Skip to main page content

• HOME
• Current Issue
• Archive
• Alerts
• About ASM
• Contact us
• Tech Support
• Journals.ASM.org

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stremlau, M. Articles by Sodroski, J. Search for Related Content PubMed PubMed Citation Articles by Stremlau, M. Articles by Sodroski, J.

 Previous Article  |  Next Article 

Journal of Virology, March 2005, p. 3139-3145, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.3139-3145.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Species-Specific Variation in the B30.2(SPRY) Domain of TRIM5 Determines the Potency of Human Immunodeficiency Virus Restriction

Matthew Stremlau,¹ Michel Perron,¹ Sohanya Welikala,¹ and Joseph Sodroski^1,2*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School,¹ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts²

Received 14 July 2004/ Accepted 13 October 2004

Top Abstract Introduction Materials and Methods Results Discussion References

 
Retroviruses encounter dominant postentry restrictions in cells of particular species. Human immunodeficiency virus type 1 (HIV-1) is blocked in the cells of Old World monkeys by TRIM5, a tripartite motif (TRIM) protein composed of RING, B-box 2, coiled-coil, and B30.2(SPRY) domains. Rhesus monkey TRIM5 (TRIM5_rh) more potently blocks HIV-1 infection than human TRIM5 (TRIM5_hu). Here, by studying chimeric TRIM5 proteins, we demonstrate that the major determinant of anti-HIV-1 potency is the B30.2(SPRY) domain. Analysis of species-specific variation in TRIM5 has identified three variable regions (v1, v2, and v3) within the B30.2 domain. The TRIM5 proteins of Old World primates exhibit expansion, duplication, and residue variation specifically in the v1 region. Replacement of three amino acids in the N terminus of the TRIM5_hu B30.2 v1 region with the corresponding TRIM5_rh residues resulted in a TRIM5 molecule that restricted HIV-1 nearly as efficiently as wild-type TRIM5_rh. Surprisingly, a single-amino-acid change in this region of TRIM5_hu allowed potent restriction of simian immunodeficiency virus, a phenotype not observed for either wild-type TRIM5_hu or TRIM5_rh. Some of the chimeric TRIM5 proteins that are >98% identical to the human protein yet mediate a strong restriction of HIV-1 infection may have therapeutic utility. These observations implicate the v1 variable region of the B30.2(SPRY) domain in TRIM5_rh antiviral potency.

Top Abstract Introduction Materials and Methods Results Discussion References

 
The primate lentiviruses include human immunodeficiency virus type 1 (HIV-1) and HIV-2 and simian immunodeficiency viruses (SIVs) (2, 5, 7, 8, 11). HIV-1 and HIV-2 infect humans, HIV-1-like viruses infect chimpanzees, and SIV variants infect African monkeys. Humans infected by HIV-1 and HIV-2 and Asian macaques infected by certain SIV strains (SIV_mac) often develop life-threatening immunodeficiency due to depletion of CD4-positive T lymphocytes (9, 19).

HIV and SIV tropism is determined by cell-type-specific and species-specific host factors. Following entry into the host cell, uncoating of the viral core, reverse transcription, nuclear access, and integration of the viral DNA into the host genome must occur to establish a permanent infection (1, 10, 33). Early postentry restrictions to retrovirus infection can determine tropism at the species level. HIV-1 encounters a postentry block in Old World monkeys, whereas SIV_mac is blocked in most New World monkey cells (15, 16, 27). These species-specific restrictions occur prior to or concurrent with reverse transcription; at most, low levels of early reverse transcripts are made in restricted cells (6, 15, 20, 27). The viral determinant of susceptibility to these blocks is the capsid protein (6, 13, 18, 22, 23, 30). The early restriction of HIV-1 and SIV is mediated by dominant host factors, the activities of which can be titrated by the introduction of virus-like particles containing proteolytically processed capsid proteins of the restricted viruses (3, 4, 6, 12, 22, 31, 32). Thus, in the cells of specific monkey species, host restriction factors apparently interact, directly or indirectly, with the HIV-1 or SIV capsid and prevent its progression along the infectious pathway. Recently, a genetic screen has identified a major restriction factor in monkey cells that acts on HIV-1 and, to a lesser extent, on SIV_mac (29). The factor, TRIM5, was selected from a cDNA library prepared from primary rhesus monkey lung fibroblasts (PRL cells). TRIM5 was shown to be sufficient to confer potent resistance to HIV-1 infection in otherwise susceptible cells. Moreover, TRIM5 was necessary for the maintenance of the block to the early phase of HIV-1 infection in Old World monkey cells, as demonstrated by interference with TRIM5 expression in these cells. HIV-1 infection in cells expressing rhesus monkey TRIM5 (TRIM5_rh) was blocked at the earliest stage of reverse transcription. Cells expressing rhesus monkey TRIM5 exhibited partial inhibition of SIV_mac infection but were as susceptible as control cells to infection by Moloney murine leukemia virus (MLV) vectors. The human ortholog, TRIM5_hu, is 87% identical in amino acid sequence to TRIM5_rh. Even when expressed at comparable levels, TRIM5_hu was less potent at suppressing HIV-1 and SIV_mac infection than TRIM5_rh (29).

TRIM5 is a member of a family of proteins that contain a tripartite motif, leading to the designation TRIM (24). The tripartite motif includes a RING domain, a B-box 2 domain, and a coiled-coil domain; hence, TRIM proteins have also been called RBCC proteins. Some TRIM proteins contain a C-terminal B30.2, or SPRY, domain. Differential splicing of the TRIM5 primary transcript gives rise to the expression of several isoforms of the protein product. The TRIM5 isoform is the largest product (493 amino acid residues) and contains the B30.2(SPRY) domain. The other TRIM5 isoforms ( and are the best substantiated of these) lack an intact B30.2(SPRY) domain. The rhesus monkey TRIM5 isoform lacks anti-HIV-1 and anti-SIV activities, indicating the importance of the B30.2(SPRY) domain to the antiviral function (29). In fact, TRIM5_rh has been shown to exhibit weak dominant-negative activity in repressing the ability of wild-type TRIM5_rh to inhibit HIV-1 infection (29). An intact RING domain also contributes, either directly or indirectly, to the anti-HIV-1 activity of TRIM5_rh. Alteration of two cysteine residues that are highly conserved in RING domains markedly diminished, but did not abolish, the antiviral potency of TRIM5_rh (29).

Here, we investigate the basis for the differences in the potencies of HIV-1 inhibition observed for TRIM5_rh and TRIM5_hu.

