It is unknown how this may affect HIV-1 proviral integration site selection. More importantly, it was shown that A3F and A3G proteins can compromise viral integration efficiency by modifying or altering adequate processing of the extremities of the long terminal repeats (LTR) of the virus 25, 26. It was previously shown that A3G and A3F can interact with the viral integrase (IN) and RT, but the role of this binding on viral integration is not yet clear 21, 22, 23, 24. Retaining low rates of A3 mutagenesis, or hypomutation, are believed to be important contributors to the genetic evolution of HIV-1 13.Ī3 proteins can also restrict HIV-1 replication via mechanisms other than deamination (e.g., binding to the viral RNA or viral reverse transcriptase (RT), which reduces vDNA synthesis) 14, 15, 16, 17, 18, 19, 20. These viruses devoid of A3, or even with highly reduced protein levels of the restriction factor, can freely infect new cells to help rapidly spread the infection. Consequently, nascent egressing virions package decreasing amounts of A3 proteins until the proteins have been expunged from the cytosol by Vif 12. However, HIV-1 can overcome the effects of A3 proteins by the increased expression of viral infectivity factor (Vif), which binds to and induces the polyubiquitination of the five anti-HIV-1 A3 proteins, thereby orchestrating their progressive depletion by proteasomal degradation 9, 10, 11. Very high levels of deamination, called hypermutation, are observed early in the infection that thoroughly inactivate the virus 6. Virion-packaged A3 then exert their antiretroviral activity in the target cells during reverse transcription primarily by deaminating cytosines (C) into uracils (U) in negative sense single-stranded viral DNA (vDNA) replication intermediates 6, 7, 8. When HIV-1 infects a new CD4+ monocyte or lymphocyte, A3 proteins associate with viral proteins and RNA, resulting in their encapsidation within nascent egressing virions 5. The human A3 family is comprised of seven members, five of which have demonstrated biologically relevant antiviral activity against HIV-1: APOBEC3D (A3D), APOBEC3F (A3F), APOBEC3G (A3G), certain haplotypes of APOBEC3H (A3H), and one polymorphic variant of APOBE3C (A3C) 1, 2, 3, 4. Our data implicates A3 as a host factor influencing HIV-1 integration site selection and also promotes what appears to be a more latent expression profile.
Both catalytic active and non-catalytic A3 mutants decrease insertions into gene coding sequences and increase integration sites into SINE elements, oncogenes and transcription-silencing non-B DNA features. Here we show that DNA editing is detected at the extremities of the long terminal repeat regions of the virus. Using a deep sequencing approach, we analyze the influence of catalytic active and inactive APOBEC3F and APOBEC3G on HIV-1 integration site selections. So far, little is known about how A3 cytosine deaminases might impact HIV-1 proviral DNA integration sites in human chromosomal DNA. Low levels of deamination are believed to contribute to the genetic evolution of HIV-1, while intense catalytic activity of these proteins can induce catastrophic hypermutation in proviral DNA leading to near-total HIV-1 restriction. APOBEC3 (A3) proteins are host-encoded deoxycytidine deaminases that provide an innate immune barrier to retroviral infection, notably against HIV-1.
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