Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts

Abstract

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 ...

Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys

“…In a recent report, we showed that mucosal CD4 ϩ T cells isolated from SMs as well as other natural SIV hosts (i.e., mandrills, sun-tailed monkeys, and African green monkeys) express low levels of CCR5 (30). Despite this finding, other lines of evidence indicate that SM CD4 ϩ T cells are readily infected in vivo and in vitro despite low CCR5 expression (G. Silvestri, unpublished observations).…”

Production of Specific mRNA Transcripts, Usage of an Alternate Promoter, and Octamer-Binding Transcription Factors Influence the Surface Expression Levels of the HIV Coreceptor CCR5 on Primary T Cells

“…These polymorphisms result in the inability to produce CCR5A in chimpanzees and CCR5B in AGM (11). The relevance of these polymorphic sequences and their potential impact on reduced expression of exon 1-containing transcripts and CCR5 surface expression is illustrated by the recent findings of Pandrea et al (57) who showed that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4 ϩ T cells from gut. Thus, taken together, we propose that in some natural hosts of SIV, polymorphic sequences that affect the Oct-1/2 cis-binding site in Pr2 or splicing patterns of CCR5 mRNA might result in the reduced CCR5 expression (57).…”

“…This might provide a possible species-specific mechanism by which primate populations modulate CCR5 gene expression. It is conceivable that loss of the Oct site and other polymorphisms may be responsible for lower levels of CCR5 expression observed in natural primate hosts of SIV infection (e.g., Sooty mangabey) that do not progress to AIDS compared with hosts in which SIV or HIV infection leads to AIDS (57). Extending this notion, the results of our current and previous studies (11) suggest that sequences that influence the production of exon 1-containing transcripts are targets for selection.…”

Acute Loss of Intestinal CD4+ T Cells Is Not Predictive of Simian Immunodeficiency Virus Virulence

“…Blood and tissue samples (superficial lymph nodes (LNs), bronchoalveolar lavage (BAL), intestinal biopsy, and intestinal resections) were collected as reported (3,23,47). Plasma and PBMC and mononuclear cells from the intestine, BAL, and LNs were isolated as described previously (3,23).…”