Top Abstract Introduction Materials and Methods Results Discussion References

 
TRIM5 chimerae. The trim5 cDNAs from humans and rhesus monkeys were obtained from a kidney cDNA library (Clontech) and from a primary rhesus monkey lung cDNA library, respectively (29). The nomenclature for the chimerae is TRIM5 A(Bx-y), in which the encoded TRIM5 amino acids from x to y from species B are inserted into the TRIM5 protein of species A (H, human; R, rhesus monkey). The numbering scheme is based on the human TRIM5 residue numbers; the same numbers are used for the rhesus monkey TRIM5 residues, after the TRIM5_rh sequence is aligned to that of TRIM5_hu.

Some of the chimeric trim5 constructs were created by exchanging fragments generated by digestion with the restriction enzymes BsmII [TRIM5 R(H286-493) and TRIM5 H(R286-493)] or BsmII and BamHI [TRIM5 R(H286-371) and TRIM5 H(R286-371)]. The following chimeric proteins were expressed by plasmids created by QuikChange mutagenesis (Stratagene): TRIM5 H(R305-314), R(H305-314), H(R323-332), R(H323-332), R(H335-340), and R(H337-338a). The predicted amino acid sequence of the TRIM5 R(H337-338a) protein in the region affected by the mutation is GTLFQSLTNF. The mutated plasmids were sequenced in the regions surrounding the introduced changes.

TRIM5_hu mutants. Plasmids expressing TRIM5_hu with single-amino-acid changes were created by QuikChange mutagenesis. The nomenclature for these mutants is TRIM5_hu followed by the wild-type amino acid residue in single-letter code, the amino acid position, and the amino acid residue to which the change was made.

Creation of cells stably expressing TRIM5 variants. Retroviral vectors encoding TRIM5_hu, TRIM5_rh, or chimeric TRIM5 proteins were created using the pLPCX vector (29). The pLPCX vectors contain only the amino acid coding sequence of the TRIM5 cDNA. In all constructs, the TRIM5 proteins possess C-terminal epitope tags derived from influenza hemagglutinin (HA). Recombinant viruses were produced in 293T cells by cotransfecting these pLPCX plasmids with the pVPack-GP and pVPack-VSV-G packaging plasmids (Stratagene). The pVPack-VSV-G plasmid encodes the vesicular stomatitis virus (VSV) G envelope glycoprotein, which allows efficient entry into a wide range of vertebrate cells. The resulting virus particles were used to transduce 10⁶ HeLa cells in the presence of 5 µg of Polybrene/ml. Cells were selected in 1 µg of puromycin (Sigma)/ml.

Immunoblotting. HA-tagged proteins were expressed in HeLa cells by transduction with pLPCX vectors as described above. The HA-tagged TRIM5 proteins were detected in whole-cell lysates [100 mM (NH₄)₂SO₄, 20 mM Tris-HCl (pH 7.5), 10% glycerol, 1% Nonidet P40] by Western blotting with horseradish peroxidase-conjugated 3F10 antibody (Roche). ß-Actin was detected with A5441 antibody (Sigma).

Infection with viruses expressing GFP. Recombinant HIV-1 expressing green fluorescent protein (GFP) was prepared as described previously (16, 22, 23, 29), and MLV-GFP was prepared by cotransfecting 293T cells with 15 µg of pFB-hrGFP, 15 µg of pVPack-GP, and 4 µg of pVPack-VSV-G (all from Stratagene). HIV-1 stocks were quantified by measuring reverse transcriptase activity as described previously (25). MLV reverse transcriptase activity was determined by the same procedure, except that 20 mM MnCl₂ was used instead of MgCl₂. For infections, 3 x 10⁴ HeLa cells seeded in 24-well plates were incubated in the presence of virus for 24 h. The cells were washed and returned to culture for 48 h and then subjected to fluorescence-activated cell sorter (FACS) analysis with a FACScan (Becton Dickinson).

Top Abstract Introduction Materials and Methods Results Discussion References

 
A carboxy-terminal TRIM5 determinant of anti-HIV-1 potency. TRIM5_rh exhibits significantly greater inhibitory activity against HIV-1 than TRIM5_hu (29). To map the determinants of this potency, chimeric proteins between TRIM5_rh and TRIM5_hu were created (Fig. 1). HeLa cells were transduced by pLPCX retroviral vectors expressing the wild-type and chimeric TRIM5 proteins, as described previously (29). All of the TRIM5 proteins have a carboxy-terminal HA tag, allowing documentation of expression levels in the transduced cells. We first studied TRIM5 chimerae containing the RING, B-box 2, and coiled-coil domains of one parent protein and the B30.2 domain of another. These chimerae, designated TRIM5 R(H286-493) and TRIM5 H(R286-493), were both expressed in HeLa cells at levels comparable to those of the parental TRIM5 proteins (Fig. 2). The HeLa cells were incubated with a recombinant HIV-1 vector (HIV-1-GFP) expressing GFP or, as a control, with an MLV vector (MLV-GFP). Figure 3 shows that, compared with HeLa cells transduced with the empty pLPCX vector, HeLa cells expressing TRIM5_rh were strongly resistant to HIV-1-GFP infection. A modest decrease in HIV-1-GFP infection was observed in cells expressing TRIM5_hu. HeLa cells expressing the TRIM5 H(R286-493) protein were almost as resistant to infection by HIV-1-GFP as cells expressing TRIM5_rh. An intermediate level of HIV-1-GFP inhibition was observed in the cells expressing TRIM5 R(H286-493). MLV-GFP infection of the cells expressing the various TRIM5 chimerae was similar to that of the control cells transduced with the empty pLPCX vector. We conclude that the B30.2 domain of TRIM5_rh is sufficient to confer potent anti-HIV-1 activity on TRIM5_hu.

View larger version (13K): [in this window] [in a new window]

FIG. 1. Chimeric TRIM5hu/TRIM5rh proteins. A diagram of the TRIM5 protein is shown, with the known domains indicated (B2, B-box 2). The numbers of the residues at the N and C termini of the protein and at the chimeric junctions are indicated. The species-specific variable regions (v1, v2, and v3) within the B30.2 domain (28) are shown. The numbering scheme and nomenclature used for the chimeric proteins is based upon the TRIM5hu sequence and is described in Materials and Methods.

View larger version (46K): [in this window] [in a new window]

FIG. 2. Expression of chimeric TRIM5 proteins. Lysates from HeLa cells expressing the parental and chimeric TRIM5 proteins, which contain C-terminal HA epitope tags, were subjected to Western blotting with an antibody against HA. Control lysates from HeLa cells transduced with the empty pLPCX vector were analyzed in parallel. The lysates were also Western blotted with an antibody directed against ß-actin.

