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. Author manuscript; available in PMC: 2024 May 1.
Published in final edited form as: AIDS. 2023 Jan 30;37(6):871–876. doi: 10.1097/QAD.0000000000003499

Predictors of intact HIV DNA levels among children in Kenya

Jillian NEARY 1, Carolyn S FISH 2, Noah AJ CASSIDY 2, Dalton WAMALWA 3, Agnes LANGAT 3, Evelyn NGUGI 3, Sarah BENKI-NUGENT 4, Hellen MORAA 3, Barbra A RICHARDSON 2,4,5, Irene NJUGUNA 4,6, Jennifer A SLYKER 1,4, Dara A LEHMAN 2,4,*, Grace JOHN-STEWART 1,4,7,8,*
PMCID: PMC10079608  NIHMSID: NIHMS1869656  PMID: 36723512

Abstract

Objective:

We determined predictors of both intact (estimate of replication-competent) and total (intact and defective) HIV DNA in the reservoir among children with HIV.

Design:

HIV DNA in the reservoir was quantified longitudinally in children who initiated antiretroviral therapy (ART) at <1 year of age using a novel cross-subtype intact proviral DNA assay that measures both intact and total proviruses. Quantitative PCR was used to measure pre-ART cytomegalovirus (CMV) viral load. Linear mixed effects models were used to determine predictors of intact and total HIV DNA levels (log10copies/million).

Results:

Among 65 children, median age at ART initiation was 5 months and median follow-up was 5.2 years; 86% of children had CMV viremia pre-ART. Lower pre-ART CD4 percent (adjusted relative risk [aRR]: 0.87, 95% confidence intervals [95%CI]: 0.79–0.97; p=0.009) and higher HIV RNA (aRR: 1.21, 95%CI: 1.06–1.39; p=0.004) predicted higher levels of total HIV DNA during ART. Pre-ART CD4 percent (aRR: 0.76, 95%CI: 0.65–0.89; p<0.001), CMV viral load (aRR: 1.16, 95%CI: 1.01–1.34; p=0,041), and first line protease inhibitor-based regimens compared to non-nucleoside reverse transcriptase-based regimens (aRR: 1.36, 95%CI: 1.04–1.77; p=0,025) predicted higher levels of intact HIV DNA.

Conclusion:

Pre-ART immunosuppression, first-line ART regimen, and CMV viral load may influence establishment and sustainment of intact HIV DNA in the reservoir.

Keywords: intact DNA, HIV DNA, HIV, pediatric, HIV reservoir, cytomegalovirus

INTRODUCTION

HIV proviruses persist in long-lived immune cells in the HIV reservoir after ART has cleared replicating virus. Over 90% of HIV proviruses in the reservoir are defective and not replication-competent.[1] However, replication-competent proviruses retain the ability to reactivate, resulting in rebound viremia upon ART interruption. Most pediatric HIV reservoir studies have evaluated total HIV in the reservoir [2–6] which include both replication-competent and defective proviruses. Only a few pediatric studies have estimated cells with replication-competent HIV DNA that can be induced ex vivo using the quantitative viral outgrowth assay (QVOA),[7,8] however QVOA underestimates the size of the reservoir.[9] These studies found that larger replication-competent HIV levels at 24 weeks post-ART was associated with replication-competent reservoir size at 2 years post-ART initiation.[7,8]

Recent PCR-based intact proviral DNA assays, more accurately estimate the replication-competent reservoir by distinguishing full-length (intact) proviruses from those with large deletions (defective).[9–11] Few studies have investigated intact HIV DNA in children. One study in Botswana found that very early ART initiation was associated with smaller intact reservoir size.[12] Identifying predictors of intact HIV DNA, which reflect replication-competent proviurses,[1,9] can inform HIV cure strategies. We assessed predictors of intact and total (intact plus defective) HIV DNA levels in children with HIV who started ART during the first year of life.

METHODS

Children with HIV who initiated ART at <1 year of age were enrolled into the OPH study from September 2007 to August 2010 at Kenyatta National Hospital in Nairobi, Kenya. OPH was a randomized controlled trial comparing treatment interruption and continued treatment following 24 months of ART (NCT00428116).[13] HIV DNA was assessed at timepoints with HIV RNA <150 copies/ml after 12 months of ART. The study was approved by the University of Washington and Fred Hutchinson Cancer Center Institutional Review Boards and Kenyatta National Hospital Ethics and Research Committee. Caregivers provided written informed consent for their children’s participation.

