Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines

1] Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA. [2] Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA. [3].
Nature medicine (Impact Factor: 27.36). 09/2012; 18(11). DOI: 10.1038/nm.2934
Source: PubMed


Live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV and AIDS, yet the basis of their robust protection remains poorly understood. Here we show that the degree of LAV-mediated protection against intravenous wild-type SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in the lymph node but not with the responses of such T cells in the blood or with other cellular, humoral and innate immune parameters. We found that maintenance of protective T cell responses is associated with persistent LAV replication in the lymph node, which occurs almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wild-type SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection, an observation that provides a rationale for the development of safe, persistent vectors that can elicit and maintain such responses.

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Available from: Adrian B Mcdermott
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    • "Identification of the mechanism(s) of protection has proven to be difficult, perhaps, at least in part, due to the focus on the measurement of responses in the peripheral circulation. Indeed, the largest study conducted to date has confirmed the absence of immune responses associated with vaccine protection in peripheral blood [11]. "
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    ABSTRACT: Vaccination of Mauritian cynomolgus macaques with the attenuated nef-truncated C8 variant of SIVmac251/32H (SIVmacC8) induces early, potent protection against pathogenic, heterologous challenge before the maturation of cognate immunity. To identify processes that contribute to early protection in this model the pathogenesis, anatomical distribution and viral vaccine kinetics were determined in relation to localised innate responses triggered by vaccination. The early biodistribution of SIVmacC8 was defined by rapid, widespread dissemination amongst multiple lymphoid tissues, detectable after 3 days. Cell-associated viral RNA dynamics identified mesenteric lymph nodes (MLN) and spleen, as well as the gut mucosae, as early major contributors of systemic virus burden. Rapid, localised infection was populated by discrete foci of persisting virus-infected cells. Localised productive infection triggered a broad innate response, with type-1 interferon sensitive IRF-7, STAT-1, TRIM5α and ApoBEC3G genes all upregulated during the acute phase but induction did not prevent viral persistence. Profound changes in vaccine-induced cell-surface markers of immune activation were detected on macrophages, B-cells and dendritic cells (DC-SIGN, S-100, CD40, CD11c, CD123 and CD86). Notably, high DC-SIGN and S100 staining for follicular and interdigitating DCs respectively, in MLN and spleen were detected by 3 days, persisting 20 weeks post-vaccination. Although not formally evaluated, the early biodistribution of SIVmacC8 simultaneously targets multiple lymphoid tissues to induce strong innate immune responses coincident at the same sites critical for early protection from wild-type viruses. HIV vaccines which stimulate appropriate innate, as well as adaptive responses, akin to those generated by live attenuated SIV vaccines, may prove the most efficacious.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Among the non-controllers, only the macaque with the lowest peak viraemia was protected from infection with SIVmac251; others progressed to early signs of immune dysfunction or replicated finally SIVmac251. Moreover, in contrast to Fukazawa et al. (2012), we found no evidence that increased presence of SIV in lymph nodes before challenge was associated with protection. Our results suggest that a certain degree of early viral replication followed by an efficient immune response that most likely includes T-cell responses in lymph nodes was associated with protection. "
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    ABSTRACT: Infection of macaques with live-attenuated SIV usually results in long-lasting efficient protection against infection with pathogenic immunodeficiency viruses. However, attenuation by deletion of regulatory genes such as nef is not complete, leading to a high viral load and fatal disease in some animals. To characterize immunological parameters and polymorphic host factors we studied 17 rhesus macaques infected with attenuated SIVmac239ΔNU. Eight animals were able to control viral replication whereas the remaining animals (non-controllers) displayed variable set-point viral loads. Peak viral load at 2 weeks post infection correlated significantly with set-point viral load (p<0.0001). CD4+ T cell frequencies differed significantly soon after infection between controllers and non-controllers. Abnormal B-cell activation previously ascribed to Nef-function can be observed in non-controllers already 8 weeks after infection despite the absence of Nef. Two non-controllers developed an AIDS-like disease within 102 weeks post infection. Virus from these animals transmitted to naïve animals replicated at low levels and the recipients did not develop immunodeficiency. This suggests that host factors determined differential viral load and subsequent disease course. Known MHC class I alleles associated with disease progression in SIV wild type infection only marginally influenced the viral load in ∆nef-infected animals. Protection from SIVmac251 was associated with homozygosity for Mhc class II in conjunction with a TLR7 polymorphism and showed a trend with initial viral replication. We speculate that host factors whose effects are usually masked by Nef are responsible for the different disease courses in individual animals upon infection with nef-deleted viruses.
    Full-text · Article · Jun 2014 · Journal of General Virology
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    • "CD8 T-cells have been shown to effectively control HIV replication in vivo [1] and in both SIV infection and vaccinated SIV-challenged NHP [2], [3]. The induction of broadly cross-reactive, anti-viral T cells is likely to be a crucial facet of an efficacious HIV vaccine [4], which would complement humoral responses containing the virus at the site of infection. "
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    ABSTRACT: A correlation between in vivo and in vitro virus control mediated by CD8+ T-cell populations has been demonstrated by CD8 T-cell-mediated inhibition of HIV-1 and SIV replication in vitro in peripheral blood mononuclear cells (PBMCs) from infected humans and non-human primates (NHPs), respectively. Here, the breadth and specificity of T-cell responses induced following vaccination with replication-defective adenovirus serotype 35 (Ad35) vectors containing a fusion protein of Gag, reverse transcriptase (RT), Integrase (Int) and Nef (Ad35-GRIN) and Env (Ad35-ENV), derived from HIV-1 subtype A isolates, was assessed in 25 individuals. The vaccine induced responses to a median of 4 epitopes per vaccinee. We correlated the CD8 responses to conserved vs. variable regions with the ability to inhibit a panel of 7 HIV-1 isolates representing multiple clades in a virus inhibition assay (VIA). The results indicate that targeting immunodominant responses to highly conserved regions of the HIV-1 proteome may result in an increased ability to inhibit multiple clades of HIV-1 in vitro. The data further validate the use of the VIA to screen and select future HIV vaccine candidates. Moreover, our data suggest that future T cell-focused vaccine design should aim to induce immunodominant responses to highly conserved regions of the virus.
    Full-text · Article · Mar 2014 · PLoS ONE
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