Stock Ticker

Aberrant strand transfer events across multiple stages of reverse transcription shape the heterogeneous landscape of the HIV-1 reservoir

  • Chun, T. W. et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA 94, 13193–13197 (1997).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wong, J. K. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291–1295 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Davey, R. T. Jr. et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc. Natl. Acad. Sci. USA 96, 15109–15114 (1999).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Finzi, D. et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat. Med. 5, 512–517 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Siliciano, J. D. et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat. Med. 9, 727–728 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ho, Y. C. et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155, 540–551 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bruner, K. M. et al. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature 566, 120–125 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cassidy, N. A. J. et al. HIV reservoir quantification using cross-subtype multiplex ddPCR. iScience 25, 103615 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gaebler, C. et al. Combination of quadruplex qPCR and next-generation sequencing for qualitative and quantitative analysis of the HIV-1 latent reservoir. J. Exp. Med. 216, 2253–2264 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Delporte, M. et al. Integrative assessment of total and intact HIV-1 reservoir by a 5-region multiplexed rainbow DNA Digital PCR assay. Clin. Chem. 71, 203–214 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Reeves, D. B. et al. Impact of misclassified defective proviruses on HIV reservoir measurements. Nat. Commun. 14, 4186 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kinloch, N. N. et al. Author Correction: HIV-1 diversity considerations in the application of the Intact Proviral DNA Assay (IPDA). Nat. Commun. 12, 2958 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gaebler, C. et al. Sequence evaluation and comparative analysis of novel assays for intact proviral HIV-1 DNA. J. Virol. 95 https://doi.org/10.1128/JVI.01986-20 (2021).

  • Simonetti, F. R. et al. Intact proviral DNA assay analysis of large cohorts of people with HIV provides a benchmark for the frequency and composition of persistent proviral DNA. Proc. Natl. Acad. Sci. USA 117, 18692–18700 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hiener, B. et al. Identification of genetically intact HIV-1 Proviruses in Specific CD4(+) T cells from effectively treated participants. Cell Rep. 21, 813–822 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, G. Q. et al. Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells. J. Clin. Investig. 127, 2689–2696 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Imamichi, H. et al. Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy. Proc. Natl. Acad. Sci. USA 113, 8783–8788 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • White, J. A. et al. Measuring the latent reservoir for HIV-1: Quantification bias in near full-length genome sequencing methods. PLoS Pathog. 18, e1010845 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bruner, K. M. et al. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat. Med. 22, 1043–1049 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mansky, L. M. & Temin, H. M. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J. Virol. 69, 5087–5094 (1995).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Abram, M. E., Ferris, A. L., Shao, W., Alvord, W. G. & Hughes, S. H. Nature, position, and frequency of mutations made in a single cycle of HIV-1 replication. J. Virol. 84, 9864–9878 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sebastian-Martin, A., Barrioluengo, V. & Menendez-Arias, L. Transcriptional inaccuracy threshold attenuates differences in RNA-dependent DNA synthesis fidelity between retroviral reverse transcriptases. Sci. Rep. 8, 627 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, W. S. & Hughes, S. H. HIV-1 reverse transcription. Cold Spring Harbor Perspect. Med. 2 https://doi.org/10.1101/cshperspect.a006882 (2012).