HIV RNA was previously measured in longitudinal plasma samples using the Gen-Probe HIV RNA assay, lower limit of detection of 150 copies/ml.[13] Quantitative PCR was used to measure cytomegalovirus (CMV) viral loads in plasma as previously described.[3] The lower limit of detection was 50 copies/ml for CMV DNA. Undetectable HIV RNA and CMV DNA were designated a value of half the limit of detection.

Total and intact HIV proviruses were quantified using the cross-subtype intact proviral DNA assay (CS-IPDA) on DNA from cryopreserved peripheral blood mononuclear cells (PBMCs).[10] PBMC samples were selected from timepoints 12, 24, 42, 60, and 96 months post-ART initiation known to have virally suppressed HIV RNA levels (<150 copies/ml). CS-IPDA was performed in duplicate, with additional replicates performed on samples with no intact HIV proviruses detected until either intact proviruses were detected or a minimum of 105 cells were interrogated. Both total and intact HIV DNA levels are determined for samples with DNA shearing rates of <40% as measured by the RPP30 reference assay.[10] Data from samples with >40% DNA shearing (n=6) is limited to total but not intact HIV DNA due to shearing. In this analysis, all samples have detectable total HIV DNA. The CS-IPDA is able to detect a single copy of intact HIV DNA,[10] and thus, samples with undetectable intact HIV DNA were set to 0.5 copies over the number of cells interrogated normalized to 106 cells. In a prior analysis, <1% of sequences were incorrectly classified as defective when they were intact, suggesting that underestimating intact due to sequence diversity is rare.[10]

Potential predictors of HIV DNA levels included infant sex, pre-ART CD4 percent (continuous, assessed per 10% change); pre-ART HIV RNA (log10 copies/ml); first-line ART regimen (protease inhibitors [PI]/non-nucleoside reverse transcriptase inhibitors [NNRTI]) among children who did and did not switch regimens; and pre-ART CMV viremia (log10DNA copies/ml). Inverse probability weighting was conducted to account for differential missingness by age at enrollment into the study. All models adjusted for time on ART at HIV DNA measurement, age at ART initiation, and randomization arm. Linear mixed effects models were used to determine predictors of total and intact HIV DNA levels (log10copies/million T cells). Linear mixed effects models are commonly used to analyze correlated data; we used these models to account for nonindependence of longitudinal HIV DNA measurements within individuals.[14] Adjustment variables were considered collinear if the standard error changed >10% when the variable was removed from the model. Stata version 17.0 (Stata Corporation, College Station, Texas USA) was used for all analyses.

RESULTS

Sixty-five children had PBMCs available during times of HIV RNA suppression in which total HIV DNA was measured. Of those, 59 children had HIV DNA samples with minimal shearing (0.2–22%) allowing for quantification of intact HIV DNA without risk of underestimation due to DNA shearing. Median number of HIV DNA measurements per child was 2 (IQR: 1, 3; Table 1). Half of the children were male, 45% (n=29) had a PI-based first-line regimen, and 26% (n=17) were randomized at 24 months post-ART to a short treatment interruption (median 4.3 months). Median age at ART initiation was 5.0 (IQR: 4.2–8.1) months and median follow-up time was 5.2 (IQR: 3.3–8.0) years. Most (86%) children had detectable CMV viremia pre-ART with a median CMV viral load of 3.6 (IQR: 2.9–4.0) log10copies/ml. Total and intact HIV DNA decayed over time on ART, with a median total and intact HIV DNA of 3.1 (IQR: 2.8–3.3) and 2.2 (IQR: 1.1–2.3) log10copies/million T cells, respectively, at 1 year post-ART initiation, which decayed to 2.8 (IQR: 2.5–3.0) and 0.9 (IQR: 0.6–1.3) log10copies/million T cells, respectively, by 8 years post-ART (Supplementary Figure 1).

Table 1.

