Complex decay dynamics of HIV virions, intact and defective proviruses, and 2LTR circles following initiation of antiretroviral therapy

White, Jennifer A.; Simonetti, Francesco R.; Beg, Subul; McMyn, Natalie F; Dai, Weiwei; Bachmann, Niklas; Lai, Jun; Ford, William C; Bunch, Christina; Jones, Joyce; Ribeiro, Ruy M.; Perelson, Alan S.; Siliciano, Janet D.; Siliciano, Robert F.

doi:10.1073/pnas.2120326119

Cited by 56 publications

(80 citation statements)

References 91 publications

(186 reference statements)

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“…Instead, our estimate of the mean lifespan of a productively infected cell (1/ δ ) is effectively a weighted average of the mean lifespans of all productively-infected subpopulations. Our estimate (16 days) is consistent with the median lifespan of 17 days we estimated previously from the VL dynamics in a subset of these infants who achieved suppression [ 4 ], and roughly in line with a recent estimate of the loss rate of infected CD4 T cells with intact proviruses [ 35 ]. Second, we do not explicitly model the dynamics of latently infected cells as they are not directly observed.…”

Section: Discussionsupporting

confidence: 91%

Healthy dynamics of CD4 T cells may drive HIV resurgence in perinatally-infected infants on antiretroviral therapy

Strehlau¹,

Shiau²,

Abrams³

et al. 2022

PLoS Pathog

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In 2019 there were 490,000 children under five living with HIV. Understanding the dynamics of HIV suppression and rebound in this age group is crucial to optimizing treatment strategies and increasing the likelihood of infants achieving and sustaining viral suppression. Here we studied data from a cohort of 122 perinatally-infected infants who initiated antiretroviral treatment (ART) early after birth and were followed for up to four years. These data included longitudinal measurements of viral load (VL) and CD4 T cell numbers, together with information regarding treatment adherence. We previously showed that the dynamics of HIV decline in 53 of these infants who suppressed VL within one year were similar to those in adults. However, in extending our analysis to all 122 infants, we find that a deterministic model of HIV infection in adults cannot explain the full diversity in infant trajectories. We therefore adapt this model to include imperfect ART adherence and natural CD4 T cell decline and reconstitution processes in infants. We find that individual variation in both processes must be included to obtain the best fits. We also find that infants with faster rates of CD4 reconstitution on ART were more likely to experience resurgences in VL. Overall, our findings highlight the importance of combining mathematical modeling with clinical data to disentangle the role of natural immune processes and viral dynamics during HIV infection.

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Section: Discussionsupporting

confidence: 91%

Healthy dynamics of CD4 T cells may drive HIV resurgence in perinatally-infected infants on antiretroviral therapy

Strehlau¹,

Shiau²,

Abrams³

et al. 2022

PLoS Pathog

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“…Even more concerning is the fact that for two participants (P10 and P11), no intact proviruses were detected at the first time point (1–9 months after ART initiation). Although sampling issues or a very low frequency of intact provirus could explain these results, previous studies have shown that intact proviruses make up the majority of proviruses during early ART suppression [ 40 ], and large-scale studies with the IPDA rarely identify subjects for whom no intact proviruses are present [ 33 ]. Multiplexing of four qPCRs could reduce the sensitivity of individual primer-probe sets that have a dim fluorophore and lower efficiency.…”

Section: Discussionmentioning

confidence: 99%

Measuring the latent reservoir for HIV-1: Quantification bias in near full-length genome sequencing methods

et al. 2022

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Antiretroviral therapy (ART) effectively inhibits HIV-1 replication but is not curative due to the persistence of a latent viral reservoir in resting CD4+ T cells. This reservoir is a major barrier to cure. Sequencing studies have revealed that the population of proviruses persisting in ART-treated individuals is dominated by defective proviruses that cannot give rise to viral rebound due to fatal defects including large deletions and APOBEC3-mediated hypermutation. Near full genome sequencing (nFGS) of individual proviruses is used in reservoir assays to provide an estimate of the fraction of proviruses that are intact. nFGS methods rely on a long-distance outer PCR capturing most (~9 kb) of the genome, followed by nested inner PCRs. The outer PCR is carried out at limit dilution, and interpretation of the results is based on the assumption that all proviruses are quantitatively captured. Here, we evaluate nFGS methods using the intact proviral DNA assay (IPDA), a multiplex digital droplet PCR assay that quantitates intact and defective proviruses with single molecule sensitivity using only short, highly efficient amplicons. We analyzed proviral templates of known sequence to avoid the additional complication of sequence polymorphism. With the IPDA, we quantitated molecular yields at each step of nFGS methods. We demonstrate that nFGS methods are inefficient and miss ~70% of full-length proviruses due to amplification failure at the initial outer PCR step. In contrast, proviruses with large internal deletions encompassing 70% of the genome can be quantitatively amplified under the same conditions. Accurate measurement of the latent reservoir of HIV-1 is essential for evaluating the efficacy of cure strategies, and the bias against full length proviruses in nFGS methods must be considered.

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“…Intact HIV-1 proviruses which have the potential to support viral rebound, have been estimated to represent 2-5% of the persistent provirus pool as measured in peripheral blood mononuclear cells (PBMCs) [8,9]. Longitudinal tracking of intact provirus sequences in PLWH before and after ART initiation suggests that most of the latent intact HIV reservoir has been seeded at the time of ART initiation and there is no additional infection post-ART [30][31][32], although ART initiation has been suggested to shape the latent reservoir [30][31][32]. It has also been suggested that the virus circulating at the time of ART initiation is overrepresented in the reservoir [30].…”

Section: Defective Hiv-1 Genomes Dominate the Proviral Landscapementioning

confidence: 99%

Defective HIV-1 genomes and their potential impact on HIV pathogenesis

Henderson

2022

Retrovirology

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Defective HIV-1 proviruses represent a population of viral genomes that are selected for by immune pressures, and clonally expanded to dominate the persistent HIV-1 proviral genome landscape. There are examples of RNA and protein expression from these compromised genomes which are generated by a variety of mechanisms. Despite the evidence that these proviruses are transcribed and translated, their role in HIV pathogenesis has not been fully explored. The potential for these genomes to participate in immune stimulation is particularly relevant considering the accumulation of cells harboring these defective proviruses over the course of antiretroviral therapy in people living with HIV. The expression of defective proviruses in different cells and tissues could drive innate sensing mechanisms and inflammation. They may also alter antiviral T cell responses and myeloid cell functions that directly contribute to HIV-1 associated chronic comorbidities. Understanding the impact of these defective proviruses needs to be considered as we advance cure strategies that focus on targeting the diverse population of HIV-1 proviral genomes. Graphical abstract

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Complex decay dynamics of HIV virions, intact and defective proviruses, and 2LTR circles following initiation of antiretroviral therapy

Cited by 56 publications

References 91 publications

Healthy dynamics of CD4 T cells may drive HIV resurgence in perinatally-infected infants on antiretroviral therapy

Healthy dynamics of CD4 T cells may drive HIV resurgence in perinatally-infected infants on antiretroviral therapy

Measuring the latent reservoir for HIV-1: Quantification bias in near full-length genome sequencing methods

Defective HIV-1 genomes and their potential impact on HIV pathogenesis

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