View larger version (14K): [in this window] [in a new window]

FIG. 3. Effects of expression of the chimeric TRIM5 proteins on HIV-1 infection. HeLa cells expressing the parental and chimeric TRIM5 proteins, or control HeLa cells transduced with the empty pLPCX vector, were incubated with various amounts of HIV-1-GFP or MLV-GFP. Infected GFP-positive cells were counted by FACS. The results of a typical experiment are shown. Similar results were obtained in three independent experiments. RT, reverse transcriptase.

Functional importance of variation in the v1 region of the TRIM5 B30.2 domain. Analysis of the sequences of rodent and primate TRIM5 proteins has revealed the existence of three regions within the B30.2 domain that exhibit dramatic species-specific length and amino acid variations (28). These regions have been designated v1, v2, and v3 (Fig. 1). The v1 region of the TRIM5 B30.2 domain in Old World primates is longer than those of other primates (28). Thirteen of the 33 differences in amino acid sequence between the B30.2 domains of TRIM5_hu and TRIM5_rh occur within the v1 region. We hypothesized that variation in the B30.2 v1 region contributes to the differences between the HIV-1-restricting activities of human and rhesus monkey TRIM5 proteins. To test this hypothesis, we created additional chimeric proteins that would allow an assessment of the contribution of the v1 region independently of the other B30.2 variable regions. These chimeric proteins, TRIM5 R(H286-371) and TRIM5 H(R286-371) (Fig. 1), were expressed stably in HeLa cells transduced with pLPCX vectors. The levels of expression of these chimeric proteins were equivalent to those of the wild-type TRIM5_hu and TRIM5_rh proteins (Fig. 2). The abilities of the wild-type and chimeric proteins to inhibit HIV-1-GFP infection were examined (Fig. 3). The TRIM5 H(R286-371) chimera, which contains the B30.2 v1 region of TRIM5_rh in a TRIM5_hu background, suppressed HIV-1-GFP infection nearly as efficiently as TRIM5_rh. Conversely, the reciprocal chimera, TRIM5 R(H286-371), exhibited no inhibitory activity against HIV-1-GFP infection. Expression of these chimeric TRIM5 proteins did not significantly affect the susceptibility of the HeLa cells to infection by MLV-GFP. These results indicate that the major determinant of anti-HIV-1 potency in TRIM5 is located between residues 286 and 371 in a segment including the B30.2 v1 region.

Mapping of the potency determinant within the B30.2 v1 region. To investigate whether the determinant of anti-HIV-1 potency could be defined more precisely, specific changes within the B30.2 v1 region were made. The v1 region was arbitrarily divided into two segments, and the appropriate chimerae were constructed (Fig. 4). We also tested the importance to the TRIM5 phenotype of amino acid differences in a region N-terminal to the B30.2 v1 region (residues 305 to 314) (Fig. 4). After verifying that approximately equivalent levels of the chimeric proteins were made in transduced HeLa cells (Fig. 2), the ability of the cells to support HIV-1-GFP infection was tested. The TRIM5 H(R323-332) chimera, which contains the amino-terminal segment of the B30.2 v1 region, strongly inhibited HIV-1 infection (Fig. 5A). The inhibition observed for the TRIM5 H(R323-332) chimera was slightly less than that seen for the TRIM5_rh protein. The levels of inhibition of HIV-1-GFP infection by the TRIM5 H(R323-332) and H(R286-371) chimerae were comparable (data not shown). We conclude that the amino-terminal segment of the B30.2 v1 region is the major determinant of anti-HIV-1 potency.

View larger version (21K): [in this window] [in a new window]

FIG. 4. Chimeric TRIM5 proteins containing heterologous elements of the B30.2 domain v1 region. A diagram of the TRIM5 B30.2 domain, with the variable regions (v1, v2, and v3) indicated is provided at the top of the figure. The region of interest is expanded, with the primary amino acid sequence of TRIM5hu shown. Amino acid residues in TRIM5rh that differ from those in TRIM5hu are shown. The numbers refer to the human TRIM5 residue. The relevant segments of the chimeric TRIM5 proteins are shown. The white segments indicate that the protein is identical to TRIM5hu except for the amino acid residues shown. The black segments indicate that the protein is identical to TRIM5rh except for the indicated residues.

View larger version (30K): [in this window] [in a new window]

FIG. 5. The N-terminal half of the B30.2 domain v1 region as a determinant of anti-HIV-1 potency. HeLa cells expressing the parental and chimeric TRIM5 proteins, or control HeLa cells transduced with the empty pLPCX vector, were incubated with various amounts of HIV-1-GFP or MLV-GFP. Infected, GFP-positive cells were counted by FACS. In the top row of panel A, a human TRIM5 variant [TRIM5 H(R323-332)] containing the N-terminal half of the rhesus monkey TRIM5 B30.2 domain v1 region was tested. In the bottom row of panel A and in panel B, TRIM5 chimerae containing heterologous segments other than the N-terminal portion of the B30.2 v1 region were tested. The results of typical experiments are shown. In panel A, the results of one experiment are separated into upper and lower rows for ease of viewing. Similar results were obtained in two independent experiments. RT, reverse transcriptase.

Insertion of carboxy-terminal segments of the B30.2 v1 region from the TRIM5_hu protein had no significant effect on the ability of the rhesus monkey TRIM5 molecule to restrict HIV-1 infection [Fig. 4 and 5B, TRIM5 R(H335-340) and TRIM5 R(H337-338a)]. Similarly, substitution of the human TRIM5 sequences amino-terminal to the B30.2 v1 region into the TRIM5_rh protein did not affect the anti-HIV-1 potency of the latter molecule [Fig. 4 and 5A, TRIM5 R(H305-314)]. The reciprocal chimera, TRIM5 H(R305-314), did not restrict HIV-1 infection (Fig. 4 and 5A). These results indicate that, of the species-specific amino acid differences in the TRIM5 sequences extending from residues 304 to 340, only those in the segment comprised of residues 323 to 332 appreciably affect the anti-HIV-1 potency of the molecule.