  • Hwang, C. K., Svarovskaia, E. S. & Pathak, V. K. Dynamic copy choice: steady state between murine leukemia virus polymerase and polymerase-dependent RNase H activity determines frequency of in vivo template switching. Proc. Natl. Acad. Sci. USA 98, 12209–12214 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Svarovskaia, E. S., Delviks, K. A., Hwang, C. K. & Pathak, V. K. Structural determinants of murine leukemia virus reverse transcriptase that affect the frequency of template switching. J. Virol. 74, 7171–7178 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Roda, R. H. et al. Strand transfer occurs in retroviruses by a pause-initiated two-step mechanism. J. Biol. Chem. 277, 46900–46911 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jetzt, A. E. et al. High rate of recombination throughout the human immunodeficiency virus type 1 genome. J. Virol. 74, 1234–1240 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schlub, T. E., Smyth, R. P., Grimm, A. J., Mak, J. & Davenport, M. P. Accurately measuring recombination between closely related HIV-1 genomes. PLoS Comput. Biol. 6, e1000766 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhuang, J. et al. Human immunodeficiency virus type 1 recombination: rate, fidelity, and putative hot spots. J. Virol. 76, 11273–11282 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cromer, D., Grimm, A. J., Schlub, T. E., Mak, J. & Davenport, M. P. Estimating the in-vivo HIV template switching and recombination rate. AIDS 30, 185–192 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mangeat, B. et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424, 99–103 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lecossier, D., Bouchonnet, F., Clavel, F. & Hance, A. J. Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science 300, 1112 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, H. et al. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature 424, 94–98 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Suspene, R. et al. APOBEC3G is a single-stranded DNA cytidine deaminase and functions independently of HIV reverse transcriptase. Nucleic Acids Res. 32, 2421–2429 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pace, C. et al. Population level analysis of human immunodeficiency virus type 1 hypermutation and its relationship with APOBEC3G and vif genetic variation. J. Virol. 80, 9259–9269 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sheehy, A. M., Gaddis, N. C., Choi, J. D. & Malim, M. H. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418, 646–650 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Imamichi, H. et al. Defective HIV-1 proviruses produce viral proteins. Proc. Natl. Acad. Sci. USA 117, 3704–3710 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Singh, K. et al. Long-term persistence of transcriptionally active ‘defective’ HIV-1 proviruses: implications for persistent immune activation during antiretroviral therapy. AIDS 37, 2119–2130 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scrimieri, F. et al. Transcriptionally active defective HIV-1 Proviruses and their association with immunological nonresponse to antiretroviral therapy. J. Infect. Dis. 229, 1786–1790 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dube, M. et al. Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4(+) and CD8(+) T cells. Cell Host Microbe 31, 1507–1522.e1505 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pollack, R. A. et al. Defective HIV-1 Proviruses are expressed and can be recognized by Cytotoxic T Lymphocytes, which shape the proviral landscape. Cell Host Microbe 21, 494–506.e494 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lambrechts, L. et al. HIV-PULSE: a long-read sequencing assay for high-throughput near full-length HIV-1 proviral genome characterization. Nucleic Acids Res. 51, e102 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pinzone, M. R. et al. Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion. Nat. Commun. 10, 728 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liang, B. et al. A comparison of parallel pyrosequencing and sanger clone-based sequencing and its impact on the characterization of the genetic diversity of HIV-1. PloS one 6, e26745 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cho, Y. K., Jung, Y., Sung, H. & Joo, C. H. Frequent Genetic Defects in the HIV-1 5’ LTR/gag Gene in Hemophiliacs Treated with Korean Red Ginseng: Decreased Detection of Genetic Defects by Highly Active Antiretroviral Therapy. J. Ginseng Res. 35, 413–420 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Council, O. D. et al. The persistent pool of HIV-1-infected cells is formed episodically during untreated infection. J. Virol. e0097924 (2024).

