High-fat diet exacerbates SIV pathogenesis and accelerates disease progression

He, Tianyu; Xu, Cuiling; Krampe, Noah; Dillon, Stephanie M.; Sette, Paola; Falwell, Elizabeth; Haret-Richter, George S.; Butterfield, Tiffany R; Dunsmore, Tammy; McFadden, William M.; Martin, Kathryn J.; Policicchio, Benjamin B.; Raehtz, Kevin; Penn, Ellen; Tracy, Russell P.; Ribeiro, Ruy M.; Frank, Daniel N.; Wilson, Cara C.; Landay, Alan; Apetrei, Cristian; Pandrea, Ivona

doi:10.1172/jci121208

Cited by 30 publications

(18 citation statements)

References 49 publications

(82 reference statements)

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“…3Coinfections with opportunistic or other pathogens, hygiene, or microbial and climatic environment and (4) Medications (antibiotics, anticancer drugs, immune suppressors, and proton pump inhibitors...) may also induce microbial translocation. (5) Food and substance intake, particularly alcohol intake (52) and high fat diet, are known to have a direct impact on microbial translocation and on the emergence of inflammation and metabolic syndrome, as shown experimentally in non-human primate SIV infection models (53). (6) All these factors may also affect the development of the immune system during early life, including fetal life, with differential expansion and polarization of adaptive and innate immune cell populations, compartment seeding and epigenetic imprinting.…”

Section: Discussionmentioning

confidence: 99%

Conventional Dendritic Cells and Slan+ Monocytes During HIV-2 Infection

et al. 2020

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HIV-2 infection is characterized by low viremia and slow disease progression as compared to HIV-1 infection. Circulating CD14 ++ CD16 + monocytes were found to accumulate and CD11c + conventional dendritic cells (cDC) to be depleted in a Portuguese cohort of people living with HIV-2 (PLWHIV-2), compared to blood bank healthy donors (HD). We studied more precisely classical monocytes; CD16 + inflammatory (intermediate, non-classical and slan + monocytes, known to accumulate during viremic HIV-1 infection); cDC1, important for cross-presentation, and cDC2, both depleted during HIV-1 infection. We analyzed by flow cytometry these PBMC subsets from Paris area residents: 29 asymptomatic, untreated PLWHIV-2 from the IMMUNOVIR-2 study, part of the ANRS-CO5 HIV-2 cohort: 19 long-term non-progressors (LTNP; infection ≥8 years, undetectable viral load, stable CD4 counts≥500/µL; 17 of West-African origin-WA), and 10 non-LTNP (P; progressive infection; 9 WA); and 30 age-and sex-matched controls: 16 blood bank HD with unknown geographical origin, and 10 HD of WA origin (GeoHD). We measured plasma bacterial translocation markers by ELISA. Non-classical monocyte counts were higher in GeoHD than in HD (54 vs. 32 cells/µL, p = 0.0002). Slan + monocyte counts were twice as high in GeoHD than in HD (WA: 28 vs. 13 cells/µL, p = 0.0002). Thus cell counts were compared only between participants of WA origin. They were similar in LTNP, P and GeoHD, indicating that there were no HIV-2 related differences. cDC counts did not show major differences between the groups. Interestingly, inflammatory monocyte counts correlated with plasma sCD14 and LBP only in PLWHIV-2, especially LTNP, and not in GeoHD. In conclusion, in LTNP PLWHIV-2, inflammatory monocyte counts correlated with LBP or sCD14 plasma levels, indicating a potential innate immune response to subclinical bacterial translocation. As GeoHD had higher inflammatory monocyte counts than HD, our data also show that specific controls are important to refine innate immunity studies.

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Section: Discussionmentioning

confidence: 99%

Conventional Dendritic Cells and Slan+ Monocytes During HIV-2 Infection

et al. 2020

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“…reported the presence of granulomas induced by atypical mycobacteria in the liver of SIV + pig-tailed macaques [42], and He, et al similarly reported the presence of granulomas in the liver of SIV + African Green monkeys treated with a high fat diet although mycobacteria could not be identi ed by acid-fast staining [43]. It is important to note that detection of Mycobacterium DNA requires specialized lysis steps to rupture the cell wall [44,45].…”

Section: Discussionmentioning

confidence: 99%

Liver bacterial dysbiosis occurs in SIV-infected macaques and persists during antiretroviral therapy