Child characteristics

Children with Total HIV DNA Children with Intact HIV DNA
N Median (IQR) or n(%) N Median (IQR) or n(%)
Age at ART initiation (months) 65 5.0 (4.2, 8.1) 59 4.9 (4.2, 7.9)
Male (ref: Female) 65 34 (52) 59 31 (53)
Time followed (time to last DNA measurement in years) 65 5.2 (3.3, 8.0) 59 5.2 (3.4, 8.0)
Pre-ART CD4% (every 10% change) 65 1.9 (1.4, 2.5) 59 1.8 (1.4, 2.4)
Pre-ART HIV RNA (log10copies/ml) 43 6.6 (6.0, 7.0) 39 6.6 (6.0, 7.0)
First line PI-based Regimen (ref: NNRTI)
 Among all children 64 29 (45) 58 25 (43)
 Among children with no switches 41 25 (61) 38 22 (58)
Treatment interruption arm in OPH study 65 17 (26) 59 16 (27)
Pre-ART Cytomegalovirus (CMV)
 CMV (>50 copies/ml) (ref: no CMV) 22 19 (86) 20 18 (90)
 CMV viral load (log10copies/ml) 22 3.6 (2.9, 4.0) 20 3.7 (3.4, 4.1)
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Children with a 10% higher pre-ART CD4 percent had 13% and 24% lower total and intact HIV DNA levels (adjusted relative risk [aRR]: 0.87, 95% confidence interval [95%CI]: 0.79–0.97, p=0.009 and aRR: 0.76, 95%CI: 0.65–0.89, p<0.001), respectively during longitudinal follow-up (Figure 1). One-log higher pre-ART HIV RNA was significantly associated with 21% higher total (aRR: 1.21, 95%CI: 1.06–1.39, p=0.004) and higher intact HIV DNA levels but this association was not statistically significant (aRR: 1.13, 95%CI: 0.90–1.42, p=0.305).

Figure 1.

Figure 1.

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Predictors of total and intact HIV DNA levels (continuous log10 copies/million T cells) during longitudinal follow-up up to 8 years post-ART

Children with PI-based first-line ART had higher intact HIV DNA compared to children with NNRTI-based regimens (aRR: 1.36, 95%CI: 1.04–1.77, p=0.025); this effect was similar in the subset of children without treatment switches (aRR: 1.32, 95%CI: 0.90–1.92, p=0.153). Infant sex was not associated with HIV DNA levels (Figure 1).

Each 1-log10 increase in CMV DNA copies/ml was associated with a 16% larger intact HIV DNA (aRR: 1.16, 95%CI: 1.01–1.34, p=0.041) but was not associated with total HIV DNA (aRR: 0.96, 95%CI: 0.87–1.04, p=0.317).

DISCUSSION

We assessed predictors of total and intact HIV DNA among children who started ART within the first year of life and were followed up to 8 years post-ART. Higher pre-ART HIV viral load and lower CD4 percent predicted higher total HIV DNA levels during suppressive ART, while higher pre-ART CMV viral load, first-line PI-based regimens, and lower CD4 percent predicted higher intact HIV DNA levels over serial longitudinal assessments.

We found that lower pre-ART CD4 percent predicted both higher total and intact HIV DNA levels. Our findings are consistent with a pediatric study in South Africa which found that lower pre-ART CD4 percent and higher pre-ART HIV viral load were associated with higher total HIV DNA after 1 year of ART.[15] Several studies have noted that very early initiation of ART limits HIV DNA levels.[6,16–23] However, there remain shortfalls in early infant diagnosis and treatment initiation globally, with only 59% of children with HIV with a known HIV status in 2020.[24] Delayed diagnosis and treatment is a lost opportunity to lower HIV DNA in children with HIV.