  • Lu, C. L. et al. Relationship between intact HIV-1 proviruses in circulating CD4(+) T cells and rebound viruses emerging during treatment interruption. Proc. Natl. Acad. Sci. USA 115, E11341–E11348 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yoshinaga, T. & Fujiwara, T. Different roles of bases within the integration signal sequence of human immunodeficiency virus type 1 in vitro. J. Virol. 69, 3233–3236 (1995).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Esposito, D. & Craigie, R. Sequence specificity of viral end DNA binding by HIV-1 integrase reveals critical regions for protein-DNA interaction. EMBO J. 17, 5832–5843 (1998).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vink, C., Van Gent, D., Elgersma, Y. & Plasterk, R. Human immunodeficiency virus integrase protein requires a subterminal position of its viral DNA recognition sequence for efficient cleavage. J. Virol. 65, 4636–4644 (1991).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oh, J., Chang, K. W. & Hughes, S. H. Integration of rous sarcoma virus DNA: a CA dinucleotide is not required for integration of the U3 end of viral DNA. J. Virol. 82, 11480–11483 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Joseph, K. W. et al. Deep sequencing analysis of individual HIV-1 proviruses reveals frequent asymmetric long terminal repeats. J. Virol. 96, e00122–e00122 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pfeiffer, J. K. & Telesnitsky, A. Effects of limiting homology at the site of intermolecular recombinogenic template switching during Moloney murine leukemia virus replication. J. Virol. 75, 11263–11274 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Berkhout, B., van Wamel, J. & Klaver, B. Requirements for DNA strand transfer during reverse transcription in mutant HIV-1 virions. J. Mol. Biol. 252, 59–69 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • An, W. & Telesnitsky, A. Effects of varying sequence similarity on the frequency of repeat deletion during reverse transcription of a human immunodeficiency virus type 1 vector. J. Virol. 76, 7897–7902 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dang, Q. & Hu, W. S. Effects of homology length in the repeat region on minus-strand DNA transfer and retroviral replication. J. Virol. 75, 809–820 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hardy, J. et al. Reverse transcription of plasma-derived HIV-1 RNA generates multiple artifacts through tRNA(Lys-3)-priming. Microbiol. Spectr. 12, e0387223 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Lanciault, C. & Champoux, J. J. Pausing during reverse transcription increases the rate of retroviral recombination. J. Virol. 80, 2483–2494 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moumen, A. et al. Evidence for a mechanism of recombination during reverse transcription dependent on the structure of the acceptor RNA. J. Biol. Chem. 278, 15973–15982 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Watts, J. M. et al. Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 460, 711–716 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Piekna-Przybylska, D., Sharma, G. & Bambara, R. A. Mechanism of HIV-1 RNA dimerization in the central region of the genome and significance for viral evolution. J. Biol. Chem. 288, 24140–24150 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shen, W., Gao, L., Balakrishnan, M. & Bambara, R. A. A recombination hot spot in HIV-1 contains guanosine runs that can form a G-quartet structure and promote strand transfer in vitro. J. Biol. Chem. 284, 33883–33893 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harpster, C., Boyle, E., Musier-Forsyth, K. & Kankia, B. HIV-1 genomic RNA U3 region forms a stable quadruplex-hairpin structure. Biophys. Chem. 272, 106567 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fukuda, H. et al. Cooperative methylation of human tRNA3Lys at positions A58 and U54 drives the early and late steps of HIV-1 replication. Nucleic Acids Res. 49, 11855–11867 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, T., Guo, J., Bess, J., Henderson, L. E. & Levin, J. G. Molecular requirements for human immunodeficiency virus type 1 plus-strand transfer: analysis in reconstituted and endogenous reverse transcription systems. J. Virol. 73, 4794–4805 (1999).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jain, V. et al. Antiretroviral therapy initiated within 6 months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size. J. Infect. Dis. 208, 1202–1211 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Buzon, M. J. et al. Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells. J. Virol. 88, 10056–10065 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Peluso, M. J. et al. Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy. JCI Insight 5 https://doi.org/10.1172/jci.insight.132997 (2020).

  • Gandhi, R. T. et al. Selective decay of intact HIV-1 Proviral DNA on antiretroviral therapy. J. Infect. Dis. 223, 225–233 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Anderson, E. M. et al. Dynamic shifts in the HIV proviral landscape during long term combination antiretroviral therapy: implications for persistence and control of HIV Infections. Viruses 12 https://doi.org/10.3390/v12020136 (2020).

  • Lian, X. et al. Progressive transformation of the HIV-1 reservoir cell profile over two decades of antiviral therapy. Cell Host Microbe 31, 83–96.e85 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wiegand, A. et al. Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART. Proc. Natl. Acad. Sci. 114, E3659–E3668 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kuniholm, J., Coote, C. & Henderson, A. J. Defective HIV-1 genomes and their potential impact on HIV pathogenesis. Retrovirology 19, 13 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Avettand-Fenoel, V. et al. LTR real-time PCR for HIV-1 DNA quantitation in blood cells for early diagnosis in infants born to seropositive mothers treated in the HAART area (ANRS CO 01). J. Med. Virol. 81, 217–223 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Source link

    Get RawNews Daily

    Stay informed with our RawNews daily newsletter email

    Dr. Dre Finally Sells Longtime Malibu Beach House for $16.5 Million

    FTSE 100 drops sharply — are serious bargains emerging in UK stocks?

    Crude oil futures settle up $3.87 and $94.77

    President Trump says oil price surge ‘small price to pay’ for peace