Contributions of individual amino acids in the v1 region to TRIM5 antiviral potency. To dissect the species-specific determinants of TRIM5 antiviral potency further, additional TRIM5_hu mutants were created in which individual amino acid residues in the 323 to 332 segment were changed to those found in TRIM5_rh. In addition, the TRIM5_hu sequence from residues 328 to 332 was changed to that found in TRIM5_rh [Fig. 4, TRIM5 H(R328-332)]. HeLa cells were transduced with vectors expressing these TRIM5_hu variants. All of the TRIM5 variants were expressed in these HeLa cells, although a slight variation in the level of expression of the TRIM5 proteins was seen (Fig. 6A). The abilities of these TRIM5_hu mutants to inhibit HIV-1-GFP infection were examined and compared with those of TRIM5_rh, TRIM5_hu, and TRIM5 H(R323-332) (Fig. 6B). The levels of inhibition of HIV-1-GFP infection by the TRIM5 H(R328-332) and TRIM5 H(R323-332) proteins were comparable and only slightly less than that seen in cells expressing the wild-type TRIM5_rh protein. Of the TRIM5_hu mutants with single-amino-acid changes, TRIM5_rh R332P was most potent at restricting HIV-1 infection. The TRIM5_hu K324N mutant was reproducibly more effective than the wild-type TRIM5_hu protein at inhibiting HIV-1. The other single-amino-acid changes did not potentiate the anti-HIV-1 activity of TRIM5_hu. We conclude that the major determinant of anti-HIV-1 potency of TRIM5_rh resides in the sequence 328 to 332, in which three amino acids differ between TRIM5_rh and TRIM5_hu. Of the B30.2 domain v1 residues that differ between these two TRIM5 orthologs, differences in residues 332 and, to a lesser extent, 324 contribute to potency in restricting HIV-1 infection.

View larger version (31K): [in this window] [in a new window]

FIG. 6. Expression and antiviral activities of mutant TRIM5 proteins. (A) Lysates from HeLa cells expressing the parental and mutant TRIM5 proteins, which contain C-terminal HA epitope tags, were subjected to Western blotting with an antibody against HA. Control lysates from HeLa cells transduced with the empty pLPCX vector were analyzed in parallel. The lysates were also Western blotted with an antibody directed against ß-actin. (B and C) HeLa cells expressing TRIM5rh, TRIM5hu, or TRIM5hu mutants or control HeLa cells transduced with the empty pLPCX vector were incubated with various amounts of HIV-1-GFP (B) or SIV-GFP (C). Infected GFP-positive cells were counted by FACS. The results of a typical experiment are shown. Similar results were obtained in two independent experiments. RT, reverse transcriptase.

The abilities of the mutant TRIM5_hu proteins to restrict SIV_mac infection were also studied. As has been previously reported (29), TRIM5_hu exerted little effect on the efficiency of SIV-GFP infection, whereas TRIM5_rh partially inhibited SIV-GFP infection (Fig. 6C). Most of the TRIM5_hu mutants were no better than the wild-type TRIM5_hu in restricting SIV_mac infection. Two variants, TRIM5 H(R323-332) and TRIM5 H(R328-332), inhibited SIV-GFP infection to the same degree as TRIM5_rh. Surprisingly, the TRIM5_hu R332P mutant very potently inhibited SIV-GFP infection. This inhibition was specific, as these cells were infectible by MLV-GFP to the same degree as cells transduced with the empty control vector (data not shown). We conclude that a single-amino-acid change in the TRIM5_hu B30.2 v1 region results in a gain in SIV_mac inhibitory activity beyond that exhibited by either TRIM5_hu or TRIM5_rh.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Here, we show that the B30.2 domain is the major determinant of the differences in anti-HIV-1 potency between human and rhesus monkey TRIM5. The B30.2 domain of TRIM5_rh has been shown to be essential for the ability to restrict HIV-1 infection (29). The B30.2 domain is a component of a number of proteins, including some other TRIM proteins, butyrophilin-like proteins, and stonustoxin (14). Although B30.2 domain-containing proteins have proliferated in chordate lineages, the functions of these domains are not well understood (14, 26). In a few instances, the B30.2 domain has been implicated in binding to intracellular ligands. For example, the B30.2 domain of butyrophilin has been reported to bind xanthine oxidase (17). The B30.2 domain of TRIM11 has been shown to be important for interaction with humanin (21). Our results are consistent with the B30.2 domain of TRIM5 playing a role in interaction with the viral capsid. Interestingly, in an HIV-1-restricting factor, TRIMCyp, found in owl monkeys, the TRIM5 B30.2 domain is replaced by cyclophilin A, which is known to bind the HIV-1 capsid (21a, 25a).

The amino acid sequences of the TRIM5 proteins of a number of primate and rodent species have been determined (28). Although species-specific variation is observed in all of the TRIM5 domains, the type of variation in the B30.2 domain is noteworthy. Significant length polymorphism, as well as individual amino acid variation, is found in three regions within the B30.2 domains of TRIM5 proteins from different species (28). These variable regions (designated v1, v2, and v3) probably represent surface-exposed loops, as such length variation would not be readily tolerated within the core fold of the protein. The v1 region is particularly long in Old World monkeys, apes, and humans, whereas the v3 region exhibits additional length in New World monkeys (28). Thus, among the Old World primates, it appears that the B30.2 v1 region has evolved special features. Our results demonstrate that the major determinant of the anti-HIV-1 potency of the TRIM5_rh protein resides within the amino-terminal half of the B30.2 v1 segment. The sequence of African green monkey TRIM5, which also restricts HIV-1 infection (13a, 17a, 28a, 34), is nearly identical to that of TRIM5_rh in this part of the v1 region. By contrast, within a stretch of 10 residues in this region, five amino acid differences between TRIM5_rh and TRIM5_hu exist. Our studies indicate that three differences, in residues 328, 330, and 332, largely explain the different anti-HIV-1 potencies of TRIM5_rh and TRIM5_hu. Particularly important is residue 332, in which a change can increase the potency of HIV-1 restriction and result in a gain in anti-SIV_mac activity beyond that of either parental TRIM5 protein. The amino acid composition of the TRIM5 320 to 333 region is suggestive of that of a surface-exposed loop, consistent with a role in interaction with the HIV-1 capsid and/or TRIM5 cofactors.

Additional studies will be required to address the mechanism of the enhanced antiviral potency of TRIM5_hu variants with alterations in the v1 region of the B30.2 domain. Previous studies (29) and some of the experiments in this study indicate that differences in the expression levels of TRIM5_hu and TRIM5_rh cannot account for the observed differences in anti-HIV-1 potency. Nonetheless, for the panel of TRIM5 variants presented in Fig. 6, a correlation between anti-HIV-1 potency and the steady-state level of expression is apparent. This correlation, however, was not evident with respect to anti-SIV_mac activity. Nevertheless, the observed differences in steady-state levels may reflect properties of the TRIM5 variants relevant to antiviral activity, such as subcellular compartmentalization or association with cofactors.

The TRIM5 H(R328-332) and H(R323-332) chimerae created in this study exhibit >98% sequence identity to human TRIM5 yet inhibit HIV-1 with potencies that approach that of the rhesus monkey TRIM5 protein. Expression of these chimeric proteins in human cells would be expected to be tolerated better and to be less immunogenic than the expression of TRIM5_rh. Therefore, the TRIM5 H(R328-332) and H(R323-332) proteins, or similarly designed chimerae, might be useful in gene therapy approaches designed to protect human cells from HIV-1 infection.