Nearly all Kenyan infants with HIV acquire CMV by 3 months of age and, in the absence of ART, experience persistent CMV viremia.[25] In this cohort, most (86%) children had detectable CMV viremia pre-ART. We previously found that children with detectable CMV DNAemia pre-ART had larger total HIV DNA levels at 24 months post-ART than children without CMV DNA pre-ART.[3] In our current analysis, HIV DNA was assessed longitudinally for a median of 5 years post-ART, and we found that higher pre-ART CMV DNA level was associated with higher intact HIV DNA. There is evidence that the replication-competent DNA is established near the time of ART initiation.[26,27] Among children with HIV with concurrent acute CMV infection at the time of ART initiation, proliferation of activated CMV-specific CD4+ T cells may expand the population of HIV-permissive cells, leading to larger HIV intact DNA levels, consistent with our findings.[28] The effect of subclinical CMV on certain T-cell subsets – specifically effector memory T-cells – may play an important role in sustainment of intact HIV DNA.[29,30]

Children treated with first-line PI-based regimens had significantly higher intact DNA levels than children on NNRTI-based regimens. This effect persisted in the smaller subset of children who did not switch regimens, but lost statistical significance, potentially due to the limited sample size. A recent study among adults with HIV found that those on PI-based regimens had higher levels of cell-associated HIV RNA and DNA compared to adults on NNRTIs. [31] Existing literature has also found that adults on NNRTIs have lower levels of residual HIV viremia compared to those on PIs.[32] Additionally, there is evidence that adults on NNRTIs may have a longer time to viral rebound after treatment interruption,[33] which may result from the longer half-life of NNRTIs or could indicate lower levels of replication-competent reservoirs among those on NNRTIs compared to those on PIs. It will be important to further evaluate the association between regimen and total and intact HIV DNA levels in pediatric populations and to understand how newer dolutegravir-based regimens affect HIV reservoir decay.

Limitations of this study include an inability to assess the effect of dolutegravir-based ART regimens on HIV DNA levels given the regimens in use at the time of cohort establishment. In addition, DNA measurements were limited to samples with HIV RNA below detection with HIV RNA measurements available only every 6 months. Thus, we cannot rule out viremia between timepoints. There were a limited number of longitudinal timepoints per child at which children were virally suppressed. Additionally, there was a relatively small number of samples for which pre-ART CMV viral load was quantified; however, pre-ART CMV viral load was associated with intact DNA in this analysis despite the sample size. The parent study included randomization to a short treatment interruption at 24 months post-ART initiation, however, there were no differences in total HIV DNA between children randomized to continue versus interrupt ART, by 18 months after treatment interruption,[34] and randomization arm was included in adjusted models.

In summary, we evaluated total and intact HIV DNA over a median of 5 years post-ART among children <1 year of age. Pre-treatment immune status and CMV viremia influenced HIV DNA in the long-term reservoir. CMV viral levels pre-ART specifically influenced the replication-competent intact HIV DNA.

Supplementary Material

Supplemental Figure 1

ACKNOWLEDGEMENTS

We are grateful to the children and families who participated in this research, to the clinic and laboratory staff who provide clinical care and monitoring of this cohort, and to the Comprehensive Care Clinic and Kenyatta National Hospital where the research was conducted. We are also grateful to Julie Overbaugh at Fred Hutchinson Cancer Center for providing advice, human immunodeficiency virus (HIV) viral load testing, and technical support.

FUNDING

This work was supported by the National Institutes of Health (NIH) (Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number F31HD106261 to JN and National Institute of Allergy and Infectious Diseases grants K01AI087369 to JAS [principal investigator (PI)] and R01 AI076105-07S1 to Julie Overbaugh [PI] and Fogarty International Center K43 TW 011422-01A1 to IN and Eunice Kennedy Shriver National Institute of Child Health and Human Development grants R01HD-23412 and K24HD054314 to G. J. S. [PI] and R01HD094718 to DAL and GJS [MPIs]), the University of Washington Center for AIDS Research (New Investigator and HIV-Associated Malignancy Awards; the Center is funded by NIH grant P30AI027757), and the University Washington Global Center for Integrated Health of Women, Adolescents and Children.

Footnotes

CONFLICTS OF INTEREST

Authors have no conflicts of interest to disclose.

