- Open Access
HIV-1 Vif inhibits G to A hypermutations catalyzed by virus-encapsidated APOBEC3G to maintain HIV-1 infectivity
© Wang et al.; licensee BioMed Central Ltd. 2014
Received: 19 March 2014
Accepted: 23 September 2014
Published: 11 October 2014
HIV-1 viral infectivity factor (Vif) is an essential accessory protein for HIV-1 replication. The predominant function of Vif is to counteract Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G, A3G), a potent host restriction factor that inhibits HIV-1 replication. Vif mediates the proteasomal degradation of A3G and inhibits A3G translation, thus diminishing the pool of A3G that is available to be packaged into budding virion. Although Vif is robust in degrading A3G, the protection provided against A3G is not absolute. Clinical and laboratory evidence have shown that A3G is not completely excluded from HIV-1 viral particles during HIV-1 replication. It remains unclear why the viral samples are still infectious when A3G has been packaged into the virions.
In this study, we provide evidence that Vif continues to protect HIV-1 from the deleterious effects of A3G, even after packaging of A3G has occurred. When equal amounts of A3G were packaged into budding virions, the virus expressing functional Vif was more infectious and incurred fewer G to A hypermutations in the second round of infection compared to Vif-deficient virus. A Vif mutant with a defect in viral packaging showed a reduced ability to protect the HIV-1 genome from G to A hypermutations.
Our data suggest that even packaged A3G is still under the tyranny of Vif. Our work brings to light an additional caveat for any therapy that hopes to exploit the Vif-A3G axis. The ideal strategy would not only enhance A3G viral packaging, but also reduce HIV-1 Vif viral encapsidation.
Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G, A3G) is a member of the APOBEC3 family of cytidine deaminases, which includes A3A, B, C, D/E and F, with A3G being the most potent against HIV-1 . In the absence of Vif, A3G will encapsidate into HIV-1 virions and induce G to A hypermutations in the newly synthesized viral DNA -. A3G also exerts inhibitory effects at several other steps of HIV-1 replication, such as reverse transcription and viral DNA integration .
HIV-1 Vif is a 23 kDa accessory protein of HIV-1. The critical role of Vif in HIV-1 infectivity was observed shortly after the discovery of HIV-1 ,; however, the mechanism by which Vif protects the integrity of HIV-1 took over a decade to decode. Seminal work by Sheehy et al. led to the discovery that the predominant function of Vif is to counteract A3G . The general consensus is that Vif orchestrates proteasomal degradation of A3G, thus preventing its packaging into the budding virion -. During this process, HIV-1 Vif interacts with Cullin 5, A3G and the newly identified T cell differentiation factor, CBfβ, to promote formation of the Cullin 5-Vif- A3G ubiquitin E3 ligase complex, which marks A3G for proteasomal degradation -. While Vif-mediated degradation of A3G is the well-recognized mechanism by which Vif rescues HIV-1, it has also been proposed that Vif prevents A3G viral packaging through inhibiting A3G translation , or another unknown mechanism .
In addition to inhibiting A3G packaging, it has also been shown that Vif has the capability of directly inhibiting A3G cytidine deaminase activity in a degradation-independent manner. Santa-Marta et al. showed that A3G-induced cytidine deamination is inhibited by the expression of Vif, without the depletion of a deaminase domain, in an Escherichia coli system. Moreover, inhibition of deaminase-mediated bacterial hypermutation is dependent on a single amino acid substitution D128K that renders A3G resistant to Vif inhibition . Britan-Rosich et al. also showed that Vif is able to inhibit A3G cytidine deaminase activity in vitro. Recently, Feng et al. reported that HIV-1 Vif alters processive single-stranded DNA scanning of A3G in vitro. However, it remains unclear if the inhibitory effect of Vif on A3G cytidine deaminase activity is integral for successful HIV-1 replication following Vif-A3G encapsidation into progeny virions. In this study, we provide evidence that Vif continues to protect HIV-1 from the deleterious effects of A3G even after packaging of A3G has occurred. When equal amounts of A3G were packaged into budding virions with functional or non-functional Vif, the virus expressing functional Vif was more infectious, and fewer G to A hypermutations were generated in the second round of infection compared to virions without functional Vif. Our work indicates that Vif plays an additional role in protecting HIV-1 from A3G after encapsidation. This work sheds light on the fact that any therapy that hopes to exploit the Vif-A3G axis needs to take into account that even though A3G becomes packaged, Vif is still able to maintain the fidelity of the virus.
Antiviral activity of A3G is less potent against wild-type virus compared to Vif-deficient virus
HIV-1 Vif inhibits A3G cytidine deaminase activity in both cells and virion
HIV-1 Vif reduces the G to A hypermutation rate catalyzed by A3G
VifB3 mutant encapsidation into HIV particles is defective
Vif retains infectivity but HIV-1 replication is delayed in HAA3G22K-expressing Jurkat cells
The discovery of A3G as a potent anti-HIV-1 host restriction factor has fostered interest in blocking the Vif-A3G interaction and ultimately inhibiting Vif-mediated A3G degradation as a potential treatment strategy. Vif drastically reduces the cellular pool of A3G and consequently prevents A3G from hitch-hiking a ride with the nucleocapsid of Gag, viral RNA or 7SL RNA into the budding virion, thus preserving HIV-1 infectivity . Several studies have also shown that Vif prevents A3G viral packaging through inhibiting A3G translation , or other mechanisms .
A3G inhibits HIV-1 replication at several steps of the HIV-1 life cycle, such as reverse transcription and viral cDNA integration. However, the hallmark of the potent antiviral phenotype of A3G is found in its ability to induce lethal G to A hypermutations in the viral genome. A3G has a strong bias towards catalyzing hypermutations on minus strand DNA 5’ CC or 5’ CCC. These mutations may lead to the introduction of premature stop codons and/or result in non-infectious or defective proviruses . Although Vif is robust in degrading A3G, thus maintaining viral infectivity, the protection provided against A3G is not absolute. This notion is evident by the G to A hypermutations found in genomes of primary viruses isolated from AIDS patients -. The dominant mutation patterns found among those hypermutations were in the GG to AG context, which suggests that these mutations were induced by A3G. These findings illustrate that A3G is not completely excluded from HIV-1 viral particles even in the presence of Vif. Observations by Gillick et al. suggest that detectable amounts of A3G are present in wild-type HIV-1 particles produced from CD4+ T cells during the course of infection . However, Xu et al. reported that virion incorporation of approximately seven A3G molecules is sufficient to inhibit the replication of Vif-deficient HIV-1 . The obvious discrepancy is that the primary isolates from viral samples were Vif-competent virus, whereas the latter study involved Vif-deficient virus. Taken together, these studies give credence to the argument that Vif may preserve HIV-1 infectivity even after A3G has been packaged into the virion, and our results are consistent with this idea. As shown in Figure 1, even though more A3G was incorporated into Vif-competent HIV (sample 5) compared to Vif-incompetent HIV (sample 7), the infectivity of Vif-competent HIV was much higher than the one of Vif -incompetent HIV. Furthermore, when HAA3G22K, the A3G mutant resistant to Vif-mediated degradation, was used to ensure equal packaging of A3G into both wild-type and Vif-deficient viruses, the infectivity of wild-type virus was 10-fold greater than that of Vif-deficient virus. This result corresponds to the G to A hypermutation rate of wild-type virus, which was significantly lower than that of Vif-deficient virus (Figure 3). Ultimately, our results provide evidence that Vif harbors a backup mechanism to counteract A3G antiviral function even after A3G is packaged into the budding virion.
Our lab previously demonstrated that A3G reduces early and late viral reverse transcription products equally in the presence or absence of Vif . This ability of A3G may explain why the viral infectivity of wild-type virus HXB2N in the presence of HAA3G22K was reduced 10-fold compared to HXB2N with the pcDNA3.1 control vector in our system (Figure 3B). In the absence of Vif, however, A3G would further diminish the integrity of the viral genome through G to A hypermutations in the newly synthesized viral cDNA, which would not occur in a Vif-proficient virus, as shown in Figure 3C. These data suggest that G to A hypermutations further reduce the infectivity of Vif-deficient HIV-1. A3G cytidine deaminase inactive mutants (such as H257R, C288S and C291S) inhibit HIV-1 replication through reducing viral cDNA production . These mutants do not generate G to A hypermutations . Therefore, we do not expect Vif will have effects on the antiviral function of the intraviral form of these mutants.
In summary, we used an HIV-1 replication system to show that HIV-1 Vif has alternate functions for counteracting A3G and preserving HIV-1 infectivity. While the initial function of Vif is to prevent A3G viral incorporation, this work confirms that Vif also inhibits the G to A hypermutations catalyzed by A3G. Therefore, any therapy that hopes to exploit the Vif-A3G axis must take into account the ability of Vif to overcome A3G in both the producer cell and the virion. Thus, even though A3G becomes packaged, Vif is still able to maintain the fidelity of the virus. A practical strategy for an antiviral treatment would be not only to increase A3G viral incorporation but also to reduce Vif viral packaging.
Plasmids, antibodies and reagents
The proviral DNA constructs of wild-type HIV-1 (HXB2N) and Vif mutant (HXB2NΔVif) as well as Vif-cMyc expression vectors were provided by Xiao-Fang Yu (Johns Hopkins University) ,. HXB2B3 contains three point mutations in the C-terminal region of Vif as previously described . The three point mutations were first introduced into a Vif transfer vector, which contained the EcoRI- EcoRI DNA fragment of HXB2N, using the primer GATGGAACAAGCCCCAGGCGACCGCGGGCCACGCAGGGAGCCACACAATGA and QuikChange Lightning Multi Site-Directed Mutagenesis Kit (Agilent Technologies). The DNA fragment containing the three point mutations was then sub-cloned into the HXB2N construct to generate HXB2B3. Wild-type A3G and A3GD128K mutant plasmids were gifts from Yong-Hui Zheng (Michigan State University). The Vif-resistant A3G mutant, HA-A3G20K/RΔ2K (hereafter referred to as HAA3G22K), was previously described . The monoclonal anti-V5 antibody was purchased from Invitrogen. The rabbit anti-Vif antibody, rabbit anti-A3G antibody  and HIV-1 p24 monoclonal antibody  were obtained from NIH-ARRRP.
Cell culture, HIV-1 preparation, HIV-1 purification, DNA transfection, Western blot analysis and viral infectivity (MAGI) assay
Human embryonic kidney (HEK) 293T cells and TZM-bl cells  (NIH-ARRRP) were cultured in DMEM containing 10% fetal bovine serum (FBS) in 5% CO2 atmosphere at 37°C. The culture supernatant was harvested 48 h post-transfection for the MAGI assay and viral preparation. HIV-1 virions were prepared from the cell culture supernatant and separated from cellular debris by centrifugation at 1,000 × g for 15 min and filtered through a 0.2 μm pore size membrane. Virus particles were concentrated by ultracentrifugation at 100,000 × g for 2 h on a 20% sucrose cushion. Transfections were performed using polyethylenimine (PEI). Western blot analysis and the MAGI assay were carried out as previously described ,.
293T cells were cotransfected with HIV-1 expression vectors and A3G expression vectors as indicated. Culture supernatants were collected 48 h post-transfection and treated with DNase I (20 U/ml) at 37°C for 1 h. SupT1 cells (1 × 106) were spin-infected with DNase I-treated HIV-1 (150 ng p24Gag equivalent) at 2000 × g for 2 h at room temperature. The cells were then washed with fresh medium and cultured at 37°C, 5% CO2 atmosphere. Cells were harvested 12 h post-infection. DNA was isolated using a DNeasy Blood and Tissue DNA isolation kit (QIAGEN). A 650-bp DNA fragment covering a portion of nef, U3, and R of HIV-1 was amplified with Taq DNA polymerase (Invitrogen) using the primers HIV-1-F (5′-AGGCAGCTGTAGATATTAGCCAC) and HIV-1-R (5′-GTATGAGGGATCTCTAGCTACCA). The PCR products were cloned into the TOPO TA-cloning vector pCR2.1 (Invitrogen). The clones were sequenced, and the sequencing results were analyzed using the CLC Main Workbench software. Statistical analysis was performed using the GraphPad Prism 5 software.
A3G cytidine deaminase assay
The FRET-based cytidine deaminase assay was performed based on a modified protocol adapted from a previously described method . 293T cells were cotransfected with the indicated HIV-1 expression vector and the indicated A3G expression vector. At 48 h post-transfection, cells and supernatant were harvested, and the virus was concentrated from the supernatant by ultracentrifugation. NP40 buffer (0.626% NP40, 10 mM Tris acetate pH 7.5, 50 mM potassium acetate, 10 mM NaCl) was used to lyse both cell and viral samples. The cell or viral lysate (15-20 μl) was mixed with 70 μl master mix containing 20 pmol Taqman positive control probe (56-FAM/TTATTATTCCCATTTGATT/-36TAMSp), 1.0 unit uracil DNA glycosylase (NEB), 50 mM Tris (pH 7.4), 10 mM EDTA, 250 μg/ml RNase A (Qiagen) and 1 μM fluorescence. Cell and viral lysate samples were incubated at 37°C for 3 h or overnight, respectively. Thereafter, 4 μl of 4 M NaOH was added to the reaction and incubated for 30 min at 37°C. The reaction was then neutralized by adding 4 μl of 4 M HCl and 36 μl of 2 M Tris (pH 7.9). The samples were cooled to 4°C, and fluorescence was measured using a MyiQ ICycler (Bio-Rad). To measure the background of each sample, the Taqman negative control probe (56-FAM/TTATTATTGGGATTTGATT/36-TAMSp) was used. The cytidine deaminase activity was calculated as a function of the activity generated from the positive probe minus the activity generated from the negative probe.
Jurkat A3G and Jurkat HAA3G22K stably expressing cell lines and HIV-1 replication
To establish stable cell lines, Jurkat cells (1 × 106) were washed twice with PBS and pulsed with the A3G or HAA3G22K plasmid (3 μg each) suspended in 10 μl Buffer R using the Invitrogen Neon Transfection System (pulse voltage 1425 V, pulse width 10 ms and pulse number 3). After electroporation, the cells were cultured in RPMI with 10% FBS for two days. G418 (1 mg/ml, Invitrogen) was added to the culture on day 3 for neomycin resistance selection. Single clones were selected using the limited dilution method. The APOBEC expression of the selected cell lines was monitored by Western blot. HXB2N, HXB2NΔVif and HXB2B3 proviral constructs were transfected into 293T cells to produce the corresponding viruses. Jurkat, Jurkat/A3G and Jurkat/HAA3G22K cells (6 × 105) were spin-infected with 150 ng of p24 HXB2N, HXB2NΔVif or HXB2B3 virus. After extensive washes with RPMI, the infected Jurkat cell lines were cultured at 37°C in a 5% CO2 incubator, and the supernatant (200 μl) was harvested on days 1, 3, 5 and 7 post-infection. An equal volume of fresh culture media was added to the culture to maintain a constant culture volume after each harvest. HIV-1 levels were assayed using a p24 ELISA kit (AIDS and Cancer Virus Program, National Cancer Institute, Frederick, MD).
YW, BLK and QS performed experiments. YW, BLK, QS, TMT and BL contributed to the experimental design and result discussion. YW, BLK, QS and BL wrote the manuscript. All authors read and approved the final manuscript.
We thank X-F Yu (Johns Hopkins University) and Y-H Zheng (Michigan State University) for reagents. The following reagents were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: HIV-1HXB2 Vif antiserum; TZM-bl from J C. Kappes, X Wu and Tranzyme Inc; HIV-1 p24 monoclonal antibody from Dr. Bruce Chesebro and Kathy Wehrly; Anti-ApoC17 from Dr. Klaus Strebel.
This work was partially supported by NIH grants SC1GM089269, G12MD007586, U54MD007593, P30AI054999 and UL1TR000445 to BL. BLK and TMT are supported by NIH training grant T32HL007737 and T32AI007281 respectively.
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