The unique features of natural SIV infections have been the subject of a number of recent reviews on the topic7–9
. Here we focus on those features that we believe can be exploited for new vaccine strategies. There are two types of conventional HIV vaccine approaches currently being explored: HIV-specific CTL–based vaccines designed to delay disease progression by killing infected target cells and HIV-specific antibody–based vaccines designed to inhibit HIV transmission. We believe that studies of natural SIV infections point to additional avenues that should be exploited in an attempt to increase protection against both infection and disease progression.
Natural SIV infections are characterized by levels of chronic immune activation that are consistently and substantially lower than those observed in pathogenic HIV and SIV infections14–18,23,24,31,36,37,42
. Notably, both innate and adaptive immune activation are observed during the acute phase of SIV infection of natural hosts16–18,37,42
, including strong upregulation of type I interferon–stimulated genes in both peripheral blood and lymph nodes19
(J.G.E., G.S., S. Bosinger, S.N. Gordon, N.R. Klatt et al.
, unpublished data; Li, Q., Duan, L., Smith, A.J., Zeng, M., Masopust, D. et al.
, unpublished data; M.M.-T., B. Jacquelin, V. Mayau, B. Targat, A.S. Liovat et al.
, unpublished data) as well as type I interferon production by plasmacytoid dendritic cells in lymph nodes (J.D.E., L. Harris, S.N. Gordon, G.S. and J.M.B., unpublished data). However, marked differences in the levels of immune activation between natural and non-natural HIV and SIV hosts are observed after the transition from the acute to the chronic phase of infection. This finding suggests the presence of active immune downmodulatory mechanisms rather than an intrinsically attenuated innate immune response to SIV infection15,17,40,43
. This conclusion is also supported by recent studies in which immune activation and CD4+
T cell depletion were successfully induced in AGMs after administration of lipopolysaccharide44
. Several properties of the AGM and sooty mangabey hosts that may contribute to the low immune activation during chronic infection have recently been identified and warrant further investigation, particularly with regard to the association between increased immune activation and effective SIV-specific adaptive immune responses. These potential immunomodulatory mechanisms include the rapid establishment of an anti-inflammatory milieu, the early upregulation of the negative regulator PD-1 in lymph node–derived T cells, a partial refractoriness of plasmacytoid dendritic cells to produce type I interferon in response to SIV RNA, absence of microbial translocation from the intestinal lumen to the systemic circulation, low levels of CCR5 expression on CD4+
T cells and downregulation of CD4 expression by T cells15,17,33,40,42,43,45
. In addition, lower immune activation in natural hosts may also be associated with virus-specific properties, particularly the lack of a vpu
gene and the ability of the accessory Nef protein to suppress the activation of virally infected T cells46,47
. The absence of chronic hyperimmune activation may be crucial to preserve T cell homeostasis (particularly at the level of naive and central memory cells), maintain normal lymphoid tissue architecture, preserve non–T cell immune functions, including those of antigen-presenting cells, and allow the natural host to better cope with instances of mucosal and generalized CD4+
T cell depletion16,17,34,37,48
The low numbers of CD4+
target cells observed in SIV natural hosts represent a striking contrast to what has been reported in Asian macaques and humans41
. However, the biological relevance of this observation is still unclear—especially because these low amounts of CCR5 on CD4+
T cells do not result in lower virus replication in natural hosts or preclude CD4+
T cells from being the main source of virus production in natural SIV infections8,25,26,49
. It is conceivable that, in natural SIV hosts, a restriction of CCR5 expression to more activated effector and/or CD4+
T cells may confine SIV replication to a subset of more ‘expendable’ cells, thus better preserving the homeostasis of central memory CD4+
T cells despite similarly high levels of viremia. Low CCR5 expression may also reduce the homing of activated CD4+
T cells to inflamed tissues, thus eliciting an anti-inflammatory effect41
. Finally, a paucity of CD4+
T cells in mucosal tissues may also influence SIV transmission, as it may affect the overall receptivity of the mucosal microenvironment to the establishment and early dissemination of the transmitted virus. Thus, a successful HIV vaccine may have to circumvent CD4+
T cell activation, particularly at mucosal sites that are important for HIV transmission. Alternatively, it might be advantageous if an HIV vaccine induces T cell populations that can provide the proper T cell helper function but do not express the CD4 receptor and therefore are refractory to HIV infection (CD3+
(C.A., T. Gaufin, E. Blake, R. Gautam and I.P. Pattison, unpublished data).