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Journal of Virology, December 2007, p. 13932-13937, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01760-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antiretroviral Activity and Vif Sensitivity of Rhesus Macaque APOBEC3 Proteins{triangledown}

Cesar A. Virgen and Theodora Hatziioannou*

Aaron Diamond AIDS Research Center and the Rockefeller University, New York, New York

Received 11 August 2007/ Accepted 2 October 2007


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ABSTRACT
 
The inability of human immunodeficiency virus type 1(HIV-1) to replicate in rhesus macaque cells is in part due to the failure of HIV-1 Vif to counteract the restriction factor APOBEC3G. However, in this study we demonstrate that several rhesus macaque APOBEC3 (rhAPOBEC3) proteins are capable of inhibiting HIV-1 infectivity. There was considerable variation in the ability of a panel of Vif proteins to induce degradation of rhAPOBEC3 proteins, and mutations within HIV-1 Vif that render it capable of degrading rhAPOBEC3G did not confer activity against other antiviral rhAPOBEC3 proteins. These findings suggest that multiple APOBEC3 proteins can contribute to primate lentivirus species tropism.


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TEXT
 
Human immunodeficiency virus type 1 (HIV-1) is unable to replicate in most nonhuman primate species, including rhesus macaques. This is at least in part due to blocks in the viral replication cycle that have been identified in macaque-derived cells in vitro. Specifically, the rhesus macaque restriction factors TRIM5{alpha} and APOBEC3G are major barriers to HIV-1, but not simian immunodeficiency virus strain MAC239 (SIVMAC), replication in primary rhesus macaque cells (2, 12, 13, 18, 27, 30). Engineering HIV-1 to avoid and counteract these factors by replacing HIV-1 capsid and Vif proteins with their SIVMAC counterparts results in a virus that can replicate in primary rhesus macaque cells almost as efficiently as SIVMAC (12, 13).

Mutant HIV-1 Vif proteins that are capable of counteracting rhesus macaque APOBEC3G (rhAPOBEC3G) have recently been described (26). Specifically, changing amino acids 14 to 19 (from DRMR to SEMQ) resulted in an HIV-1 Vif protein that is capable of counteracting rhAPOBEC3G-mediated restriction. Therefore, we determined whether overcoming rhAPOBEC3G would be sufficient for HIV-1 to replicate in rhesus macaque T cells. The SEMQ substitution was introduced into a chimeric HIV-1 provirus encoding the SIVMAC capsid protein (Fig. 1A) (12). Since the Vif open reading frame overlaps with that of integrase, the C-terminal five amino acids of HIV-1 integrase were altered from RQDAD to KRDAD. This change did not have a significant effect on the ability of the virus to replicate in human CEMx174 cells, and its replication was only marginally slower than that of viruses expressing SIVMAC capsid and wild-type HIV-1 or SIVMAC Vif proteins (Fig. 1B). However, only the virus expressing SIVMAC Vif was able to replicate efficiently in rhesus macaque 221 T cells (Fig. 1B). Since HIV(SEMQ) Vif can counteract rhAPOBEC3G, this finding suggests that rhAPOBEC3G is not the only Vif-targeted restriction factor active in rhesus macaque T cells.


Figure 1
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  		FIG. 1. Replication of chimeric HIV-1-based viruses expressing different Vif proteins in human and rhesus macaque T cells. (A) Schematic representation of the viruses used in replication assays; wild-type HIV-1, HIV(SEMQ) mutant, and SIVMAC Vif proteins were expressed in the context of a replication-competent HIV-1-based chimeric virus expressing a SIVMAC capsid that was adapted to improve replication capacity in human and rhesus macaque cells (12). LTR, long terminal repeat. (B) Results of replication assays. Human CEMx174 and rhesus macaque 221 T cells were inoculated with equivalent infectious titers as measured on TZM cells (a human cell line expressing HIV-1 receptors and ß-galactosidase under the control of the HIV-1 long terminal repeat). Infected cells were washed the day after being inoculated, and the supernatant was collected every 3 days and assayed for infectivity on TZM cells.

