TRIM5α and Species Tropism of HIV/SIV

Abstract

Human immunodeficiency virus type 1 (HIV-1) infects humans and chimpanzees but not old world monkeys (OWMs) such as the rhesus monkey (Rh) and cynomolgus monkey (CM). HIV-1 efficiently enters cells of OWMs but encounters a block before reverse transcription. This narrow host range is attributed to a barrier in the host cell. In 2004, the screening of a Rh cDNA library identified tripartite motif 5α (TRIM5α) as a cellular antiviral factor. TRIM5α is one of splicing variants produced by TRIM5 gene and TRIM5 proteins are members of the TRIM family containing RING, B-box 2, and coiled-coil domains. The RING domain is frequently found in E3 ubiquitin ligase and TRIM5α is degraded via the ubiquitin-proteasome-dependent pathway. Among TRIM5 splicing variants, TRIM5α alone has an additional C-terminal PRYSPRY (B30.2) domain. Previous studies have shown that sequence variation in variable regions of the PRYSPRY domain among different monkey species affects species-specific retrovirus infection, while amino acid sequence differences in the viral capsid protein determine viral sensitivity to restriction. TRIM5α recognizes the multimerized capsid proteins (viral core) of an incoming virus by its PRYSPRY domain and is thus believed to control retroviral infection. There are significant intraspecies variations in the Rh-TRIM5 gene. It has also been reported that some Rh and CM individuals have retrotransposed cyclophilin A open reading frame in the TRIM5 gene, which produces TRIM5-cyclophilin A fusion protein (TRIMCyp). TRIMCyp, which was originally identified as an anti-HIV-1 factor of New World owl monkeys, is an interesting example of the gain of a new function by retrotransposition. As different TRIM5 genotypes of Rh showed different levels of simian immunodeficiency virus replication in vivo, the TRIM5 genotyping is thought to be important in acquired immunodeficiency syndrome monkey models.

Keywords: HIV-1; HIV-2; SIV; TRIM5α; TRIMCyp; cynomolgus monkey; rhesus monkey.

Figure 1

Cellular factors involved in human immunodeficiency virus (HIV) replication cycle. (+) Positive factors required for viral replication. (−) Negative factors that suppress viral replication.

Figure 2

Domains of rhesus monkey (Rh) TRIM5α and TRIMCyp proteins. The RING, B-box2, Coiled-coil, PRYSPRY, or CypA domains of Rh-TRIM5α and TRIMCyp are shown by squares. Polymorphisms are shown outside the squares. The numbers in parentheses show the amino acid positions counting from the initiation methionine codon of the CypA open reading frame.

Figure 3

Species-specific restriction by TRIM5α. “Yes” denotes restriction. “Weak” denotes weak restriction. “No” denotes no restriction. “N. D.” denotes no result has yet been published. SIVmac, simian immunodeficiency virus isolated from a macaque (Ohkura et al., 2006). SIVagm, simian immunodeficiency virus isolated from an African green monkey (Song et al., 2005b). N-MLV, N-tropic murine leukemia virus (Ohkura et al., 2006); B-MLV, B-tropic murine leukemia virus (Ohkura et al., 2006). AGM, African green monkey (Nakayama et al., ; Kim et al., 2011). Rhesus monkey (Stremlau et al., ; Ylinen et al., ; Ohkura et al., 2006), cynomolgus monkey (Nakayama et al., 2005), and owl monkey TRIMCyp (Nisole et al., ; Sayah et al., 2004) are also included.

Figure 4

HIV-2/SIV capsid sequence variations and restriction patterns of rhesus (Rh) and cynomolgus monkey (CM) TRIM5α/TRIMCyp alleles. “Yes” denotes restriction. “Weak” denotes weak restriction. “No” denotes no restriction. “N. D.” denotes no result has yet been published. The unique QQ sequence at the 89th–90th positions of SIVmac, which is critical for escape from Rh TRIMCyp, Rh^CypA (Kirmaier et al., 2010), is shown in red. Arginine 97 at the base of the loop between helices 4 and 5, which is important to escape from TFP alleles of Rh-TRIM5α, Rh^TFP (Kirmaier et al., 2010), is shown in blue. The glutamine and alanine residues at position 120 of GH123 or analogous positions of other HIV-2 strains, which is critical for resistance against Q alleles of Rh-TRIM5α, Rh^Q (Kirmaier et al., 2010) and CM TRM5α (Song et al., ; Kono et al., 2008), are shown in green. CM^CypA(NE) and CM^CypA(DK) denote the minor and major alleles of CM TRIMCyp, respectively.

Figure 5

Structure of the N-terminal half of HIV-2 capsid monomer. The ribbons represent the backbone of HIV-2 capsid proteins, and seven α-helices are labeled. The positions important in Rh-TRIM5α recognition are highlighted as N-termini (the 5th to 13th amino acid residues) in purple, the loop between α-helices 4 and 5 (L4/5) in green, the 109th T in blue, the 111th E in orange, and the 120th P in red.

Figure 6

The hydrogen bond between two external loops of HIV-2 capsid. The structures of the N-terminal domain of GH123 are shown, and seven color-coded α-helices are labeled. Blue and red wireframes denote side chains of glutamic acid at the 97th (D97) and arginine at the 119th (R119) positions, respectively. Black lines indicate hydrogen bonds between D97 and R119. Models are shown from two different angles.

Figure 7

Diversity of Rh and CM TRIM5 genes. The RING, B-box2, Coiled-coil, and PRYSPRY domains of TRIM5α and TRIMCyp are shown by squares. CypA domains in TRIMCyp are shown as filled squares. Major alleles in Rh and CM are shown in bold lines. Polymorphisms are shown outside the squares.