 
We thank Yvette McLaughlin and Sheri Farnum for manuscript preparation.

This work was supported by a grant from the National Institutes of Health (HL54785) and by a Center for AIDS Research award (P30 AI28691). We also acknowledge the support of the Bristol-Myers Squibb Foundation, the International AIDS Vaccine Initiative, and the late William F. McCarty Cooper.

 
* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney St., JFB 824, Boston, MA 02115. Phone: (617) 632-3371. Fax: (671) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu.

Top Abstract Introduction Materials and Methods Results Discussion References

 

1
1. Arts, E. J., and M. A. Wainberg. 1996. Human immunodeficiency type 1 reverse transcriptase and early events in reverse transcription. Adv. Virus Res. 46:97-163.[Medline]
2
2. Barre-Sinoussi, F., J. C. Chermann, F. Rey, M. T. Nugeyre, S. Chamaret, J. Gruest, C. Dauguet, C. Axler-Blin, F. Vezinet-Brun, C. Rouzioux, W. Rosenbaum, and L. Montagnier. 1983. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immunodeficiency syndrome (AIDS). Science 220:868-871.[Abstract/Free Full Text]
3
3. Besnier, C., Y. Takeuchi, and G. Towers. 2002. Restriction of lentivirus in monkeys. Proc. Natl. Acad. Sci. USA 99:11920-11925.[Abstract/Free Full Text]
4
4. Bieniasz, P. D. 2003. Restriction factors: a defense against retroviral infection. Trends Microbiol. 11:286-291.[CrossRef][Medline]
5
5. Clavel, F. 1987. HIV-2, the West African AIDS virus. AIDS 1:135-140.[Medline]
6
6. Cowan, S., T. Hatziioannou, T. Cunningham, M. A. Muesing, H. G. Gottlinger, and P. D. Bieniasz. 2002. Cellular inhibitors with Fv1-like activity restrict human and simian immunodeficiency virus tropism. Proc. Natl. Acad. Sci. USA 99:11914-11919.[Abstract/Free Full Text]
7
7. Daniel, M. D., N. L. Letvin, N. W. King, M. Kannagi, P. K. Sehgal, R. D. Hunt, P. J. Kanki, M. Essex, and R. C. Desrosiers. 1985. Isolation of T-cell tropic HTLV-III-like retrovirus from macaques. Science 228:1201-1204.[Abstract/Free Full Text]
8
8. Desrosiers, R. C. 1990. The simian immunodeficiency viruses. Annu. Rev. Immunol. 8:557-578.[CrossRef][Medline]
9
9. Fauci, A., A. M. Macher, D. L. Longo, H. C. Lane, A. H. Rook, H. Masur, and E. P. Gelman. 1984. NIH Conference. Acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic, and therapeutic considerations. Ann. Intern. Med. 100:91-106.
10
10. Freed, E. O. 1998. HIV-1 gag proteins: diverse functions in the virus life cycle. Virology 251:1-15.[CrossRef][Medline]
11
11. Gallo, R. C., S. Z. Salahuddin, M. Popovic, G. M. Shearer, M. Kaplan, B. F. Haynes, T. J. Palker, R. Redfield, J. Oleske, B. Safai, G. White, P. Foster, and P. D. Markham. 1984. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 224:500-503.[Abstract/Free Full Text]
12
12. Hatziioannou, T., S. Cowan, S. P. Goff, P. D. Bieniasz, and G. J. Towers. 2003. Restriction of multiple divergent retroviruses by Lv1 and Ref 1. EMBO J. 22:385-394.[CrossRef][Medline]
13
13. Hatziioannou, T., S. Cowan, U. K. von Schwedler, W. I. Sundquist, and P. Bieniasz. 2004. Species-specific tropism determinants in the human immunodeficiency virus type 1 capsid. J. Virol. 78:6005-6012.[Abstract/Free Full Text]
13
14. Hatziioannou, T., D. Perez-Caballero, A. Yang, S. Cowan, and P. D. Bieniasz. 2004. Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5. Proc. Natl. Acad. Sci. USA 101:10774-10779.[Abstract/Free Full Text]
14
15. Henry, J., I. H. Mather, M. F. McDermott, and P. Pontarotti. 1998. B30.2-like domain proteins: update and new insights into a rapidly expanding family of proteins. Mol. Biol. Evol. 15:1696-1705.[Abstract]
15
16. Himathongkham, S., and P. A. Luciw. 1996. Restriction of HIV-1 (subtype B) replication at the entry step in rhesus macaque cells. Virology 219:485-488.[CrossRef][Medline]
16
17. Hofmann, W., D. Schubert, J. LaBonte, L. Munson, S. Gibson, J. Scammell, P. Ferrigno, and J. Sodroski. 1999. Species-specific, postentry barriers to primate immunodeficiency virus infection. J. Virol. 73:10020-10028.[Abstract/Free Full Text]
17
18. Ishii, T., N. Aoki, A. Noda, T. Adachi, R. Nakamura, and T. Matsuda. 1995. Carboxy-terminal cytoplasmic domain of mouse butyrophilin specifically associates with a 150-kDa protein of mammary epithelial cells and milk fat globule membrane. Biochim. Biophys. Acta 1245:285-292.[Medline]
17
19. Keckesova, Z., L. M. J. Ylinen, and G. J. Towers. 2004. The human and African green monkey TRIM genes encode Ref1 and Lv1 retroviral restriction factor activities. Proc. Natl. Acad. Sci. USA 101:10780-10785.[Abstract/Free Full Text]