The APOBEC3 family expanded during mammalian evolution, and many of its members have been under strong positive selection pressure in primates (6, 23), presumably as a consequence of past retroviral epidemics. At least seven APOBEC3 proteins are present in humans, and some family members, such as APOBEC3DE (7) and APOBEC3H (21), have only recently been characterized. As yet, there has been no systematic examination of all APOBEC3 proteins expressed in rhesus macaque T cells and their effects on HIV-1. While the rhesus macaque genome has recently been sequenced, the region in and around the APOBEC3 locus has not been completely assembled. Therefore, based on the sequences of APOBEC3 genes identified in humans, we have isolated cDNAs encoding their counterparts from rhesus macaque 221 T cells. Using primers based on the human APOBEC3DE (huAPOBEC3DE) sequence, we isolated three different APOBEC3-coding sequences. One of these proteins was similar to huAPOBEC3DE, including an insertion near the N terminus that is absent from other members of the family (Fig. 2A). We termed this protein rhAPOBEC3DE-I. The second protein, rhAPOBEC3DE-II, lacked the N-terminal insertion but was otherwise identical to rhAPOBEC3DE-I. The third protein, named rhAPOBEC3C, was highly homologous to huAPOBEC3C (Fig. 2B). The rhesus macaque genome sequence contains a sequence coding for a predicted APOBEC-like 3D protein (XM_001094328); however, using primers based on this coding sequence, we were unable to amplify any APOBEC coding sequences from the 221 cell cDNA. Additionally we were unable to amplify any APOBEC3-related products using primers based on huAPOBEC3A. Using primers based on huAPOBEC3B sequences, we isolated rhAPOBEC3B (Fig. 2C). Finally, using a mixture of primers based on human and rhesus macaque APOBEC3H, we isolated two variants of African green monkey APOBEC3H (agmAPOBEC3H) (Fig. 2D).


Figure 2
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  		FIG. 2. Amino acid alignment of human, rhesus macaque, and African green monkey APOBEC3 proteins. (A) Amino acid alignment of two variants of rhAPOBEC3DE (rhAPOBEC3DE-I [rhA3DE-I] and rhAPOBEC3DE [rhA3DE-II]) with huAPOBEC3DE (huA3DE). (B) Amino acid alignment of rhAPOBEC3C (rhA3C) with huAPOBEC3C (huAC3). (C) Amino acid alignment of rhAPOBEC3B (rhA3B) with huAPOBEC3B (huA3B). (D) Amino acid alignment of two variants of agmAPOBEC3H (agmAPOBEC3H.1 [agmA3H.1] and agmAPOBEC3H.2 [agmAcH.2]) with huAPOBEC3H (huA3H) and rhAPOBEC3H (rhA3H). The nucleotide deaminase zinc-binding motifs are underlined. Shading denotes amino acid homology.

Each of these cDNAs, together with rhAPOBEC3G, 3F (35), and 3H (21), was cloned into an expression plasmid introducing an N-terminal myc tag, as were human and agmAPOBEC3G, which served as controls. We next determined the ability of each APOBEC3 protein to be incorporated into HIV-1 particles. Importantly, APOBEC3 protein expression did not have any gross effects on HIV-1 GagPol expression or particle release (Fig. 3A). All APOBEC3G proteins were well-expressed and incorporated efficiently into HIV-1 particles, as was rhAPOBEC3F (Fig. 3B), in agreement with previous reports (1, 4, 5, 9, 10, 14, 16, 18, 24, 31, 36). The myc-green fluorescent protein (GFP) protein used as a control for the specificity of protein incorporation into particles was not detected in the virions, even though it was expressed at levels similar to those of the APOBEC3G proteins (Fig. 3B). Both rhAPOBEC3H and agmAPOBEC3H proteins were incorporated into particles significantly less efficiently than their APOBEC3G counterparts. Neither rhAPOBEC3B nor rhAPOBEC3B3C was incorporated into particles at detectable levels, despite being expressed at levels equivalent to that of rhAPOBEC3G. Finally, both rhAPOBEC3DE proteins were incorporated into particles at levels comparable to that of rhAPOBEC3G (Fig. 3B).


Figure 3
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  		FIG. 3. Expression and particle incorporation of APOBEC3 proteins. 293T cells (in 6-well plates) transfected with various myc-tagged APOBEC3 expression plasmids (900 ng per well) or a control myc-GFP expression plasmid together with an HIV-1 GagPol (450 ng per well) and a packageable genome (CSGW; 450 ng per well) were harvested 2 days posttransfection. Virions were purified by ultracentrifugation through a 20% sucrose cushion. Cell and virion lysates were analyzed by immunoblotting with an antibody against the HIV-1 capsid (A) or an antibody against the myc epitope (B). huA3G, huAPOBEC3G; agmA3G, agmAPOBEC3G; rhA3G, rhAPOBEC3G; rhA3F, rhAPOBEC3F; rhA3H, rhAPOBEC3H; rhA3B, rhAPOBEC3B; rhA3C, rhAPOBEC3C; rhA3DE-I, rhAPOBECDE-I; rhA3DE-II, rhAPOBECDE-II; agmA3H, agmAPOBEC3H.

