Persistence of intracellular HIV-1 mRNA correlates with HIV-1-specific immune responses in infected subjects on stable HAART

Patterson, Bruce K.; McCallister, Scott; Schütz, Malte; Siegel, Joan N.; Shults, Keith; Flener, Zareefa; Landay, Alan

doi:10.1097/00002030-200109070-00005

Cited by 49 publications

(38 citation statements)

References 43 publications

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“…We demonstrated a correlation between the fold increase in HIV replication in intact cells and the fold increase in the ViraStim tubes relative to those in the EDTA tubes. We have previously shown the utility of SUSHI in measuring decreases in viral replication associated with antiretroviral therapy (21,22). In the present study, we demonstrate utility in the detection of increased viral replication in HIV-1 reservoirs infected with replication-competent virus, a potentially useful tool in the monitoring of eradication strategies.…”

Section: Discussionsupporting

confidence: 57%

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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Section: Discussionsupporting

confidence: 57%

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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“…Cell-associated HIV RNA load, which reflects the level of viral transcription, including abortive transcription, also correlates with immune activation in untreated patients, patients on cART, and natural controllers (204,255,256,257). In patients on cART with undetectable viremia, HIV transcript loads correlate negatively with the CD4 T cell count (257) and positively with lymphoproliferative responses to HIV p24 antigen (258). Activa-tion stimulates transcription of persistent virus (257).…”

Section: Discussionmentioning

confidence: 99%

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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“…However, a number of studies over the past several years have suggested that low levels of ongoing viral replication continue to persist and consequently prolong the overall half-life of HIV in patients receiving antiviral therapy (9)(10)(11)(12). These include the persistence of replication-competent virus (2-4), unintegrated proviral DNA, both linear (2) and circularized (13,14), and cell-associated HIV RNA (6,7,11,15,16). In addition, other studies have demonstrated that intensification of conventional antiviral regimens in patients who remained aviremic accelerated the decay of the latent HIV reservoir in the resting CD4 + T cell compartment (12) and further suppressed plasma viremia to well below the limit of detection (3.2-23 copies of HIV RNA per ml) (17).…”

Section: Introductionmentioning

confidence: 99%

HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir

Chun¹

2005

Journal of Clinical Investigation

244

203

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The persistence of latently infected, resting CD4 + T cells is considered to be a major obstacle in preventing the eradication of HIV-1 even in patients who have received effective antiviral therapy for an average duration of 5 years. Although previous studies have suggested that the latent HIV reservoir in the resting CD4 + T cell compartment is virologically quiescent in the absence of activating stimuli, evidence has been mounting to suggest that low levels of ongoing viral replication persist and in turn, prolong the overall half-life of HIV in patients receiving antiviral therapy. Here, we demonstrate the persistence of replication-competent virus in CD4 + T cells in a cohort of patients who had received uninterrupted antiviral therapy for up to 9.1 years that rendered them consistently aviremic throughout that time. Surprisingly, substantially higher levels of HIV proviral DNA were found in activated CD4 + T cells when compared with resting CD4 + T cells in the majority of patients we studied. Phylogenetic analyses revealed evidence for cross infection between the resting and activated CD4 + T cell compartments, suggesting that ongoing reactivation of latently infected, resting CD4 + T cells and spread of virus by activated CD4 + T cells may occur in these patients. Such events may allow continual replenishment of the CD4 + T cell reservoir and resetting of the half-life of the latently infected, resting CD4 + T cells despite prolonged periods of aviremia.

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Persistence of intracellular HIV-1 mRNA correlates with HIV-1-specific immune responses in infected subjects on stable HAART

Abstract: These results suggest that HIV-1-specific immune responses correlate with evidence of ongoing HIV-1 replication.

Cited by 49 publications

References 43 publications

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

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

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir

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