Dataset Information

Brief Report: Toll-like Receptor 9-1635A/G Polymorphism Is Associated With HIV-1 Rebound After Four Weeks of Interruption of Antiretroviral Therapy.

ABSTRACT:

Objectives

This study aims to analyze the association of the presence of common polymorphisms [single nucleotide polymorphisms (SNPs)] on Toll-like receptors (TLRs), such as TLR9-1635A/G, TLR2-1892A/C, TLR2-2258G/A, TLR4-899A/G, and TLR4-1196C/T, with the viral rebound after stopping antiretroviral treatment (ART). CCR5-Δ32 deletion and HLA-A/HLA-B alleles were also analyzed.

Design

Interruption of ART may be required to investigate the outcome of strategies aimed to achieve drug-free HIV remission or cure. However, interruption of ART is currently not indicated. This was a retrospective longitudinal study that included 57 long-term suppressed HIV-1-infected individuals.

Methods

TLR SNPs were detected by real-time polymerase chain reaction (PCR). CCR5-Δ32 was analyzed by conventional PCR and HLA-A and HLA-B alleles by PCR-SSOP Luminex.

Results

HIV-1 RNA rebound at week 4 after treatment interruption positively correlated with pre-ART HIV-1 load (P = 0.025). The TLR9-1635AA genotype was independently associated with a higher HIV-1 rebound compared with those with AG + GG genotype (multivariate stepwise regression analysis, P = 0.004). Women had lower HIV-1 RNA load both at rebound and during the 72 weeks of follow-up compared with men (P < 0.05 at all time-points), whereas CD4 nadir and CD4 count set-point were similar according to sex. The pre-ART viral load was independently associated with the viral set-point (P = 0.001), whereas the presence of the HLA-A01 allele (P = 0.027) and the CD4 nadir (P = 0.001) were associated with the CD4 count set-point.

Conclusions

The association of the TLR9-1635AA genotype with a higher HIV-1 rebound suggests that this SNP may affect the results from strategies requiring interruption of ART aimed to cure HIV-1 infection.

SUBMITTER: Vallejo A

PROVIDER: S-EPMC10019827 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Brief Report: Toll-like Receptor 9-1635A/G Polymorphism Is Associated With HIV-1 Rebound After Four Weeks of Interruption of Antiretroviral Therapy.

Vallejo Alejandro A Molina-Pinelo Sonia S de Felipe Beatriz B Abad-Fernández María M González-Escribano María Francisca MF Leal Manuel M Soriano-Sarabia Natalia N

Journal of acquired immune deficiency syndromes (1999) 20201001 2

<h4>Objectives</h4>This study aims to analyze the association of the presence of common polymorphisms [single nucleotide polymorphisms (SNPs)] on Toll-like receptors (TLRs), such as TLR9-1635A/G, TLR2-1892A/C, TLR2-2258G/A, TLR4-899A/G, and TLR4-1196C/T, with the viral rebound after stopping antiretroviral treatment (ART). CCR5-Δ32 deletion and HLA-A/HLA-B alleles were also analyzed.<h4>Design</h4>Interruption of ART may be required to investigate the outcome of strategies aimed to achieve drug- ...[more]

PMID: 32658127

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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: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

Brief Report: Toll-like Receptor 9-1635A/G Polymorphism Is Associated With HIV-1 Rebound After Four Weeks of Interruption of Antiretroviral Therapy.

Objectives

Design

Methods

Results

Conclusions

Publications

Brief Report: Toll-like Receptor 9-1635A/G Polymorphism Is Associated With HIV-1 Rebound After Four Weeks of Interruption of Antiretroviral Therapy.

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