To determine the effect of the various rhAPOBEC3 proteins on HIV-1 infectivity, increasing amounts of the APOBEC3 proteins were coexpressed with HIV-1 GagPol, a packageable HIV-1 vector expressing GFP (CSGW) and vesicular stomatitis virus G glycoprotein (VSV-G) (11). Simultaneously, HIV-1, HIV(SEMQ) mutant, HIV-2, SIVMAC, and SIVAGM Vif proteins were expressed in trans to determine their ability to counteract APOBEC3-mediated restriction as well as their effects on APOBEC3 protein levels. All Vif proteins were expressed at similar levels (data not shown). As expected, we reproduced previously published findings on the inhibition and degradation of APOBEC3G from different species by the various Vif proteins (3, 14, 15, 17-20, 25, 28, 34, 35). For example, all Vif proteins tested, with the exception of SIVAGM Vif, were able to decrease huAPOBEC3G expression levels and overcome huAPOBEC3G-mediated restriction (Fig. 4). In contrast, HIV-1 Vif, unlike the other Vif proteins tested, was not able to counteract rhAPOBEC3G and agmAPOBEC3G. rhAPOBEC3F was also a very strong inhibitor of HIV-1 infectivity and was largely resistant to the Vif proteins tested (Fig. 4) (35). The inability of SIVMAC Vif to downregulate rhAPOBEC3F efficiently is interesting, given that SIVMAC and simian-tropic HIV are capable of replicating very efficiently in rhesus macaque T cells, and suggests that the natural expression levels of rhAPOBEC3F in T cells might not be sufficiently high to inhibit virus replication.


Figure 4
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  		FIG. 4. Inhibition of HIV-1 infectivity by APOBEC3 proteins and ability of Vif proteins to overcome inhibition. (A) Viral stocks were generated by cotransfecting 293T cells with increasing amounts of APOBEC3 expression plasmids (0, 75, 150, and 300 ng in a 24-well plate) and fixed amounts of HIV-1 GagPol (150 ng), HIV-1 GFP vector (150 ng), and VSV-G (100 ng) expression plasmids and Vif or a control (150 ng) expression plasmid. Infectivity was measured by using human CEMx174 T cells as target cells. Infected cells were enumerated by fluorescence-activated cell sorter analysis. Results representative of two experiments are shown. huA3G, huAPOBEC3G; agmA3G, agmAPOBEC3G; rhA3G, rhAPOBEC3G; rhA3F, rhAPOBEC3F; rhA3H, rhAPOBEC3H; rhA3B, rhAPOBEC3B; rhA3DE-I, rhAPOBECDE-I; rhA3DE-II, rhAPOBECDE-II; rhA3C, rhAPOBEC3C; agmA3H, agmAPOBEC3H. (B) Transfected 293T cells were lysed, and expression of each APOBEC3 protein in the absence or presence of the various Vif proteins, as indicated, was monitored by immunoblotting with an antibody against myc. Each group of three lanes represents cells transfected with decreasing amounts (300, 150, and 75 ng), from left to right, of each APOBEC3 expression plasmid.

In agreement with a previous study (21), rhAPOBEC3H was also a very potent inhibitor of HIV-1 infectivity, decreasing titers by 100-fold (Fig. 4). HIV-2, SIVMAC, and SIVAGM Vif profoundly reduced rhAPOBEC3H levels and overcame rhAPOBEC3H-mediated inhibition; however, both HIV-1 and the HIV(SEMQ) Vif mutant were inactive against rhAPOBEC3H. huAPOBEC3H is poorly expressed (21) (data not shown) and is therefore not a potent antiviral factor. To determine whether the potent restriction by APOBEC3H was a general characteristic of Old World monkey proteins, we isolated agmAPOBEC3H from Vero cell cDNA. We obtained two variants that behaved similarly (Fig. 4 and data not shown). Specifically, agmAPOBEC3H was capable of inhibiting HIV-1 infectivity only modestly (twofold), even though it was expressed and incorporated into particles at a level similar to that of rhAPOBEC3H (Fig. 3B). Only SIVAGM Vif was capable of completely abolishing agmAPOBEC3H inhibition and reducing its expression, while HIV-1, HIV(SEMQ), and SIVMAC Vif proteins had only marginal effects on both agmAPOBEC3H expression levels and HIV-1 infectivity (Fig. 4).

