Association Between Cytomegalovirus and Epstein-Barr Virus Viremia And Human Immunodeficiency Virus DNA Levels in the Reservoir of Kenyan Infants Receiving Antiretroviral Therapy

Slyker, Jennifer A.; Guthrie, Brandon L.; Pankau, Mark D; Tapia, Kenneth; Wamalwa, Dalton; Benki-Nugent, Sarah; Ngugi, Evelyn; Huang, Meei‐Li; Njuguna, Irene; Langat, Agnes; John‐Stewart, Grace; Lehman, Dara A.

doi:10.1093/infdis/jiaa640

Cited by 7 publications

(6 citation statements)

References 14 publications

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“…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.…”

Section: Discussionsupporting

confidence: 45%

“…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.…”

Section: Methodsmentioning

confidence: 99%

“…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][3][4][5][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].…”

Section: Introductionmentioning

confidence: 99%

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Predictors of intact HIV DNA levels among children in Kenya

Fish

Cassidy

Wamalwa

et al. 2023

Aids

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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 less than 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+ percentage [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+ percentage (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 with nonnucleoside 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.

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Section: Discussionsupporting

confidence: 45%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Predictors of intact HIV DNA levels among children in Kenya

Fish

Cassidy

Wamalwa

et al. 2023

Aids

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“…There are multiple levels of evidence supporting an HIV-EBV interaction in addition to the appearance of EBV-positive lymphomas. For instance, Kenyan children on ART exhibited a correlation between EBV primary infection and HIV viremia, which supports that EBV influences HIV reactivation [ 140 ]. Similarly, detectable EBV load at the initiation of ART or post-ART was associated with positive markers of inflammation, non-AIDS defined malignancies, and other PLWH morbidities, such as cardiovascular disease [ 141 ].…”

Section: Hiv Steady B Cell Stimulation Creates a Lymphomagenesis Permissive Environmentmentioning

confidence: 97%

The Role of Coinfections in the EBV–Host Broken Equilibrium

Sánchez-Ponce

Fuentes‐Pananá

2021

Viruses

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The Epstein–Barr virus (EBV) is a well-adapted human virus, and its infection is exclusive to our species, generally beginning in the childhood and then persisting throughout the life of most of the affected adults. Although this infection generally remains asymptomatic, EBV can trigger life-threatening conditions under unclear circumstances. The EBV lifecycle is characterized by interactions with other viruses or bacteria, which increases the probability of awakening its pathobiont capacity. For instance, EBV infects B cells with the potential to alter the germinal center reaction (GCR)—an adaptive immune structure wherein mutagenic-driven processes take place. HIV- and Plasmodium falciparum-induced B cell hyperactivation also feeds the GCR. These agents, along with the B cell tropic KSHV, converge in the ontogeny of germinal center (GC) or post-GC lymphomas. EBV oral transmission facilitates interactions with local bacteria and HPV, thereby increasing the risk of periodontal diseases and head and neck carcinomas. It is less clear as to how EBV is localized in the stomach, but together with Helicobacter pylori, they are known to be responsible for gastric cancer. Perhaps this mechanism is reminiscent of the local inflammation that attracts different herpesviruses and enhances graft damage and chances of rejection in transplanted patients. In this review, we discussed the existing evidence suggestive of EBV possessing the potential to synergize or cooperate with these agents to trigger or worsen the disease.

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“…It is well known that infection with Mycobacterium tuberculosis can be associated with persistent systemic inflammation, which can reactivate and eventually decrease the latent HIV-1 reservoir [ 72 , 73 ], while bacterial infection can also induce HIV-1 latency in macrophages [ 74 ]. On the other hand, individuals co-infected with cytomegalovirus [ 75 , 76 ], hepatitis C virus [ 77 ], or herpes simplex virus type 2 [ 78 ] have been shown to have larger HIV-1 reservoirs, although quantified by measuring proviral DNA. Further studies, most likely in the form of clinical trials and/or longitudinal studies will be necessary to evaluate the role of acute and chronic coinfections in the latent HIV-1 reservoir.…”

Section: Discussionmentioning

confidence: 99%

Reduced and highly diverse peripheral HIV-1 reservoir in virally suppressed patients infected with non-B HIV-1 strains in Uganda

et al. 2022

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Background Our understanding of the peripheral human immunodeficiency virus type 1 (HIV-1) reservoir is strongly biased towards subtype B HIV-1 strains, with only limited information available from patients infected with non-B HIV-1 subtypes, which are the predominant viruses seen in low- and middle-income countries (LMIC) in Africa and Asia. Results In this study, blood samples were obtained from well-suppressed ART-experienced HIV-1 patients monitored in Uganda (n = 62) or the U.S. (n = 50), with plasma HIV-1 loads < 50 copies/ml and CD4+ T-cell counts > 300 cells/ml. The peripheral HIV-1 reservoir, i.e., cell-associated HIV-1 RNA and proviral DNA, was characterized using our novel deep sequencing-based EDITS assay. Ugandan patients were slightly younger (median age 43 vs 49 years) and had slightly lower CD4+ counts (508 vs 772 cells/ml) than U.S. individuals. All Ugandan patients were infected with non-B HIV-1 subtypes (31% A1, 64% D, or 5% C), while all U.S. individuals were infected with subtype B viruses. Unexpectedly, we observed a significantly larger peripheral inducible HIV-1 reservoir in U.S. patients compared to Ugandan individuals (48 vs. 11 cell equivalents/million cells, p < 0.0001). This divergence in reservoir size was verified measuring proviral DNA (206 vs. 88 cell equivalents/million cells, p < 0.0001). However, the peripheral HIV-1 reservoir was more diverse in Ugandan than in U.S. individuals (8.6 vs. 4.7 p-distance, p < 0.0001). Conclusions The smaller, but more diverse, peripheral HIV-1 reservoir in Ugandan patients might be associated with viral (e.g., non-B subtype with higher cytopathicity) and/or host (e.g., higher incidence of co-infections or co-morbidities leading to less clonal expansion) factors. This highlights the need to understand reservoir dynamics in diverse populations as part of ongoing efforts to find a functional cure for HIV-1 infection in LMICs.

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Association Between Cytomegalovirus and Epstein-Barr Virus Viremia And Human Immunodeficiency Virus DNA Levels in the Reservoir of Kenyan Infants Receiving Antiretroviral Therapy

Cited by 7 publications

References 14 publications

Predictors of intact HIV DNA levels among children in Kenya

Predictors of intact HIV DNA levels among children in Kenya

The Role of Coinfections in the EBV–Host Broken Equilibrium

Reduced and highly diverse peripheral HIV-1 reservoir in virally suppressed patients infected with non-B HIV-1 strains in Uganda

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