The Gut Mucosal Viral Reservoir in HIV-Infected Patients Is Not the Major Source of Rebound Plasma Viremia following Interruption of Highly Active Antiretroviral Therapy

Lerner, Paula; Guadalupe, Moraima; Donovan, Richard M.; Hung, Jason K. S.; Flamm, Jason; Prindiville, Thomas P; Sankaran-Walters, Sumathi; Syvanen, Michael; Wong, Joseph K.; George, Michael; Dandekar, Satya

doi:10.1128/jvi.02409-10

Cited by 71 publications

(53 citation statements)

References 45 publications

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“…However, other studies have shown a relatively large number of rebounding founder variants, suggesting that viral reactivation occurs from many latently infected cells, possibly from multiple anatomic sites (5). There is evidence that virus after treatment interruption is similar to that found in the pre-ART plasma quasispecies (1,6), but the exact cellular origin of these rebounding variants is still unclear, especially after prolonged suppressive ART (7,8).…”

Section: Importancementioning

confidence: 94%

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Kearney

Wiegand

Shao

et al. 2016

J Virol

118

123

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Understanding the origin of HIV variants during viral rebound may provide insight into the composition of the HIV reservoir and has implications for the design of curative interventions. HIV single-genome sequences were obtained from 10 AIDS Clinical Trials Group participants who underwent analytic antiretroviral therapy (ART) interruption (ATI). Rebounding variants were compared with those in pre-ART plasma in all 10 participants and with on-ART peripheral blood mononuclear cell (PBMC)-associated DNA and RNA (CA-RNA) in 7/10 participants. The highest viral diversities were found in the DNA and CA-RNA populations. In 3 of 7 participants, we detected multiple, identical DNA and CA-RNA sequences during suppression on ART that exactly matched plasma HIV sequences. Hypermutated DNA and CA-RNA were detected in four participants, contributing to diversities in these compartments that were higher than in the pre-ART and post-ATI plasma. Shifts in the viral rebound populations could be detected in some participants over the 2-to 3-month observation period. These findings suggest that a source of initial rebound viremia could be populations of infected cells that clonally expanded prior to and/or during ART, some of which were already expressing HIV RNA before treatment was interrupted. These clonally expanding populations of HIVinfected cells may represent an important target for strategies aimed at achieving reservoir reduction and sustained virologic remission. IMPORTANCEAntiretroviral therapy alone cannot eradicate the HIV reservoir, and viral rebound is generally rapid after treatment interruption. It has been suggested that clonal expansion of HIV-infected cells is an important mechanism of HIV reservoir persistence, but the contribution of these clonally proliferating cells to the rebounding virus is unknown. We report a study of AIDS Clinical Trials Group participants who underwent treatment interruption and compared rebounding plasma virus with that found within cells prior to treatment interruption. We found several incidences in which plasma HIV variants exactly matched that of multiple proviral DNA copies from infected blood cells sampled before treatment interruption. In addition, we found that these cells were not dormant but were generating unspliced RNA transcripts before treatment was interrupted. Identification of the HIV reservoir and determining its mechanisms for persistence may aid in the development of strategies toward a cure for HIV. (This study was presented in part at the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 23 to 26 2015.)

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Section: Importancementioning

confidence: 94%

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Kearney

Wiegand

Shao

et al. 2016

J Virol

118

123

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“…Because of the low levels of virus replication in DE37, the envelope sequences were obtained by standard nested PCR/cloning and not by SGA. Nonetheless, increasing evidence suggests that with an adequate number of PCR templates analyzed, bulk sequencing captures a measure of population diversity similar to that determined by SGA (22,30). Phylogenetic tree analysis of the early replicating viruses in the two monkeys showed clustering of DE37 (transient/low VL) env sequences with those of FH84 (high VL) (Fig.…”

Section: Persistent Infection and Disease Induction In Macaques Exposedmentioning

confidence: 99%

Pathogenic Consequences of Vaginal Infection with CCR5-Tropic Simian-Human Immunodeficiency Virus SHIV _SF162P3N

Shakirzyanova

Tsai

Ren

et al. 2012

J Virol

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We previously reported efficient transmission of the pathogenic R5 simian-human immunodeficiency virus SHIV SF162P3N isolate in Indian rhesus macaques by intravenous and intrarectal inoculations, with a switch to CXCR4 coreceptor usage in ∼50% of infected animals that progressed rapidly to disease. Since women continue to be disproportionately affected by HIV, we developed an animal model based on the intravaginal challenge of female rhesus monkeys with SHIV SF162P3N and sought to validate the utility of this model to study relevant aspects of HIV transmission and pathogenesis. The effect of viral dose on infection outcome was evaluated to determine the optimal conditions for the evaluation of HIV-1 preventive and therapeutic strategies. We found that the virus can successfully cross the vaginal mucosal surface to establish infection and induce disease with coreceptor switch, but with lower efficiencies compared to intravenous and rectal transmissions. In contrast to intrarectal infection, peak and cumulative viral load over a 1 year-infection period were significantly greater in macaques exposed intravaginally to lower rather than higher inoculum doses. Moreover, low and transient viremia was observed only in macaques that were challenged intravaginally twice within the same day with a high dose of virus, which can be seen as doubling the dose. Taken together, these results show that SHIV SF162P3N can successfully transmit across the genital mucosa, undergo coreceptor switch, and induce disease. However, the administered dose appears to impact SHIV SF162P3N vaginal infection outcome in an unexpected manner.

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“…Rebound viremia varients also did not replenish the GALT HIV-reservoir. Also, inflammatory responses and a severe loss in gut mucosal CD4+ T-cells were observed on STI induction at the gut mucosa [140]. In six patients whose HIV viremia was controlled for at least 20 months, the episomal and proviral HIV-DNA pre-STI were analysed phylogenetically and compared to rebound virus sequences isolated during a STI study [141].…”

Section: Viral Rebound and Its Originmentioning

confidence: 99%

Characterisation, Evaluation and Clinical Significance of Latent HIV-1 Reservoirs and Therapeutic Strategies for HIV Eradication

Williams¹,

Fidler²,

Frater³

2011

Recent Translational Research in HIV/AIDS

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The Gut Mucosal Viral Reservoir in HIV-Infected Patients Is Not the Major Source of Rebound Plasma Viremia following Interruption of Highly Active Antiretroviral Therapy

Cited by 71 publications

References 45 publications

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Pathogenic Consequences of Vaginal Infection with CCR5-Tropic Simian-Human Immunodeficiency Virus SHIV _SF162P3N

Characterisation, Evaluation and Clinical Significance of Latent HIV-1 Reservoirs and Therapeutic Strategies for HIV Eradication

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The Gut Mucosal Viral Reservoir in HIV-Infected Patients Is Not the Major Source of Rebound Plasma Viremia following Interruption of Highly Active Antiretroviral Therapy

Cited by 71 publications

References 45 publications

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Pathogenic Consequences of Vaginal Infection with CCR5-Tropic Simian-Human Immunodeficiency Virus SHIV SF162P3N

Characterisation, Evaluation and Clinical Significance of Latent HIV-1 Reservoirs and Therapeutic Strategies for HIV Eradication

Contact Info

Product

Resources

About

Pathogenic Consequences of Vaginal Infection with CCR5-Tropic Simian-Human Immunodeficiency Virus SHIV _SF162P3N