18
20. Kootstra, N. A., C. Munk, N. Tonnu, N. R. Landau, and I. M. Verma. 2003. Abrogation of postentry restriction of HIV-1-based lentiviral vector transduction in simian cells. Proc. Natl. Acad. Sci. USA 200:1298-1303.
19
21. Letvin, N. L., M. D. Daniel, P. K. Sehgal, R. C. Desrosiers, R. D. Hunt, L. M. Waldron, J. J. MacKey, D. K. Schmidt, L. V. Chalifoux, and N. W. King. 1985. Induction of AIDS-like disease in macaque monkeys with T-cell tropic retrovirus STLV-III. Science 230:71-73.[Abstract/Free Full Text]
20
22. Munk, C., S. M. Brandt, G. Luccero, and N. R. Landau. 2002. A dominant block to HIV-1 replication at reverse transcription in simian cells. Proc. Natl. Acad. Sci. USA 99:13843-13848.[Abstract/Free Full Text]
21
23. Niikura, T., Y. Hashimoto, H. Tajima, M. Ishizaka, Y. Yamagishi, M. Kawasumi, M. Nawa, K. Terashita, S. Aiso, and I. Nishimoto. 2003. A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults. Eur. J. Neurosci. 17:1150-1158.[CrossRef][Medline]
21
24. Nisole, S., C. Lynch, J. P. Stoye, and M. W. Yap. 2004. A Trim5-cyclophilin A fusion protein found in owl monkey kidney cells can restrict HIV-1. Proc. Natl. Acad. Sci. USA 101:13324-13328.[Abstract/Free Full Text]
22
25. Owens, C. M., B. Song, M. J. Perron, P. C. Yang, M. Stremlau, and J. Sodroski. 2004. Binding and susceptibility to post-entry restriction factors in monkey cells are specified by distinct regions of the human immunodeficiency virus type 1 capsid. J. Virol. 78:5423-5437.[Abstract/Free Full Text]
23
26. Owens, C. M., P. C. Yang, H. Gottlinger, and J. Sodroski. 2003. Human and simian immunodeficiency virus capsid proteins are major viral determinants of early postentry replication blocks in simian cells. J. Virol. 77:726-731.
24
27. Reymond, A., G. Meroni, A. Fantozzi, G. Merla, S. Cairo, L. Luzi, D. Riganelli, E. Zanaria, S. Messali, S. Cainarca, A. Guffanti, S. Minucci, P. G. Pelicci, and A. Ballabio. 2001. The tripartite motif family identifies cell compartments. EMBO J. 20:2140-2151.[CrossRef][Medline]
25
28. Rho, H. M., B. Poiesz, W. Ruscetti, and R. C. Gallo. 1981. Characterization of the reverse transcriptase from a new retrovirus (HTLV) produced by a human cutaneous T-cell lymphoma cell line. Virology 112:355-360.[CrossRef][Medline]
25
29. Sayah, D. M., E. Sokolskaja, L. Berthoux, and J. Luban. 2004. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430:569-573.[CrossRef][Medline]
26
30. Seto, M. H., H.-L. C. Liu, D. Zajchowski, and M. Whitlow. 1999. Protein fold analysis of the B30.2-like domain. Proteins 35:235-249.[CrossRef][Medline]
27
31. Shibata, R., H. Sakai, M. Kawamura, K. Tokunaga, and A. Adachi. 1995. Early replication block of human immunodeficiency virus type 1 in monkey cells. J. Gen. Virol. 76:2723-2730.[Abstract/Free Full Text]
28
32. Song, B., B. Gold, C. O'Huigin, H. Javanbakht, X. Li, M. Stremlau, C. Winkler, M. Dean and J. Sodroski. The B30.2(SPRY) domain of the retroviral restriction factor TRIM5 exhibits lineage-specific length and sequence variation in primates. J. Virol., in press.
28
33. Song, B., H. Javanbakht, M. Perron, D. Park, M. Stremlau and J. Sodroski. Retrovirus restriction by TRIM5 variants from Old World and New World primates. J. Virol., in press.
29
34. Stremlau, M., C. M. Owens, M. J. Perron, M. Kiessling, P. Autissier, and J. Sodroski. 2004. The cytoplasmic body component TRIM5 restricts human immunodeficiency virus (HIV-1) infection in Old World monkeys. Nature 427:848-853.[CrossRef][Medline]
30
35. Towers, G., M. Bock, S. Martin, Y. Takeuchi, J. P. Stoye, and O. Danos. 2000. A conserved mechanism of retrovirus restriction in mammals. Proc. Natl. Acad. Sci. USA 97:12295-12299.[Abstract/Free Full Text]
31
36. Towers, G., M. Collins, and Y. Takeuchi. 2002. Abrogation of Ref 1 retrovirus restriction in human cells. J. Virol. 76:2548-2550.[Abstract/Free Full Text]
32
37. Towers, G. J., T. Hatziioannou, S. Cowan, S. P. Goff, J. Luban, and P. D. Bieniasz. 2003. Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Nat. Med. 9:1138-1143.[CrossRef][Medline]
33
38. Whitcomb, J. M., and S. H. Hughes. 1992. Retroviral reverse transcription and integration: progress and problems. Annu. Rev. Cell Biol. 8:275-306.[CrossRef][Medline]
34
39. Yap, M. W., S. Nisole, C. Lynch, and J. P. Stoye. 2004. Trim5 protein restricts both HIV-1 and murine leukemia virus. Proc. Natl. Acad. Sci. USA 101:10786-10791.[Abstract/Free Full Text]

