Article

Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts.

Seattle Biomedical Research Institute, Seattle, Washington, USA.
Nature medicine (Impact Factor: 28.05). 09/2009; 15(8):861-5. DOI: 10.1038/nm.2013
Source: PubMed

ABSTRACT The design of an effective AIDS vaccine has eluded the efforts of the scientific community to the point that alternative approaches to classic vaccine formulations have to be considered. We propose here that HIV vaccine research could greatly benefit from the study of natural simian immunodeficiency virus (SIV) infections of African nonhuman primates. Natural SIV hosts (for example, sooty mangabeys, African green monkeys and mandrills) share many features of HIV infection of humans; however, they usually do not develop immunodeficiency. These natural, nonprogressive SIV infections represent an evolutionary adaptation that allows a peaceful coexistence of primate lentiviruses and the host immune system. This adaptation does not result in reduced viral replication but, rather, involves phenotypic changes to CD4(+) T cell subsets, limited immune activation and preserved mucosal immunity, all of which contribute to the avoidance of disease progression and, possibly, to the reduction of vertical SIV transmission. Here we summarize the current understanding of SIV infection of African nonhuman primates and discuss how unraveling these evolutionary adaptations may provide clues for new vaccine designs that might induce effective immune responses without the harmful consequences of excessive immune activation.

Download full-text

Full-text

Available from: Don Sodora, Jun 21, 2015
0 Followers
 · 
114 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: APOBEC3G (A3G) is a host cytidine deaminase that inhibits retroviruses. HIV and related primate lentiviruses encode Vif, which counteracts A3G by inducing its degradation. This Vif-mediated A3G inhibition is species specific, suggesting that the A3G-Vif interaction has evolved as primate lentiviruses have adapted to their hosts. We examined the evolutionary dynamics of the A3G-Vif interaction within four African green monkey (AGM) subspecies, which are each naturally infected with a distinct simian immunodeficiency virus (SIV). We identified single amino acid changes within A3G in two AGM subspecies that render it resistant to Vif proteins, except for Vif from the viruses that naturally infect these subspecies. Moreover, experimental infection of AGMs shows that Vif can rapidly adapt to these arising Vif-resistant A3G genotypes. These data suggest that despite being generally nonpathogenic in its natural host, SIV infection selects for Vif-resistant forms of A3G in AGM populations, driving Vif counterevolution and functional divergence.
    Cell host & microbe 01/2012; 11(1):91-8. DOI:10.1016/j.chom.2011.11.010 · 12.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, 'natural hosts' of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to 'fuel the fire' of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.
    Proceedings of the Royal Society B: Biological Sciences 12/2010; 277(1701):3773-81. DOI:10.1098/rspb.2010.0972 · 5.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: SIV-infected natural hosts do not progress to clinical AIDS yet display high viral replication and an acute immunologic response similar to pathogenic SIV/HIV infections. During chronic SIV infection, natural hosts suppress their immune activation, whereas pathogenic hosts display a highly activated immune state. Here, we review natural host SIV infections with an emphasis on specific immune cells and their contribution to the transition from the acute-to-chronic phases of infection.
    Microbes and Infection 10/2010; 13(1):14-24. DOI:10.1016/j.micinf.2010.09.011 · 2.73 Impact Factor

Similar Publications