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: 28.05). 09/2012; DOI: 10.1038/nm.2934
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Adrian B Mcdermott, Jun 28, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Simian immunodeficiency virus infection of rhesus macaques causes immune depletion and disease closely resembling human AIDS, and is well-recognized as the most relevant animal model for the human disease. Experimental investigations of viral pathogenesis and vaccine protection primarily involve a limited set of related viruses originating in sooty mangabeys (SIVsmm). The diversity of HIV-1 has evolved in humans in about a century; in contrast, SIV isolates used in the macaque model evolved in sooty mangabeys over millennia. To investigate the possible consequences of such different evolutionary histories on selection pressures and observed diversity in SIVsmm and HIV-1, we isolated, sequenced, and analyzed 20 independent isolates of SIV sooty mangabey (SIVsmm), including representatives of 7 distinct clades of viruses isolated from natural infection. We found SIVsmm diversity to be lower overall than HIV-1 M group diversity. Compared to HIV-1, reduced positive selection (i.e., less diversifying evolution) was evident in extended regions of SIVsmm proteins, most notably in Gag p27 and Env gp120. In addition, the relative diversity of proteins in the two lineages was distinct: SIVsmm Env and Gag were much less diverse than their HIV-1 counterparts; this may be explained by lower SIV-directed immune activity in mangabeys relative to HIV-1-directed immunity in humans. These findings add an additional layer of complexity to the interpretation, and potentially, to the predictive utility of the SIV/macaque model, and highlight the unique features of human and simian lentiviral evolution that inform studies of pathogenesis and strategies for AIDS vaccine design.
    Journal of Virology 10/2012; 86(24). DOI:10.1128/JVI.01862-12 · 4.65 Impact Factor
  • Nature medicine 11/2012; 18(11):1614-6. DOI:10.1038/nm.2986 · 28.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This article discusses HIV vaccine discovery and candidate vaccine testing in the context of current realities of funding and clinical trial practice. Lacking perfect animal models for testing candidate HIV vaccines, clinical investigators have proposed a strategy of iterative exploratory clinical trials in the model of cancer chemotherapy development. Problems with the appropriateness of this model to HIV vaccine development are discussed. Also, the future feasibility of this strategy in the context of increasing clinical trial costs and emerging new, efficacious prevention modalities is questioned. Strategies for making better use of animal models are presented as an alternative to iterative exploratory clinical efficacy testing. Some ways in which better data from preclinical studies can refine clinical product development are described. Finally, development of an HIV vaccine under the FDA's "Animal Rule" pathway to licensure when human efficacy studies are not feasible is discussed as a fall-back approach. Not making a preventive vaccine against HIV infection is simply not an option because eradication of AIDS will require a preventive vaccine.
    AIDS research and human retroviruses 02/2013; 29(11). DOI:10.1089/AID.2012.0337 · 2.46 Impact Factor