Paradoxically greater persistence of HIV RNA+ cells in lymphoid tissue when ART is initiated in the earliest stage of infection

The Journal of infectious diseases

2022 Mar 11

Kroon, E;Chottanapund, S;Buranapraditkun, S;Sacdalan, C;Colby, DJ;Chomchey, N;Prueksakaew, P;Pinyakorn, S;Trichavaroj, R;Vasan, S;Manasnayakorn, S;Reilly, C;Helgeson, E;Anderson, J;David, C;Zulk, J;de Souza, M;Tovanabutra, S;Schuetz, A;Robb, ML;Douek, DC;Phanuphak, N;Haase, A;Ananworanich, J;Schacker, TW;
PMID: 35275599 | DOI: 10.1093/infdis/jiac089

Starting antiretroviral therapy (ART) in Fiebig 1 acute HIV infection limits the size of viral reservoirs in lymphoid tissues, but does not impact time to virus rebound during a treatment interruption. To better understand why the reduced reservoir size did not increase the time to rebound we measured the frequency and location of HIV RNA+ cells in lymph nodes from participants in the RV254 acute infection cohort. HIV vRNA+ cells were detected more frequently and in greater numbers when ART was initiated in Fiebig 1 compared to later Fiebig stages and were localized to the T cell zone compared to the B cell follicle with treatment in later Fiebig stages. Variability of virus production in people treated during acute infection suggests that the balance between virus producing cells and the immune response to clear infected cells rapidly evolves during the earliest stages of infection.

Chronic immune activation and gut barrier dysfunction is associated with neuroinflammation in ART-suppressed SIV+ rhesus macaques

PLoS pathogens

2023 Mar 01

Byrnes, SJ;Busman-Sahay, K;Angelovich, TA;Younger, S;Taylor-Brill, S;Nekorchuk, M;Bondoc, S;Dannay, R;Terry, M;Cochrane, CR;Jenkins, TA;Roche, M;Deleage, C;Bosinger, SE;Paiardini, M;Brew, BJ;Estes, JD;Churchill, MJ;
PMID: 36989320 | DOI: 10.1371/journal.ppat.1011290

HIV-associated neurocognitive disorders (HAND) affect ~40% of virally suppressed people with HIV (PWH), however, the precise viral dependent and independent changes to the brain are unclear. Here we characterized the CNS reservoir and immune environment of SIV-infected (SIV+) rhesus macaques during acute (n = 4), chronic (n = 12) or ART-suppressed SIV infection (n = 11). Multiplex immunofluorescence for markers of SIV infection (vRNA/vDNA) and immune activation was performed on frontal cortex and matched colon tissue. SIV+ animals contained detectable viral DNA+ cells that were not reduced in the frontal cortex or the gut by ART, supporting the presence of a stable viral reservoir in these compartments. SIV+ animals had impaired blood brain barrier (BBB) integrity and heightened levels of astrocytes or myeloid cells expressing antiviral, anti-inflammatory or oxidative stress markers which were not abrogated by ART. Neuroinflammation and BBB dysfunction correlated with measures of viremia and immune activation in the gut. Furthermore, SIV-uninfected animals with experimentally induced gut damage and colitis showed a similar immune activation profile in the frontal cortex to those of SIV-infected animals, supporting the role of chronic gut damage as an independent source of neuroinflammation. Together, these findings implicate gut-associated immune activation/damage as a significant contributor to neuroinflammation in ART-suppressed HIV/SIV infection which may drive HAND pathogenesis.

In-depth virological and immunological characterization of HIV-1 cure after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation

Nature medicine

2023 Feb 20

Jensen, BO;Knops, E;Cords, L;Lübke, N;Salgado, M;Busman-Sahay, K;Estes, JD;Huyveneers, LEP;Perdomo-Celis, F;Wittner, M;Gálvez, C;Mummert, C;Passaes, C;Eberhard, JM;Münk, C;Hauber, I;Hauber, J;Heger, E;De Clercq, J;Vandekerckhove, L;Bergmann, S;Dunay, GA;Klein, F;Häussinger, D;Fischer, JC;Nachtkamp, K;Timm, J;Kaiser, R;Harrer, T;Luedde, T;Nijhuis, M;Sáez-Cirión, A;Schulze Zur Wiesch, J;Wensing, AMJ;Martinez-Picado, J;Kobbe, G;
PMID: 36807684 | DOI: 10.1038/s41591-023-02213-x

Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male who was carefully monitored for more than 9 years after allogeneic CCR5Δ32/Δ32 HSCT performed for acute myeloid leukemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridization assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5Δ32/Δ32 HSCT.

Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy

The Journal of clinical investigation

2022 Mar 01

Harper, J;Ribeiro, SP;Chan, CN;Aid, M;Deleage, C;Micci, L;Pino, M;Cervasi, B;Raghunathan, G;Rimmer, E;Ayanoglu, G;Wu, G;Shenvi, N;Barnard, RJ;Del Prete, GQ;Busman-Sahay, K;Silvestri, G;Kulpa, DA;Bosinger, SE;Easley, K;Howell, BJ;Gorman, D;Hazuda, DJ;Estes, JD;Sekaly, RP;Paiardini, M;
PMID: 35230978 | DOI: 10.1172/JCI155251

Interleukin (IL)-10 is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper cell (TFH) differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph node (LN) were induced by infection and not normalized with ART. During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including TFH, and predicted the frequency of CD4+ TFH and their cell-associated SIV-DNA content during ART, respectively. In ART-treated RMs, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B-cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and by extension LN memory CD4+ T-cells, including TFH and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T-cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.

	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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