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Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion.

ABSTRACT: Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.

SUBMITTER: Phan T

PROVIDER: S-EPMC11309407 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion.

Phan Tin T Conway Jessica M JM Pagane Nicole N Kreig Jasmine J Sambaturu Narmada N Iyaniwura Sarafa S Li Jonathan Z JZ Ribeiro Ruy M RM Ke Ruian R Perelson Alan S AS

PLoS pathogens 20240729 7

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to c ...[more]

PMID: 39074163

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Project description:If strategies currently in development succeed in eradicating HIV reservoirs in peripheral blood and lymphoid tissues, residual sources of virus may remain in anatomic compartments. Paired blood and semen samples were collected from 12 individuals enrolled in a randomized, double-blind, placebo-controlled therapeutic vaccine clinical trial in people with HIV (PWH) who began antiretroviral therapy (ART) during acute or early infection (ClinicalTrials registration no. NCT01859325). After the week 56 visit (postintervention), all participants interrupted ART. At the first available time points after viral rebound, we sequenced HIV-1 env (C2-V3), gag (p24), and pol (reverse transcriptase) regions amplified from cell-free HIV RNA in blood and seminal plasma using the MiSeq Illumina platform. Comprehensive sequence and phylogenetic analyses were performed to evaluate viral population structure, compartmentalization, and viral diversity in blood and seminal plasma. Compared to that in blood, HIV RNA rebound in semen occurred significantly later (median of 66 versus 42 days post-ART interruption, P < 0.01) and reached lower levels (median 164 versus 16,090 copies/ml, P < 0.01). Three of five participants with available sequencing data presented compartmentalized viral rebound between blood and semen in one HIV coding region. Despite early ART initiation, HIV RNA molecular diversity was higher in semen than in blood in all three coding regions for most participants. Higher HIV RNA molecular diversity in the genital tract (compared to that in blood plasma) and evidence of compartmentalization illustrate the distinct evolutionary dynamics between these two compartments after ART interruption. Future research should evaluate whether the genital compartment might contribute to viral rebound in some PWH interrupting ART.IMPORTANCE To cure HIV, we likely need to target the reservoirs in all anatomic compartments. Here, we used sophisticated statistical and phylogenetic methods to analyze blood and semen samples collected from 12 persons with HIV who began antiretroviral therapy (ART) during very early HIV infection and who interrupted their ART as part of a clinical trial. First, we found that HIV RNA rebound in semen occurred significantly later and reached lower levels than in blood. Second, we found that the virus in semen was genetically different in some participants compared to that in blood. Finally, we found increased HIV RNA molecular diversity in semen compared to that in blood in almost all study participants. These data suggest that the HIV RNA populations emerging from the genital compartment after ART interruption might not be the same as those emerging from blood plasma. Future research should evaluate whether the genital compartment might contribute to viral rebound in some people with HIV (PWH) interrupting ART.

Project description:Natural Killer (NK) cells play a key role in controlling HIV replication, with potential downstream impact on the size of the HIV reservoir and likelihood of viral rebound after antiretroviral therapy (ART) cessation. It is therefore important to understand how primary HIV infection (PHI) disrupts NK cell function, and how these functions are restored by early ART. We examined the impact of commencing ART during PHI on phenotypic and functional NK cell markers at treatment initiation (baseline), 3 months, 1 year, and 2 years in seven well-characterised participants in comparison to HIV seronegative volunteers. We then examined how those NK cell properties differentially impacted by ART related to time to viral rebound and HIV DNA levels in 44 individuals from the SPARTAC trial who stopped ART after 48 weeks treatment, started during PHI. NK cell markers that were significantly different between the seven people with HIV (PWH) treated for 2 years and HIV uninfected individuals included NKG2C levels in CD56dim NK cells, Tim-3 expression in CD56bright NK cells, IFN-γ expressed by CD56dim NK cells after IL-12/IL-18 stimulation and the fraction of Eomes-/T-bet+ in CD56dim and CD56bright NK cells. When exploring time to viral rebound after stopping ART among the 44 SPARTAC participants, no single NK phenotypic marker correlated with control. Higher levels of IL-12/IL-18 mediated NK cell degranulation at baseline were associated with longer times to viral rebound after treatment interruption (P=0.028). Additionally, we found higher fractions of CD56dim NK cells in individuals with lower levels of HIV DNA (P=0.048). NKG2A and NKp30 levels in CD56neg NK cells were higher in patients with lower HIV DNA levels (p=0.00174, r=-0.49 and p=0.03, r= -0.327, respectively) while CD27 levels were higher in those with higher levels of HIV DNA (p=0.026). These data show NK cell functions are heterogeneously impacted by HIV infection with a mixed picture of resolution on ART, and that while NK cells may affect HIV DNA levels and time to viral rebound, no single NK cell marker defined delayed viral rebound.

Project description:Monitoring the efficacy of novel reservoir-reducing treatments for HIV is challenging. The limited ability to sample and quantify latent infection means that supervised antiretroviral therapy (ART) interruption studies are generally required. Here we introduce a set of mathematical and statistical modeling tools to aid in the design and interpretation of ART-interruption trials. We show how the likely size of the remaining reservoir can be updated in real-time as patients continue off treatment, by combining the output of laboratory assays with insights from models of reservoir dynamics and rebound. We design an optimal schedule for viral load sampling during interruption, whereby the frequency of follow-up can be decreased as patients continue off ART without rebound. While this scheme can minimize costs when the chance of rebound between visits is low, we find that the reservoir will be almost completely reseeded before rebound is detected unless sampling occurs at least every two weeks and the most sensitive viral load assays are used. We use simulated data to predict the clinical trial size needed to estimate treatment effects in the face of highly variable patient outcomes and imperfect reservoir assays. Our findings suggest that large numbers of patients-between 40 and 150-will be necessary to reliably estimate the reservoir-reducing potential of a new therapy and to compare this across interventions. As an example, we apply these methods to the two "Boston patients", recipients of allogeneic hematopoietic stem cell transplants who experienced large reductions in latent infection and underwent ART-interruption. We argue that the timing of viral rebound was not particularly surprising given the information available before treatment cessation. Additionally, we show how other clinical data can be used to estimate the relative contribution that remaining HIV+ cells in the recipient versus newly infected cells from the donor made to the residual reservoir that eventually caused rebound. Together, these tools will aid HIV researchers in the evaluating new potentially-curative strategies that target the latent reservoir.

Dataset Information

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion.

Publications

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion.

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