TRIM5alpha Modulates Immunodeficiency Virus Control in Rhesus Monkeys.
The cytoplasmic TRIM5alpha proteins of certain mammalian lineages efficiently recognize the incoming capsids of particular retroviruses and potently restrict infection in a species-specific manner. Successful retroviruses have evolved capsids that are less efficiently recognized by the TRIM5alpha proteins of the natural hosts. To address whether TRIM5alpha contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of TRIM5 polymorphisms in rhesus monkeys on the course of a simian immunodeficiency virus (SIV) infection. Full-length TRIM5alpha cDNAs were derived from each of 79 outbred monkeys and sequenced. Associations were explored between the expression of particular TRIM5 alleles and both the permissiveness of cells to SIV infection in vitro and clinical sequelae of SIV infection in vivo. Natural variation in the TRIM5alpha B30.2(SPRY) domain influenced the efficiency of SIVmac capsid binding and the in vitro susceptibility of cells from the monkeys to SIVmac infection. We also show the importance in vivo of the interaction of SIVmac with different allelic forms of TRIM5, demonstrating that particular alleles are associated with as much as 1.3 median log difference in set-point viral loads in SIVmac-infected rhesus monkeys. Moreover, these allelic forms of TRIM5 were associated with the extent of loss of central memory (CM) CD4+ T cells and the rate of progression to AIDS in the infected monkeys. These findings demonstrate a central role for TRIM5alpha in limiting the replication of an immunodeficiency virus infection in a primate host.
Lim
So-Yon
SY
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
Rogers
Thomas
T
Chan
Tiffany
T
Whitney
James B
JB
Kim
Jonghwa
J
Sodroski
Joseph
J
Letvin
Norman L
NL
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D020022:Genetic Predisposition to Disease; D006801:Humans; D015151:Immunoblotting; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D044767:Ubiquitin-Protein Ligases
D011506:Proteins; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases