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APOBEC3G and APOBEC3F rarely co-mutate the same HIV genome.

ABSTRACT: The human immune proteins APOBEC3G and APOBEC3F (hA3G and hA3F) induce destructive G-to-A changes in the HIV genome, referred to as 'hypermutation'. These two proteins co-express in human cells, co-localize to mRNA processing bodies and might co-package into HIV virions. Therefore they are expected to also co-mutate the HIV genome. Here we investigate the mutational footprints of hA3G and hA3F in a large population of full genome HIV-1 sequences from naturally infected patients to uniquely identify sequences hypermutated by either or both of these proteins. We develop a method of identification based on the representation of hA3G and hA3F target and product motifs that does not require an alignment to a parental/consensus sequence.Out of nearly 100 hypermutated HIV-1 sequences only one sequence from the HIV-1 outlier group showed clear signatures of co-mutation by both proteins. The remaining sequences were affected by either hA3G or hA3F.Using a novel method of identification of HIV sequences hypermutated by the hA3G and hA3F enzymes, we report a very low rate of co-mutation of full-length HIV sequences, and discuss the potential mechanisms underlying this.

SUBMITTER: Ebrahimi D

PROVIDER: S-EPMC3532371 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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APOBEC3G and APOBEC3F rarely co-mutate the same HIV genome.

Ebrahimi Diako D Anwar Firoz F Davenport Miles P MP

Retrovirology 20121220

<h4>Background</h4>The human immune proteins APOBEC3G and APOBEC3F (hA3G and hA3F) induce destructive G-to-A changes in the HIV genome, referred to as 'hypermutation'. These two proteins co-express in human cells, co-localize to mRNA processing bodies and might co-package into HIV virions. Therefore they are expected to also co-mutate the HIV genome. Here we investigate the mutational footprints of hA3G and hA3F in a large population of full genome HIV-1 sequences from naturally infected patient ...[more]

PMID: 23256516

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Project description:UnlabelledThe multifunctional HIV-1 accessory protein Vif counters the antiviral activities of APOBEC3G (A3G) and APOBEC3F (A3F), and some Vifs counter stable alleles of APOBEC3H (A3H). Studies in humanized mice have shown that HIV-1 lacking Vif expression is not viable. Here, we look at the relative contributions of the three APOBEC3s to viral extinction. Inoculation of bone marrow/liver/thymus (BLT) mice with CCR5-tropic HIV-1JRCSF(JRCSF) expressing a vif gene inactive for A3G but not A3F degradation activity (JRCSFvifH42/43D) displayed either no or delayed replication. JRCSF expressing a vif gene mutated to inactivate A3F degradation but not A3G degradation (JRCSFvifW79S) always replicated to high viral loads with variable delays. JRCSF with vif mutated to lack both A3G and A3F degradation activities (JRCSFvifH42/43DW79S) failed to replicate, mimicking JRCSF without Vif expression (JRCSFΔvif). JRCSF and JRCSFvifH42/43D, but not JRCSFvifW79S or JRCSFvifH42/43DW79S, degraded APOBEC3D. With one exception, JRCSFs expressing mutant Vifs that replicated acquired enforced vif mutations. These mutations partially restored A3G or A3F degradation activity and fully replaced JRCSFvifH42/43D or JRCSFvifW79S by 10 weeks. Surprisingly, induced mutations temporally lagged behind high levels of virus in blood. In the exceptional case, JRCSFvifH42/43D replicated after a prolonged delay with no mutations in vif but instead a V27I mutation in the RNase H coding sequence. JRCSFvifH42/43D infections exhibited massive GG/AG mutations in pol viral DNA, but in viral RNA, there were no fixed mutations in the Gag or reverse transcriptase coding sequence. A3H did not contribute to viral extinction but, in combination with A3F, could delay JRCSF replication. A3H was also found to hypermutate viral DNA.ImportanceVif degradation of A3G and A3F enhances viral fitness, as virus with even a partially restored capacity for degradation outgrows JRCSFvifH42/43D and JRCSFvifW79S. Unexpectedly, fixation of mutations that replaced H42/43D or W79S in viral RNA lagged behind the appearance of high viral loads. In one exceptional JRCSFvifH42/43D infection, vif was unchanged but replication proceeded after a long delay. These results suggest that Vif binds and inhibits the non-cytosine deaminase activities of intact A3G and intact A3F, allowing JRCSFvifH42/43D and JRCSFvifW79S to replicate with reduced fitness. Subsequently, enhanced Vif function is acquired by enforced mutations. In infected cells, JRCSFΔvif and JRCSFvifH42/43DW79S are exposed to active A3F and A3G and fail to replicate. JRCSFvifH42/43D Vif degrades A3F and, in some cases, overcomes A3G mutagenic activity to replicate. Vif may have evolved to inhibit A3F and A3G by stoichiometric binding and subsequently acquired the ability to target these proteins to proteasomes.

Project description:The APOBEC3 deoxycytidine deaminase family functions as host restriction factors that can block replication of Vif (virus infectivity factor) deficient HIV-1 virions to differing degrees by deaminating cytosines to uracils in single-stranded (-)HIV-1 DNA. Upon replication of the (-)DNA to (+)DNA, the HIV-1 reverse transcriptase incorporates adenines opposite the uracils, thereby inducing C/G→T/A mutations that can functionally inactivate HIV-1. Although both APOBEC3F and APOBEC3G are expressed in cell types HIV-1 infects and are suppressed by Vif, there has been no prior biochemical analysis of APOBEC3F, in contrast to APOBEC3G. Using synthetic DNA substrates, we characterized APOBEC3F and found that similar to APOBEC3G; it is a processive enzyme and can deaminate at least two cytosines in a single enzyme-substrate encounter. However, APOBEC3F scanning movement is distinct from APOBEC3G, and relies on jumping rather than both jumping and sliding. APOBEC3F jumping movements were also different from APOBEC3G. The lack of sliding movement from APOBEC3F is due to an ¹⁹⁰NPM¹⁹² motif, since insertion of this motif into APOBEC3G decreases its sliding movements. The APOBEC3G NPM mutant induced significantly less mutations in comparison to wild-type APOBEC3G in an in vitro model HIV-1 replication assay and single-cycle infectivity assay, indicating that differences in DNA scanning were relevant to restriction of HIV-1. Conversely, mutation of the APOBEC3F ¹⁹¹Pro to ¹⁹¹Gly enables APOBEC3F sliding movements to occur. Although APOBEC3F ¹⁹⁰NGM¹⁹² could slide, the enzyme did not induce more mutagenesis than wild-type APOBEC3F, demonstrating that the unique jumping mechanism of APOBEC3F abrogates the influence of sliding on mutagenesis. Overall, we demonstrate key differences in the impact of APOBEC3F- and APOBEC3G-induced mutagenesis on HIV-1 that supports a model in which both the processive DNA scanning mechanism and preferred deamination motif (APOBEC3F, 5'TTC; APOBEC3G 5'CCC) influences the mutagenic and gene inactivation potential of an APOBEC3 enzyme.

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APOBEC3G and APOBEC3F rarely co-mutate the same HIV genome.

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APOBEC3G and APOBEC3F rarely co-mutate the same HIV genome.

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