Cell-associated HIV RNA: a dynamic biomarker of viral persistence

Pasternak, Alexander; Lukashov, Vladimir V.; Berkhout, Ben

doi:10.1186/1742-4690-10-41

Cited by 113 publications

(126 citation statements)

References 166 publications

(189 reference statements)

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“…This study demonstrated higher levels of multiply spliced HIV RNA transcripts in the cells of study participants with detectable CMV in semen but no difference in unspliced HIV RNA or 2-LTR circles. This discordant HIV RNA expression pattern (i.e., higher levels of multiply spliced than of unspliced HIV RNA) likely represents "blocked early-stage latency" as a form of latently HIVinfected cells (36,37). We also found a trend for CMV shedders to have increased multiply spliced HIV RNA/HIV DNA ratios but no difference in unspliced HIV RNA/HIV DNA ratios.…”

Section: Discussionmentioning

confidence: 62%

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 ⁺ T Cell Activation during Antiretroviral Treatment

Gianella

Massanella

Richman

et al. 2014

J Virol

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Asymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is associated with increased immune activation and HIV disease progression. To determine the connections between CMV-associated immune activation and the size of the viral reservoir, we evaluated the interactions between (i) asymptomatic seminal CMV replication, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in blood from 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. We found that asymptomatic CMV shedding in semen was associated with significantly higher levels of proliferating and activated CD4 ؉ T cells in blood (P < 0.01). Subjects with detectable CMV in semen had approximately five times higher average levels of HIV DNA in blood CD4؉ T cells than subjects with no CMV. There was also a trend for CMV shedders to have increased cellular (multiply spliced) HIV RNA transcription (P ‫؍‬ 0.068) compared to participants without CMV, but it is unclear if this transcription pattern is associated with residual HIV replication. In multivariate analysis, the presence of seminal plasma CMV (P ‫؍‬ 0.04), detectable 2-long terminal repeat (2-LTR), and lower nadir CD4 ؉ (P < 0.01) were independent predictors of higher levels of proviral HIV DNA in blood. Interventions aimed at reducing seminal CMV and associated immune activation may be important for HIV curative strategies. Future studies of anti-CMV therapeutics will help to establish causality and determine the mechanisms underlying these described associations. IMPORTANCEAlmost all individuals infected with HIV are also infected with cytomegalovirus (CMV), and the replication dynamics of the two viruses likely influence each other. This study investigated interactions between asymptomatic CMV replication within the male genital tract, levels of inflammation in blood, and the size of the HIV DNA reservoir in 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. In support of our primary hypothesis, shedding of CMV DNA in semen was associated with increased activation and proliferation of T cells in blood and also significantly higher levels of HIV DNA in blood cells. These results suggest that CMV reactivation might play a role in the maintenance of the HIV DNA reservoir during suppressive ART and that it could be a target of pharmacologic intervention in future studies.

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Section: Discussionmentioning

confidence: 62%

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 ⁺ T Cell Activation during Antiretroviral Treatment

Gianella

Massanella

Richman

et al. 2014

J Virol

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“…With HIV eradication becoming an emerging goal of HIV medicine, elucidation and monitoring of HIV-1-infected reservoirs is critical (16). To that end, we performed studies aimed to combine analyses of replication-competent HIV-1 reservoirs with the virus already present in plasma to obtain a broader representation of HIV-1 quasispecies.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of HIV-1 Latent Viral Reservoirs In Peripheral Blood

Chargin¹,

Yin²,

Song³

et al. 2015

J Clin Microbiol

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Plasma viral load and CD4 counts are effective for clinical monitoring, but they do not give a full representation of HIV-1 quasispecies in cellular reservoirs, the major repository of replication-competent HIV-1 in infected individuals. We sought to develop a diagnostic system that might stimulate the replication-competent HIV-1 reservoirs for enhanced clinical monitoring, including selection of antiretroviral regimens. Whole-blood samples from 45 HIV-infected individuals were collected into 1 ViraStim HIV-1 activation tube and 1 EDTA tube. Samples were tested for viral load and cell type-specific HIV-1 replication. Further, 7 matched activated/nonactivated samples were sequenced using the Trugene HIV-1 genotyping kit. The percentage of patients with replication-competent virus in peripheral blood mononuclear cells (PBMCs) varied, depending on the baseline plasma viral load in the EDTA tubes. Six out of 24 patients with a starting plasma viral load of <20 copies/ml (cp/ml), 6 out of 8 patients with starting viral loads of >20 and <1,000 cp/ml, and 8 out of 13 patients with starting viral loads of >1,000 all showed increases in viral replication of >5-fold. These increases came from cellular reservoirs in blood as determined by simultaneous ultrasensitive subpopulation staining/hybridization in situ (SUSHI). When resistance genotypes in plasma from activation tubes were compared to those from EDTA tubes for 7 patients, all patients showed additional mutations in the activation tube, while 3 patients demonstrated additional genotypic resistance determinants. We show that HIV-1 viral replication can be stimulated directly from infected whole blood. The sequencing results showed that 3 of 7 cases demonstrated additional drug resistance following stimulation.

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“…Changes in HIV transcription have been demonstrated in all trials by showing an increase in the level of cell-associated HIV RNA (CA RNA) in total and resting CD4 ϩ T cells (21). Synthesis of unspliced (US) HIV RNA is the first step in virus transcription, and multiple subsequent steps, including splicing, cytoplasmic export, synthesis of the regulatory proteins tat and rev, maturation, and budding, are subsequently required for virion release (22), but US HIV RNA is a marker that HIV transcription has been initiated (18).…”

mentioning

confidence: 99%

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Petravic

Rasmussen

Lewin

et al. 2017

J Virol

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Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latencyreversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3-to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life Ͼ 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment.IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.KEYWORDS latency, reactivation, human immunodeficiency virus C ombination antiretroviral therapy (ART) suppresses plasma HIV RNA below the detection limit of laboratory assays and restores the immune systems of infected patients by preventing new rounds of productive infection. However, ART cannot eradicate the infection, and virus replication starts again within weeks of ART cessation

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Cell-associated HIV RNA: a dynamic biomarker of viral persistence

Cited by 113 publications

References 166 publications

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 ⁺ T Cell Activation during Antiretroviral Treatment

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 ⁺ T Cell Activation during Antiretroviral Treatment

Identification and Characterization of HIV-1 Latent Viral Reservoirs In Peripheral Blood

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

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Cell-associated HIV RNA: a dynamic biomarker of viral persistence

Cited by 113 publications

References 166 publications

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 + T Cell Activation during Antiretroviral Treatment

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 + T Cell Activation during Antiretroviral Treatment

Identification and Characterization of HIV-1 Latent Viral Reservoirs In Peripheral Blood

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Contact Info

Product

Resources

About

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 ⁺ T Cell Activation during Antiretroviral Treatment

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 ⁺ T Cell Activation during Antiretroviral Treatment