Fisher¹,

Fancher²,

Gustin³

et al. 2020

Preprint

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Background: Liver disease remains a significant contributor to morbidity and mortality in HIV-infected individuals, even during successful treatment with combination antiretroviral therapy (cART). In non-human primates, SIV infection is associated with gut microbiome dysbiosis as well as bacterial translocation into the colonic lamina propria and liver via the portal vein. Here the liver microbiome was evaluated in rhesus macaques to discern the influence of SIV infection alone (SIV+) and during cART administration (SIV+cART) on liver bacterial dysbiosis and neutrophil infiltration.Results: Dysbiosis in liver bacterial composition was observed, encompassing changes in a number of genera, during SIV infection in the absence and presence of cART. The most striking finding was an increase in the level of Mycobacterium, which while barely detectable in the uninfected macaques, was the most abundant genus observed in the livers of a majority SIV+ and SIV+cART macaques. Multi-gene sequencing analyses identified a species of environmental mycobacteria similar to the opportunistic pathogen M. smegmatis. The effect of M. smegmatis on host gene expression in primary hepatocytes was evaluated in vitro utilizing PILAM, a glycolipid cell wall component found in atypical Mycobacteria. PILAM induced an upregulation of inflammatory responses, including an increase in the chemokines associated with neutrophil chemotaxis (CXCL1, CXCL5, and CXCL6). Assessment of the macaque livers by microscopy determined that neutrophil levels were reduced in SIV+cART macaques, suggesting that the SIV infection and/or cART treatment influence the liver-associated neutrophil response. Conclusions: A number of liver bacteria genera were altered following SIV infection even in the context of cART, possibly as a consequence of reduced neutrophil recruitment. Mycobacteria became a major component of the SIV infected macaque liver microbiome, raising the possibility that bacteria of this genus might contribute to liver disease in HIV infected patients.

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“…SIV pVLs were measured using quantitative real-time PCR as previously described (80,95). Cell-associated vRNA and vDNA quantifications were performed by using quantitative PCR (qPCR) on TRIzol-based extractions, as previously described (96). Briefly, the DNA phase was extracted by adding 500 l of DNA extraction solution (4 M guanidine thiocyanate, 50 mM sodium citrate, 1 M Tris) (97).…”

Section: Methodsmentioning

confidence: 99%

Nonhuman Primate Testing of the Impact of Different Regulatory T Cell Depletion Strategies on Reactivation and Clearance of Latent Simian Immunodeficiency Virus

Sivanandham

Kleinman

Sette

et al. 2020

J Virol

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Regulatory T cells (Tregs) may be key contributors to the HIV/SIV latent reservoir, as they harbor high levels of HIV/SIV; reverse CD4+ T cell immune activation status, increasing the pool of resting CD4+ T cells; impair CD8+ T cell function, favoring HIV persistence. We tested the hypothesis that Treg depletion is a valid intervention towards an HIV cure by depleted Tregs in fourteen SIVsab-infected RM controllers through different strategies: administration of an anti-CCR4 immunotoxin; two doses of an anti-CD25 immunotoxin (IL-2 with diphtheria toxin: IL-2-DT); or two combinations of both. All these treatments resulted in significant depletion of the circulating Tregs (>70%) and their partial depletion in the gut (25%) and lymph nodes (>50%). The fractions of CD4+ T cells expressing Ki-67 increased up-to 80% in experiments containing IL-2-DT and only 30% in anti-CCR4–treated RMs, paralleled by increases in the inflammatory cytokines. In the absence of ART, plasma virus rebounded to 103 vRNA copies/mL by day 10 post-IL-2-DT administration. A large but transient boost of the SIV-specific CD8+ T cell responses occurred in IL-2-DT–treated RMs. Such increases were minimal in the RMs receiving anti-CCR4-based regimens. Five RMs received IL-2DT on ART, but treatment was discontinued because of high toxicity and lymphopenia. As such, while all treatments depleted a significant proportion of Tregs, the side effects in the presence of ART prevent their clinical use and call for different Treg depletion approaches. Thus, based on our data, Treg targeting as a strategy for HIV cure cannot be discarded. IMPORTANCE Regulatory T cells (Tregs) can decisively contribute to the establishment and persistence of the HIV reservoir, as they harbor high levels of HIV/SIV, increase the pool of resting CD4+ T cells by reversing their immune activation status, and impair CD8+ T cell function, favoring HIV persistence. We tested multiple Treg depletion strategies and showed that all of them are at least partially successful in depleting Tregs. As such, Treg depletion appears to be a valid intervention towards an HIV cure, reducing the size of the reservoir, reactivating the virus, and boosting cell-mediated immune responses. Yet, when Treg depletion was attempted in ART-suppressed animals, the treatment had to be discontinued due to high toxicity and lymphopenia. Therefore, while Treg targeting as a strategy for HIV cure cannot be discarded, the methodology for Treg depletion has to be revisited.

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High-fat diet exacerbates SIV pathogenesis and accelerates disease progression

Cited by 30 publications

References 49 publications

Conventional Dendritic Cells and Slan+ Monocytes During HIV-2 Infection

Conventional Dendritic Cells and Slan+ Monocytes During HIV-2 Infection

Liver bacterial dysbiosis occurs in SIV-infected macaques and persists during antiretroviral therapy

Nonhuman Primate Testing of the Impact of Different Regulatory T Cell Depletion Strategies on Reactivation and Clearance of Latent Simian Immunodeficiency Virus

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