---

Journal of Virology, March 2005, p. 3139-3145, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.3139-3145.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Sebastian, S., Grutter, C., de Castillia, C. S., Pertel, T., Olivari, S., Grutter, M. G., Luban, J. (2009). An Invariant Surface Patch on the TRIM5{alpha} PRYSPRY Domain Is Required for Retroviral Restriction but Dispensable for Capsid Binding. J. Virol. 83: 3365-3373 [Abstract] [Full Text]  
• Langelier, C. R., Sandrin, V., Eckert, D. M., Christensen, D. E., Chandrasekaran, V., Alam, S. L., Aiken, C., Olsen, J. C., Kar, A. K., Sodroski, J. G., Sundquist, W. I. (2008). Biochemical Characterization of a Recombinant TRIM5{alpha} Protein That Restricts Human Immunodeficiency Virus Type 1 Replication. J. Virol. 82: 11682-11694 [Abstract] [Full Text]  
• Kar, A. K., Diaz-Griffero, F., Li, Y., Li, X., Sodroski, J. (2008). Biochemical and Biophysical Characterization of a Chimeric TRIM21-TRIM5{alpha} Protein. J. Virol. 82: 11669-11681 [Abstract] [Full Text]  
• Li, X., Sodroski, J. (2008). The TRIM5{alpha} B-Box 2 Domain Promotes Cooperative Binding to the Retroviral Capsid by Mediating Higher-Order Self-Association. J. Virol. 82: 11495-11502 [Abstract] [Full Text]  
• Richardson, M. W., Carroll, R. G., Stremlau, M., Korokhov, N., Humeau, L. M., Silvestri, G., Sodroski, J., Riley, J. L. (2008). Mode of Transmission Affects the Sensitivity of Human Immunodeficiency Virus Type 1 to Restriction by Rhesus TRIM5{alpha}. J. Virol. 82: 11117-11128 [Abstract] [Full Text]  
• Diehl, W. E., Stansell, E., Kaiser, S. M., Emerman, M., Hunter, E. (2008). Identification of Postentry Restrictions to Mason-Pfizer Monkey Virus Infection in New World Monkey Cells. J. Virol. 82: 11140-11151 [Abstract] [Full Text]  
• Kratovac, Z., Virgen, C. A., Bibollet-Ruche, F., Hahn, B. H., Bieniasz, P. D., Hatziioannou, T. (2008). Primate Lentivirus Capsid Sensitivity to TRIM5 Proteins. J. Virol. 82: 6772-6777 [Abstract] [Full Text]  
• Yap, M. W., Lindemann, D., Stanke, N., Reh, J., Westphal, D., Hanenberg, H., Ohkura, S., Stoye, J. P. (2008). Restriction of Foamy Viruses by Primate Trim5{alpha}. J. Virol. 82: 5429-5439 [Abstract] [Full Text]  
• Galla, M., Schambach, A., Towers, G. J., Baum, C. (2008). Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer. J. Virol. 82: 3069-3077 [Abstract] [Full Text]  
• Wilson, S. J., Webb, B. L. J., Ylinen, L. M. J., Verschoor, E., Heeney, J. L., Towers, G. J. (2008). From the Cover: Independent evolution of an antiviral TRIMCyp in rhesus macaques. Proc. Natl. Acad. Sci. USA 105: 3557-3562 [Abstract] [Full Text]  
• Virgen, C. A., Kratovac, Z., Bieniasz, P. D., Hatziioannou, T. (2008). From the Cover: Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species. Proc. Natl. Acad. Sci. USA 105: 3563-3568 [Abstract] [Full Text]  
• Goldschmidt, V., Ciuffi, A., Ortiz, M., Brawand, D., Munoz, M., Kaessmann, H., Telenti, A. (2008). Antiretroviral Activity of Ancestral TRIM5{alpha}. J. Virol. 82: 2089-2096 [Abstract] [Full Text]  
• Campbell, E. M., Perez, O., Anderson, J. L., Hope, T. J. (2008). Visualization of a proteasome-independent intermediate during restriction of HIV-1 by rhesus TRIM5{alpha}. JCB 180: 549-561 [Abstract] [Full Text]  
• Brennan, G., Kozyrev, Y., Kodama, T., Hu, S.-L. (2007). Novel TRIM5 Isoforms Expressed by Macaca nemestrina. J. Virol. 81: 12210-12217 [Abstract] [Full Text]  
• Schaller, T., Hue, S., Towers, G. J. (2007). An Active TRIM5 Protein in Rabbits Indicates a Common Antiviral Ancestor for Mammalian TRIM5 Proteins. J. Virol. 81: 11713-11721 [Abstract] [Full Text]  
• Diaz-Griffero, F., Kar, A., Perron, M., Xiang, S.-H., Javanbakht, H., Li, X., Sodroski, J. (2007). Modulation of Retroviral Restriction and Proteasome Inhibitor-Resistant Turnover by Changes in the TRIM5{alpha} B-Box 2 Domain. J. Virol. 81: 10362-10378 [Abstract] [Full Text]  
• Song, H., Nakayama, E. E., Yokoyama, M., Sato, H., Levy, J. A., Shioda, T. (2007). A Single Amino Acid of the Human Immunodeficiency Virus Type 2 Capsid Affects Its Replication in the Presence of Cynomolgus Monkey and Human TRIM5{alpha}s. J. Virol. 81: 7280-7285 [Abstract] [Full Text]  
• Kaiser, S. M., Malik, H. S., Emerman, M. (2007). Restriction of an Extinct Retrovirus by the Human TRIM5{alpha} Antiviral Protein. Science 316: 1756-1758 [Abstract] [Full Text]  
• Shiina, T., Briles, W. E., Goto, R. M., Hosomichi, K., Yanagiya, K., Shimizu, S., Inoko, H., Miller, M. M. (2007). Extended Gene Map Reveals Tripartite Motif, C-Type Lectin, and Ig Superfamily Type Genes within a Subregion of the Chicken MHC-B Affecting Infectious Disease. J. Immunol. 178: 7162-7172 [Abstract] [Full Text]  
• Campbell, E. M., Dodding, M. P., Yap, M. W., Wu, X., Gallois-Montbrun, S., Malim, M. H., Stoye, J. P., Hope, T. J. (2007). TRIM5{alpha} Cytoplasmic Bodies Are Highly Dynamic Structures. Mol. Biol. Cell 18: 2102-2111 [Abstract] [Full Text]  
• Perron, M. J., Stremlau, M., Lee, M., Javanbakht, H., Song, B., Sodroski, J. (2007). The Human TRIM5{alpha} Restriction Factor Mediates Accelerated Uncoating of the N-Tropic Murine Leukemia Virus Capsid. J. Virol. 81: 2138-2148 [Abstract] [Full Text]  
• Luban, J. (2007). Cyclophilin A, TRIM5, and Resistance to Human Immunodeficiency Virus Type 1 Infection. J. Virol. 81: 1054-1061 [Full Text]  
• Newman, R. M., Hall, L., Connole, M., Chen, G.-L., Sato, S., Yuste, E., Diehl, W., Hunter, E., Kaur, A., Miller, G. M., Johnson, W. E. (2006). Balancing selection and the evolution of functional polymorphism in Old World monkey TRIM5{alpha}. Proc. Natl. Acad. Sci. USA 103: 19134-19139 [Abstract] [Full Text]  
• VandeWoude, S., Apetrei, C. (2006). Going Wild: Lessons from Naturally Occurring T-Lymphotropic Lentiviruses. Clin. Microbiol. Rev. 19: 728-762 [Abstract] [Full Text]  