REFERENCES

  • 1.Bruner KM, Murray AJ, Pollack RA, Soliman MG, Laskey SB, Capoferri AA, et al. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med 2016; 22:1043–1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Payne HA, Watters S, Hsaio M, Callard R, Babiker A, Cotton MF, et al. Early ART and sustained virologic suppression limits HIV proviral DNA reservoir: CHER evidence. Conference on Retroviruses and Opportunistic Infections (CROI) 2015;Abstract 35 [Google Scholar]
  • 3.Slyker JA, Guthrie B, Pankau M, Tapia K, Wamalwa D, Benki-Nugent S, et al. Association between Cytomegalovirus and Epstein-Barr Virus Viremia and Human Immunodeficiency Virus DNA Levels in the Reservoir of Kenyan Infants Receiving Antiretroviral Therapy. Journal of Infectious Diseases 2021; 223:1923–1927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Martínez-Bonet M, Puertas MC, Fortuny C, Ouchi D, Mellado MJ, Rojo P, et al. Establishment and Replenishment of the Viral Reservoir in Perinatally HIV-1-infected Children Initiating Very Early Antiretroviral Therapy. Clinical Infectious Diseases 2015; 61:1169–1178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Brice J, Sylla M, Desire N, Sayon S, Telly F, Bocar-Fofana D, et al. Characterization of drug resistance and the defective HIV reservoir in virally suppressed vertically infected children in Mali. Journal of Antimicrobial Chemotherapy 2020; 75:1272–1279. [DOI] [PubMed] [Google Scholar]
  • 6.Brice J, Sylla M, Sayon S, Telly F, Bocar-Fofana D, Murphy R, et al. Qualitative and quantitative HIV antibodies and viral reservoir size characterization in vertically infected children with virological suppression. Journal of Antimicrobial Chemotherapy 2017; 72:1147–1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Uprety P, Chadwick EG, Rainwater-Lovett K, Ziemniak C, Luzuriaga K, Capparelli E v., et al. Cell-Associated HIV-1 DNA and RNA Decay Dynamics during Early Combination Antiretroviral Therapy in HIV-1-Infected Infants. Clinical Infectious Diseases 2015; 61:1862–1870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Persaud D, Palumbo PE, Ziemniak C, Hughes MD, Alvero CG, Luzuriaga K, et al. Dynamics of the resting CD4+ T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age. AIDS 2012; 26:1483–1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Abdel-Mohsen M, Richman D, Siliciano RF, Nussenzweig MC, Howell BJ, Martinez-Picado J, et al. Recommendations for measuring HIV reservoir size in cure-directed clinical trials. Nat Med 2020; 26:1339–1350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Cassidy NAJ, Fish CS, Levy CN, Roychoudhury P, Reeves DB, Hughes SM, et al. HIV reservoir quantification using cross-subtype multiplex ddPCR. iScience 2022; 25. doi: 10.1016/j.isci.2021.103615 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Bruner KM, Wang Z, Simonetti FR, Bender AM, Kwon KJ, Sengupta S, et al. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature 2019; 566:120–125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Garcia-Broncano P, Maddali S, Einkauf KB, Jiang C, Gao C, Chevalier J, et al. Early antiretroviral therapy in neonates with HIV-1 infection restricts viral reservoir size and induces a distinct innate immune profile. ; 2019. http://stm.sciencemag.org/ [DOI] [PMC free article] [PubMed]
  • 13.Wamalwa D, Benki-Nugent S, Langat A, Tapia K, Ngugi E, Moraa H, et al. Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy. AIDS 2016; 30:2303–2313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Diez-Roux A v. Multilevel analysis in public health research. Annu Rev Public Health 2000; 21. [DOI] [PubMed] [Google Scholar]
  • 15.Kuhn L, Paximadis M, da Costa Dias B, Shen Y, Mncube S, Strehlau R, et al. Predictors of Cell-Associated Human Immunodeficiency Virus (HIV)-1 DNA Over 1 Year in Very Early Treated Infants. Clinical Infectious Diseases 2022; 74:1047–1054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Katusiime MG, van Zyl GU, Cotton MF, Kearney MF. HIV-1 persistence in children during suppressive ART. Viruses 2021; 13. doi: 10.3390/v13061134 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Luzuriaga K Early combination antiretroviral therapy limits HIV-1 persistence in children. Annu Rev Med 2016; 67:201–213. [DOI] [PubMed] [Google Scholar]
