in SIV-infected Mamu-B*08؉ rhesus macaques-a model of HLA-B*27-mediated elite control. Here, we investigated whether a monotypic vaccine-induced CD8 ؉ T-cell response targeting the conserved "late-escaping" Nef RL10 epitope can increase the incidence of elite control in Mamu-B*08 ؉ monkeys. Surprisingly, vaccine-induced Nef RL10-specific CD8 ؉ T cells selected for variants within days after infection and, ultimately, did not facilitate the development of elite control. Elite control is, therefore, likely to involve CD8 ؉ T-cell responses against more than one epitope. Together, these results underscore the complexity and multidimensional nature of virologic control of lentivirus infection.
The yellow fever 17D (YF-17D) vaccine is one of the most efficacious vaccines developed to date. Interestingly, vaccination with YF-17D induces IFN-γ production early after vaccination (d 5–7) before the development of classical antigen-specific CD8+ and CD4+ T cell responses. Here we investigated the cellular source of this early IFN-γ production. At days 5 and 7 post vaccination activated CD8+ gamma-delta TCR T cells produced IFN-γ and TNF-α. Activated CD4+ T cells produced IFN-γ and TNF-α at day 7 post vaccination. This early IFN-γ production was also induced after vaccination with recombinant YF-17D (rYF-17D), but was not observed after recombinant Adenovirus type 5 (rAd5) vaccination. Early IFN-γ production, therefore, might be an important aspect of yellow fever vaccination.
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