Persistence of viral RNA in lymph nodes in ART-suppressed SIV/SHIV-infected Rhesus Macaques

Cadena, Anthony M.; Ventura, John D.; Abbink, Peter; Borducchi, Erica N.; Tuyishime, Hubert; Mercado, Noe B.; Walker-Sperling, Victoria E.; Siamatu, Mazuba; Liu, Po Ting; Chandrashekar, Abishek; Nkolola, Joseph P.; McMahan, Katherine; Kordana, Nicole; Hamza, Venous; Bondzie, Esther A.; Fray, Emily J.; Kumar, Mithra R.; Fischinger, Stephanie; Shin, Sally; Lewis, Mark G.; Siliciano, Robert F.; Alter, Galit; Barouch, Dan H.

doi:10.1038/s41467-021-21724-0

Cited by 26 publications

(22 citation statements)

References 70 publications

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“…HIV GKO is a second-generation dual reporter virus and features eGFP marker under the control of the HIV LTR promoter and a Kusabira Orange 2 (mKO2) fluorescent marker under the control of the host elongation factor 1a (EF1a) promoter (31)(32)(33)(34)(35). Given the propensity for HIV infected cells to be recovered from lymphoid tissues (7,(36)(37)(38), we used HIV GKO to investigate latency establishment and maintenance in lymphoid-derived, tonsillar CD4 + T cells. Using this system, we were able to integrate datasets from single cell technologies to evaluate protein expression, host gene expression, and HIV transcript expression to characterize latently infected cells.…”

Section: Introductionmentioning

confidence: 99%

The Effect of JAK1/2 Inhibitors on HIV Reservoir Using Primary Lymphoid Cell Model of HIV Latency

et al. 2021

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HIV eradication is hindered by the existence of latent HIV reservoirs in CD4+ T cells. Therapeutic strategies targeting latent cells are required to achieve a functional cure, however the study of latently infected cells from HIV infected persons is extremely challenging due to the lack of biomarkers that uniquely characterize them. In this study, the dual reporter virus HIVGKO was used to investigate latency establishment and maintenance in lymphoid-derived CD4+ T cells. Single cell technologies to evaluate protein expression, host gene expression, and HIV transcript expression were integrated to identify and analyze latently infected cells. FDA-approved, JAK1/2 inhibitors were tested in this system as a potential therapeutic strategy to target the latent reservoir. Latent and productively infected tonsillar CD4+ T cells displayed similar activation profiles as measured by expression of CD69, CD25, and HLADR, however latent cells showed higher CXCR5 expression 3 days post-infection. Single cell analysis revealed a small set of genes, including HIST1-related genes and the inflammatory cytokine, IL32, that were upregulated in latent compared to uninfected and productively infected cells suggesting a role for these molecular pathways in persistent HIV infection. In vitro treatment of HIV-infected CD4+ T cells with physiological concentrations of JAK1/2 inhibitors, ruxolitinib and baricitinib, used in clinical settings to target inflammation, reduced latent and productive infection events when added 24 hr after infection and blocked HIV reactivation from latent cells. Our methods using an established model of HIV latency and lymphoid-derived cells shed light on the biology of latency in a crucial anatomical site for HIV persistence and provides key insights about repurposing baricitinib or ruxolitinib to target the HIV reservoir.

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Section: Introductionmentioning

confidence: 99%

The Effect of JAK1/2 Inhibitors on HIV Reservoir Using Primary Lymphoid Cell Model of HIV Latency

et al. 2021

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“…This was not due to a lack of viral replication, as the highest amounts of virus in the granuloma as detected by RNAscope was in GrALT structures. Germinal centers have been proposed to be an 'immunologically privileged' site for viral persistence, perhaps due to the inability of cytotoxic T cells to interact with infected TFH CD4 T cells, so it is possible that less effective killing by SIV-specific cytotoxic T cells may be responsible for the decreased depletion of GrALT-resident CD4 T cells 42,43 .…”

Section: Resultsmentioning

confidence: 99%

CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection

Foreman

Nelson

Kauffman

et al. 2021

Preprint

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The HIV-mediated decline in circulating CD4 T cells correlates with increased risk of active tuberculosis (TB). However, HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals also have an increased incidence of TB prior to loss of CD4 T cells in blood, raising the possibility that HIV co-infection leads to disruption of CD4 T cell responses at the site of lung infection before they are observed systemically. Here we used a rhesus macaque model of SIV/Mtb co-infection to study the early effects of acute SIV infection on CD4 T cells in pulmonary Mtb granulomas. Two weeks after SIV co-infection CD4 T cells were dramatically depleted from granulomas, before significant bacterial outgrowth, disease reactivation as measured by PET-CT imaging, or CD4 T cell loss in blood, airways, and lymph nodes. Mtb-specific CD4 T cells, CCR5-expressing, in granulomas were preferentially depleted by SIV infection. Moreover, CD4 T cells were preferentially depleted from the granuloma core and lymphocyte cuff relative to B cell-rich regions, and live imaging of granuloma explants showed that SIV co-infection reduced T cell motility. Thus, Mtb-specific CD4 T cells in pulmonary granulomas may be decimated before many patients even experience the first symptoms of acute HIV infection.

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“…The persistently elevated SHIV.C.CH505 RNA in the GI tract we observed during ART could underly the early expansion of virally infected cells in this region and would align with a previous report of transcriptionally active cells contributing to HIV-1 rebound ( 10 ). Data from adult macaques have also implicated lymphoid tissue, including from the GI tract, as a persistent source of viral RNA during suppressive ART ( 35 , 36 ). Future studies using barcoded viruses may provide increased precision regarding viral reactivation rates from various tissues and cell types as well as recombination events that may contribute to rebound viremia ( 26 , 37 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

Dynamics and origin of rebound viremia in SHIV-infected infant macaques following interruption of long-term ART

Obregon-Perko¹,

Bricker²,

Mensah³

et al. 2021

JCI Insight

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Understanding viral rebound in pediatric HIV-1 infection may inform the development of alternatives to lifelong antiretroviral therapy (ART) to achieve viral remission. We thus investigated viral rebound after analytical treatment interruption (ATI) in 10 infant macaques orally infected with SHIV.C.CH505 and treated with long-term ART. Rebound viremia was detected within 7-35 days of ATI in 9/10 animals, with post-treatment control of viremia seen in 5/5 Mamu-A*01 + macaques. Single-genome sequencing revealed initial rebound virus was similar to viral DNA present in CD4+ T cells from blood, rectum, and lymph nodes before ATI. We assessed the earliest sites of viral reactivation immediately following ATI using ImmunoPET imaging. The largest increase in signal that preceded detectable viral RNA in plasma was found in the gastrointestinal (GI) tract, a site with relatively high SHIV RNA/DNA ratios in CD4+ T cells prior to ATI. Thus, the GI tract may be an initial source of rebound virus but as ATI progresses, viral reactivation in other tissues likely contributes to the composition of plasma virus. Our study provides novel insight into the features of viral rebound in pediatric infection and highlights the application of a non-invasive technique to monitor areas of HIV-1 expression in children.

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Persistence of viral RNA in lymph nodes in ART-suppressed SIV/SHIV-infected Rhesus Macaques

Cited by 26 publications

References 70 publications

The Effect of JAK1/2 Inhibitors on HIV Reservoir Using Primary Lymphoid Cell Model of HIV Latency

The Effect of JAK1/2 Inhibitors on HIV Reservoir Using Primary Lymphoid Cell Model of HIV Latency

CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection

Dynamics and origin of rebound viremia in SHIV-infected infant macaques following interruption of long-term ART

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