Cross-species transmission of simian immunodeficiency virus from sooty mangabeys (SIVsm) into rhesus macaques, and subsequent emergence of pathogenic SIVmac, required adaptation to overcome restriction encoded by the macaque TRIM5 gene.

In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4 ؉ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts IntroductionIt is now clear that human immunodeficiency virus type 1 (HIV-1) evolved from a closely related virus of chimpanzees (Pan troglodytes) named simian immunodeficiency virus (SIVcpz). [1][2][3] Similarly, HIV-2 originated from a related virus, SIVsmm, which naturally infects sooty mangabeys (SMs). [4][5][6] In marked contrast to HIV infection, which almost invariably progresses to AIDS unless treated with antiretrovirals, natural SIVcpz infection of chimpanzees and SIVsmm infection in SMs rarely result in clinical symptoms. [7][8][9][10][11][12] Similarly, other natural hosts for SIV, such as African green monkeys (AGMs), mandrills, and several other African nonhuman primate (NHP) species, generally live normal lifespans despite many years of infection with a highly replicating virus. [13][14][15][16][17][18][19][20][21][22][23] Importantly, the inoculation of SIV, which naturally infects African monkeys, into NHPs that are not natural hosts for SIV, such as macaques and baboons, may result in chronic infection that eventually progresses to a disease closely resembling AIDS. 16,[24][25][26][27][28] Given that the earliest documented exposure of a human to HIV-1 infection was in 1959, 29 it is thought that the introduction of primate lentiviruses into a new host species results in AIDS because of the inability of a naive immune system to cope with a virus recently transmitted from another species. Although it is agreed that the rarity of disease likely reflects a pacific coevolution between SIV and its natural hosts resulting from many thousands of years of endemic infection, the exact mechanisms underlying this absence of disease are still poorly understood. It should be noted, however, that the preservation of the immune system in natural SIV hosts does not simply result from immune control of viral replication, a task obviously not achieved in these animals given their high level of viral load (VL). 7,8,12,14,[19][20][21][22][23] In addition, the differences in virulence between the SIVs naturally infecting African NHP hosts and the pathogenic HIV/SIV strains are not related to differences in virus biology. As do most HIV/SIVmac/ SIVsmm strains, SIVs from African species use CD4 as a receptor 30 and CCR5 as a major coreceptor ...

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.

Retroviral restriction factor TRIM5␣ exhibits a high degree of sequence variation among primate species. It has been proposed that this diversity is the cumulative result of ancient, lineagespecific episodes of positive selection. Here, we describe the contribution of within-species variation to the evolution of TRIM5␣. Sampling within two geographically distinct Old World monkey species revealed extensive polymorphism, including individual polymorphisms that predate speciation (shared polymorphism). In some instances, alleles were more closely related to orthologues of other species than to one another. Both silent and nonsynonymous changes clustered in two domains. Functional assays revealed consequences of polymorphism, including differential restriction of a small panel of retroviruses by very similar alleles. Together, these features indicate that the primate TRIM5␣ locus has evolved under balancing selection. Except for the MHC there are few, if any, examples of long-term balancing selection in primates. Our results suggest a complex evolutionary scenario, in which fixation of lineage-specific adaptations is superimposed on a subset of critical polymorphisms that predate speciation events and have been maintained by balancing selection for millions of years.HIV ͉ retrovirus ͉ restriction