Untreated human immunodeficiency virus (HIV) infection in humans is typically characterised by persistent high virus load, failure of the immune response to clear the virus, and fatal disease outcome. Natural hosts of closely related simian immunodeficiency viruses (SIVs)e.g., sooty mangabeys ,maintain comparably high persistent virus levels and yet remain healthy. These contrasting observations have two important implications. First, the virulence (disease-causing ability) of HIV is not an inevitable consequence of its massive replication in the infected hosts. SIVsm, the virus of sooty mangabeys, can replicate to high levels without any discernible effect on the host. The prevalence of SIV infection among wild-living sooty mangabeys can exceed 50 , which is also consistent with nonpathogenic infection. The direct metabolic cost of virus production must therefore be small, and disease in HIV infection cannot be explained by a simple diversion of host resources to virus production. Second, sooty mangabeys do not avoid disease by controlling the virus to low levels. While humans with HIV and macaques experimentally infected with SIVsm mount a vigorous T cell response that can temporarily suppress virus replication, sooty mangabeys display hardly any T cell proliferation upon infection , and allow high levels of virus replication from the beginning of the infection. Instead of eliminating the direct effects of infection by suppressing the virus, they can apparently avoid the indirect effects that are responsible for disease in HIV infection.
The clinical progression of HIV infection is characterised by a gradual loss of CD4 T cells, which constitute the primary target cell type of the virus and which are key players in adaptive immunity. Immune functions slowly decline, eventually giving rise to opportunistic infections that ultimately result in death in nearly all untreated cases. These processes were first thought to be driven by the loss of infected CD4 T cells, killed directly by the cytopathic effect of the virus. However, accumulating evidence (reviewed in ) indicates that the aetiology of HIV infection involves a generalised chronic hyperactivation of the immune system, rather than direct cytopathic effects.
In addition to infected CD4 T cells, the turnover of uninfected CD4 T cells, CD8 T cells, and B cells is also elevated, and persistent activation is probably responsible for the dysfunction and apoptotic death of immune cells. The immediate decline of activation markers (e.g., the percentage of dividing CD4 and CD8 T cells , and the frequency of antibody-secreting cells ) after the initiation of effective antiretroviral therapy indicates that hyperactivation is induced by the virus itself, rather than by a homeostatic mechanism. Natural hosts of SIV, however, show hardly any sign of immune hyperactivation despite high virus levels, which may be their key to benign infection . We here propose the integration hypothesis, claiming that the evolutionary pathway to peaceful coexistence may have involved the integration of retroviral elements into the germline of the hosts, and the subsequent expression of retroviral antigens during the maturation of host lymphocytes to induce partial tolerance to the host-specific viruses. Mammalian genomes have long been known to contain a large number of retrovirus-derived sequences , and HIV-1 proviral DNA has been found in the sperm cells of individuals who are infected , which demonstrates the possibility of germline integration. Natural hosts of SIV infections may thus have acquired germline-integrated SIV elements that could be expressed during the negative selection of T cells and/or B cells in the thymus and the bone marrow , respectively. Once their antigen specificity has been determined by the rearrangement of their receptor genes, immature T cells spend about one to two weeks in the thymus , while immature B cells spend one to three days in the bone marrow , where they