rhAPOBEC3B was also capable of reducing HIV-1 infectivity by about 10-fold and was resistant to HIV-1, HIV(SEMQ), and HIV-2 Vif proteins (Fig. 4). In contrast, both SIVMAC and SIVAGM Vif proteins efficiently downregulated rhAPOBEC3B protein levels and rescued HIV-1 infectivity. The ability of rhAPOBEC3B to inhibit HIV-1 infectivity was surprising, given that undetectable levels were incorporated into HIV-1 particles (Fig. 3B). rhAPOBEC3DE-II, but not rhAPOBEC3DE-I, showed some antiviral activity against HIV-1, reducing titers by about sevenfold (Fig. 4A). Restriction was overcome by SIVMAC, SIVAGM, and, surprisingly, HIV-1 Vif but not HIV-2 or HIV(SEMQ) Vif proteins (Fig. 4). In contrast, rhAPOBEC3C did not significantly inhibit HIV-1 (Fig. 4A). Interestingly, HIV-2, SIVMAC, and SIVAGM Vif dramatically reduced rhAPOBEC3C expression (Fig. 4B). This activity could be biologically relevant, because huAPOBEC3C inhibits SIVMAC but not HIV-1 (33), and it is possible that the same is true of rhAPOBEC3C.

This study demonstrates that several members of the APOBEC3 family can potentially inhibit HIV-1 replication in rhesus macaque cells (Table 1). In addition to confirming that the well-characterized rhAPOBEC3G and rhAPOBEC3F can inhibit HIV-1 infectivity, we confirmed the results of a previous study (21) that demonstrated that rhAPOBEC3H can also inhibit HIV-1 infectivity. rhAPOBEC3H is incorporated into HIV-1 particles significantly less efficiently than rhAPOBEC3G, yet, surprisingly, can inhibit HIV-1 infectivity more potently. This is not a general property of Old World monkey APOBEC3H proteins and was not conserved in agmAPOBEC3H. Importantly, rhAPOBEC3H-mediated inhibition cannot be overcome by a mutant HIV-1(SEMQ) Vif protein that can target rhAPOBEC3G. Recently, it was reported that the determinants of interaction with huAPOBEC3G and huAPOBEC3F map to different regions of the HIV-1 Vif protein (22, 29, 32). Evidently, the determinants of rhAPOBEC3H recognition are also different from those of rhAPOBEC3G. This also applies to rhAPOBEC3B. huAPOBEC3B may inhibit HIV-1 and cannot be counteracted by HIV-1 or SIVMAC Vif (8, 33); however, rhAPOBEC3B is sensitive to SIVMAC but not HIV-1 or HIV(SEMQ) Vif. Furthermore, rhAPOBEC3B may be unusually potent or inhibit HIV-1 infectivity by a mechanism different from that of other APOBEC3 proteins, as it was undetectable in HIV-1 particles. Interestingly, the modest inhibition of infectivity mediated by rhAPOBEC3DE-II could be overcome by HIV-1 but not HIV(SEMQ) Vif, suggesting that rhAPOBEC3DE is recognized by overlapping Vif determinants, as is rhAPOBEC3G, but imposes different amino acid requirements for interaction on Vif. Overall, we found a very good correlation between the ability of each Vif protein to reduce the various APOBEC3 protein levels and its ability to rescue HIV-1 infectivity. Of the Vif proteins tested herein, HIV-1 Vif appeared to have the most-limited breadth of activity against rhAPOBEC3 and agmAPOBEC3 proteins, whereas SIVMAC and SIVAGM Vif proteins had significantly broader specificities. Moreover, HIV-2 Vif did not inhibit as wide a range of APOBEC3 proteins as SIVMAC Vif, even though these viruses are closely related. In conclusion, this study suggests that a number of APOBEC3 proteins could limit cross-species lentivirus transmission and that future attempts to engineer HIV-1 Vif so as to allow the virus to replicate in rhesus macaque T cells will have to take into account the activity of several rhAPOBEC3 proteins.


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  		TABLE 1. Ability of APOBEC3 proteins to inhibit HIV-1 infectivity in the presence of various Vif proteins


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ACKNOWLEDGMENTS
 
We are grateful to P. D. Bieniasz for advice and useful discussions and M. Emerman for the gift of human and rhesus macaque APOBEC3H plasmids.

This work was supported by a grant from the NIH (R21AI071896).


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FOOTNOTES
 
* Corresponding author. Mailing address: Aaron Diamond AIDS Research Center, 455 1st Avenue, New York, NY 10016. Phone: (212) 448-5091. Fax: (212) 448-5158. E-mail: thatziio{at}adarc.org Back

{triangledown} Published ahead of print on 17 October 2007. Back


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Journal of Virology, December 2007, p. 13932-13937, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01760-07
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