  • 18.Martínez-Bonet M, Puertas MC, Fortuny C, Ouchi D, Mellado MJ, Rojo P, et al. Establishment and Replenishment of the Viral Reservoir in Perinatally HIV-1-infected Children Initiating Very Early Antiretroviral Therapy. Clinical Infectious Diseases 2015; 61:1169–1178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Uprety P, Patel K, Karalius B, Ziemniak C, Chen YH, Brummel SS, et al. Human immunodeficiency virus type 1 DNA decay dynamics with early, long-term virologic control of perinatal infection. Clinical Infectious Diseases 2017; 64:1471–1478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Veldsman KA, Janse Van Rensburg A, Isaacs S, Naidoo S, Laughton B, Lombard C, et al. HIV-1 DNA decay is faster in children who initiate ART shortly after birth than later. Published Online First: 2019. doi: 10.1002/jia2.25368/full [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Tagarro A, Chan M, Zangari P, Ferns B, Foster C, de Rossi A, et al. Early and Highly Suppressive Antiretroviral Therapy Are Main Factors Associated With Low Viral Reservoir in European Perinatally HIV-Infected Children. ; 2018. www.jaids.com|269 [DOI] [PMC free article] [PubMed]
  • 22.Bitnun A, Ransy DG, Brophy J, Kakkar F, Hawkes M, Samson L, et al. Clinical correlates of human immunodeficiency virus-1 (HIV-1) DNA and inducible HIV-1 RNA reservoirs in peripheral blood in children with perinatally acquired HIV-1 infection with sustained virologic suppression for at least 5 years. Clinical Infectious Diseases 2020; 70:859–866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Kuhn L, Strehlau R, Shiau S, Patel F, Shen Y, Technau KG, et al. Early antiretroviral treatment of infants to attain HIV remission. EClinicalMedicine 2020; 18. doi: 10.1016/j.eclinm.2019.100241 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.UNAIDS. UNAIDS special analysis, 2021. Geneva: ; 2021. [Google Scholar]
  • 25.Slyker JA, Lohman-Payne BL, John-Stewart GC, Maleche-Obimbo E, Emery S, Richardson B, et al. Acute cytomegalovirus infection in Kenyan HIV-infected infants. AIDS 2009; 23:2173–2181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Abrahams M-R, Joseph SB, Garrett N, Tyers L, Moeser M, Archin N, et al. The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation. Sci Transl Med 2019; 11:5589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Pankau MD, Reeves DB, Harkins E, Ronen K, Jaoko W, Mandaliya K, et al. Dynamics of HIV DNA reservoir seeding in a cohort of superinfected Kenyan women. PLoS Pathog 2020; 16. doi: 10.1371/journal.ppat.1008286 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Hiener B, Horsburgh BA, Eden JS, Barton K, Schlub TE, Lee E, et al. Identification of Genetically Intact HIV-1 Proviruses in Specific CD4+ T Cells from Effectively Treated Participants. Cell Rep 2017; 21:813–822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Duette G, Hiener B, Morgan H, Mazur FG, Mathivanan V, Horsburgh BA, et al. The HIV-1 proviral landscape reveals that Nef contributes to HIV-1 persistence in effector memory CD4+ T cells. Journal of Clinical Investigation 2022; 132. doi: 10.1172/jci154422 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Christensen-Quick A, Vanpouille C, Lisco A, Gianella S. Cytomegalovirus and HIV Persistence: Pouring Gas on the Fire. AIDS Res Hum Retroviruses 2017; 33:S23–S30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Pasternak AO, Vroom J, Kootstra NA, Wit FWNM, de Bruin M, de Francesco D, et al. Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated hiv rna and dna levels as compared with therapy based on protease inhibitors. Elife 2021; 10. doi: 10.7554/eLife.68174 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Darcis G, Berkhout B, Pasternak AO. Differences in HIV markers between infected individuals treated with different ART regimens: Implications for the persistence of viral reservoirs. Viruses 2020; 12. doi: 10.3390/v12050489 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Li JZ, Etemad B, Ahmed H, Aga E, Bosch RJ, Mellors JW, et al. The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. AIDS 2015; :1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Pankau MD, Wamalwa D, Benki-Nugent S, Tapia K, Ngugi E, Langat A, et al. Decay of HIV DNA in the Reservoir and the Impact of Short Treatment Interruption in Kenyan Infants. Open Forum Infect Dis 2018; 5. doi: 10.1093/ofid/ofx268 [DOI] [PMC free article] [PubMed] [Google Scholar]

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Supplementary Materials

Supplemental Figure 1
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