Council Olivia D, Tyers Lynn, Moeser Matthew, Sondgeroth Amy, Spielvogel Ean, Richardson Brian D, Doolabh Deelan, Zhou Shuntai, Emery Ann, Archin Nancie M, Shook-Sa Bonnie, Margolis David M, Abdool Karim Salim S, Kosakovsky Pond Sergei, Garrett Nigel, Abrahams Melissa-Rose, Joseph Sarah B, Williamson Carolyn, Swanstrom Ronald
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Division of Medical Virology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Rondebosch, Western Cape, South Africa.
J Virol. 2025 Feb 25;99(2):e0097924. doi: 10.1128/jvi.00979-24. Epub 2024 Dec 26.
Previous studies have shown that the majority of long-lived cells harboring persistent HIV-1 proviral genomes originates from viruses circulating in the year prior to antiretroviral therapy (ART) initiation, but a smaller proportion originates from viruses circulating much earlier in untreated infection. These observations suggest that discrete biological factors influence the entry and persistence of viruses into the persistent proviral pool, and there may be periods earlier in untreated infection with increased seeding. Therefore, we examined the timing of formation of the long-lived pool of infected cells that persists during ART in seven women (after a median of 5.1 years of suppressive ART) by comparing the phylogenetic distance between unique 3' half genome on-ART proviral sequences and longitudinally sampled pre-ART viral RNA sequences, focusing on the period >1 year prior to ART initiation (i.e., the "early" proviral pool). We constructed models of continuous entry into the persistent proviral pool prior to ART initiation and analyzed the fit of our experimentally derived data to these models. We found that the pattern of persistent proviral pool formation in five of seven participants is incongruent with a model of continuous entry, implying that persistent proviral pool formation can occur episodically during untreated infection. Notably, increased entry into the persistent proviral pool was not universally observed during acute infection, and the timing of enhanced early entry differed across the participants.IMPORTANCECells harboring HIV-1 proviruses that persist on antiretroviral therapy (ART) constitute the main barrier to an HIV-1 cure. Recent work has elucidated that the majority of persisting proviruses harbor HIV-1 variants circulating near the time of ART initiation, whether the proviruses are intact or defective, though a portion forms earlier in untreated infection. We examined the formation of the "early-forming" persistent proviral pool and found that in 5/7 participants, persistent proviral pool formation was episodic, rather than continuous, suggesting that there are host/biological factors that periodically enhance the formation of the persistent proviral pool. Further characterization of these factors will aid in the development of methods to abrogate their effect, thereby reducing the size of the persistent proviral pool.
先前的研究表明，大多数携带持续性HIV-1前病毒基因组的长寿细胞起源于抗逆转录病毒疗法（ART）开始前一年流行的病毒，但较小比例起源于未经治疗感染中更早流行的病毒。这些观察结果表明，离散的生物学因素会影响病毒进入并持续存在于持续性前病毒库中，并且在未经治疗的感染早期可能存在播种增加的时期。因此，我们通过比较ART期间持续存在的受感染细胞长寿库形成的时间，这七名女性（在接受中位数为5.1年的抑制性ART后）通过比较ART前病毒序列上独特的3'半基因组与纵向采样的ART前病毒RNA序列之间的系统发育距离，重点关注ART开始前>1年的时期（即“早期”前病毒库）。我们构建了ART开始前持续进入持续性前病毒库的模型，并分析了我们实验得出的数据与这些模型的拟合情况。我们发现，七名参与者中有五名的持续性前病毒库形成模式与持续进入模型不一致，这意味着持续性前病毒库的形成可能在未经治疗的感染期间偶发发生。值得注意的是，在急性感染期间并非普遍观察到进入持续性前病毒库的增加，并且不同参与者早期进入增加的时间也不同。
携带在抗逆转录病毒疗法（ART）中持续存在的HIV-1前病毒的细胞构成了治愈HIV-1的主要障碍。最近的研究表明，大多数持续存在的前病毒携带在ART开始时附近流行的HIV-1变体，无论前病毒是完整的还是有缺陷的，尽管有一部分在未经治疗的感染中形成得更早。我们研究了“早期形成”的持续性前病毒库的形成，发现5/7的参与者中，持续性前病毒库的形成是偶发性的，而不是连续性的，这表明存在宿主/生物学因素会周期性地增强持续性前病毒库的形成。对这些因素的进一步表征将有助于开发消除其影响的方法，从而减少持续性前病毒库的大小。