• Ohkura, S., Yap, M. W., Sheldon, T., Stoye, J. P. (2006). All Three Variable Regions of the TRIM5{alpha} B30.2 Domain Can Contribute to the Specificity of Retrovirus Restriction.. J. Virol. 80: 8554-8565 [Abstract] [Full Text]  
• Ylinen, L. M. J., Keckesova, Z., Webb, B. L. J., Gifford, R. J. M., Smith, T. P. L., Towers, G. J. (2006). Isolation of an Active Lv1 Gene from Cattle Indicates that Tripartite Motif Protein-Mediated Innate Immunity to Retroviral Infection Is Widespread among Mammals.. J. Virol. 80: 7332-7338 [Abstract] [Full Text]  
• Bishop, K. N., Mortuza, G. B., Howell, S., Yap, M. W., Stoye, J. P., Taylor, I. A. (2006). Characterization of an amino-terminal dimerization domain from retroviral restriction factor fv1.. J. Virol. 80: 8225-8235 [Abstract] [Full Text]  
• Li, Y., Li, X., Stremlau, M., Lee, M., Sodroski, J. (2006). Removal of Arginine 332 Allows Human TRIM5{alpha} To Bind Human Immunodeficiency Virus Capsids and To Restrict Infection. J. Virol. 80: 6738-6744 [Abstract] [Full Text]  
• Li, X., Li, Y., Stremlau, M., Yuan, W., Song, B., Perron, M., Sodroski, J. (2006). Functional Replacement of the RING, B-Box 2, and Coiled-Coil Domains of Tripartite Motif 5{alpha} (TRIM5{alpha}) by Heterologous TRIM Domains.. J. Virol. 80: 6198-6206 [Abstract] [Full Text]  
• Perron, M. J., Stremlau, M., Sodroski, J. (2006). Two Surface-Exposed Elements of the B30.2/SPRY Domain as Potency Determinants of N-Tropic Murine Leukemia Virus Restriction by Human TRIM5{alpha}.. J. Virol. 80: 5631-5636 [Abstract] [Full Text]  
• Wu, X., Anderson, J. L., Campbell, E. M., Joseph, A. M., Hope, T. J. (2006). Proteasome inhibitors uncouple rhesus TRIM5{alpha} restriction of HIV-1 reverse transcription and infection. Proc. Natl. Acad. Sci. USA 103: 7465-7470 [Abstract] [Full Text]  
• Si, Z., Vandegraaff, N., O'hUigin, C., Song, B., Yuan, W., Xu, C., Perron, M., Li, X., Marasco, W. A., Engelman, A., Dean, M., Sodroski, J. (2006). Evolution of a cytoplasmic tripartite motif (TRIM) protein in cows that restricts retroviral infection. Proc. Natl. Acad. Sci. USA 103: 7454-7459 [Abstract] [Full Text]  
• Keckesova, Z., Ylinen, L. M. J., Towers, G. J. (2006). Cyclophilin A Renders Human Immunodeficiency Virus Type 1 Sensitive to Old World Monkey but Not Human TRIM5{alpha} Antiviral Activity.. J. Virol. 80: 4683-4690 [Abstract] [Full Text]  
• Stremlau, M., Perron, M., Lee, M., Li, Y., Song, B., Javanbakht, H., Diaz-Griffero, F., Anderson, D. J., Sundquist, W. I., Sodroski, J. (2006). From the Cover: Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5{alpha} restriction factor. Proc. Natl. Acad. Sci. USA 103: 5514-5519 [Abstract] [Full Text]  
• Sokolskaja, E., Berthoux, L., Luban, J. (2006). Cyclophilin A and TRIM5{alpha} Independently Regulate Human Immunodeficiency Virus Type 1 Infectivity in Human Cells. J. Virol. 80: 2855-2862 [Abstract] [Full Text]  
• Passerini, L. D., Keckesova, Z., Towers, G. J. (2006). Retroviral Restriction Factors Fv1 and TRIM5{alpha} Act Independently and Can Compete for Incoming Virus before Reverse Transcription. J. Virol. 80: 2100-2105 [Abstract] [Full Text]  
• Speelmon, E. C., Livingston-Rosanoff, D., Li, S. S., Vu, Q., Bui, J., Geraghty, D. E., Zhao, L. P., McElrath, M. J. (2006). Genetic Association of the Antiviral Restriction Factor TRIM5{alpha} with Human Immunodeficiency Virus Type 1 Infection. J. Virol. 80: 2463-2471 [Abstract] [Full Text]  
• Saenz, D. T., Teo, W., Olsen, J. C., Poeschla, E. M. (2005). Restriction of Feline Immunodeficiency Virus by Ref1, Lv1, and Primate TRIM5{alpha} Proteins. J. Virol. 79: 15175-15188 [Abstract] [Full Text]  
• Perez-Caballero, D., Hatziioannou, T., Zhang, F., Cowan, S., Bieniasz, P. D. (2005). Restriction of Human Immunodeficiency Virus Type 1 by TRIM-CypA Occurs with Rapid Kinetics and Independently of Cytoplasmic Bodies, Ubiquitin, and Proteasome Activity. J. Virol. 79: 15567-15572 [Abstract] [Full Text]  
• Mische, C. C., Javanbakht, H., Song, B., Diaz-Griffero, F., Stremlau, M., Strack, B., Si, Z., Sodroski, J. (2005). Retroviral Restriction Factor TRIM5{alpha} Is a Trimer. J. Virol. 79: 14446-14450 [Abstract] [Full Text]  
• Berthoux, L., Sebastian, S., Sokolskaja, E., Luban, J. (2005). Cyclophilin A is required for TRIM5{alpha}-mediated resistance to HIV-1 in Old World monkey cells. Proc. Natl. Acad. Sci. USA 102: 14849-14853 [Abstract] [Full Text]  
• Ylinen, L. M. J., Keckesova, Z., Wilson, S. J., Ranasinghe, S., Towers, G. J. (2005). Differential Restriction of Human Immunodeficiency Virus Type 2 and Simian Immunodeficiency Virus SIVmac by TRIM5{alpha} Alleles. J. Virol. 79: 11580-11587 [Abstract] [Full Text]  
• Javanbakht, H., Diaz-Griffero, F., Stremlau, M., Si, Z., Sodroski, J. (2005). The Contribution of RING and B-box 2 Domains to Retroviral Restriction Mediated by Monkey TRIM5{alpha}. J. Biol. Chem. 280: 26933-26940 [Abstract] [Full Text]  
• Nakayama, E. E., Miyoshi, H., Nagai, Y., Shioda, T. (2005). A Specific Region of 37 Amino Acid Residues in the SPRY (B30.2) Domain of African Green Monkey TRIM5{alpha} Determines Species-Specific Restriction of Simian Immunodeficiency Virus SIVmac Infection. J. Virol. 79: 8870-8877 [Abstract] [Full Text]  
• Song, B., Gold, B., O'hUigin, C., Javanbakht, H., Li, X., Stremlau, M., Winkler, C., Dean, M., Sodroski, J. (2005). The B30.2(SPRY) Domain of the Retroviral Restriction Factor TRIM5{alpha} Exhibits Lineage-Specific Length and Sequence Variation in Primates. J. Virol. 79: 6111-6121 [Abstract] [Full Text]  
• Song, B., Javanbakht, H., Perron, M., Park, D. H., Stremlau, M., Sodroski, J. (2005). Retrovirus Restriction by TRIM5{alpha} Variants from Old World and New World Primates. J. Virol. 79: 3930-3937 [Abstract] [Full Text]  

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stremlau, M. Articles by Sodroski, J. Search for Related Content PubMed PubMed Citation Articles by Stremlau, M. Articles by Sodroski, J.