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. 2024 Aug 8;9(18):e181968.
doi: 10.1172/jci.insight.181968.

Effect of metabolic status on response to SIV infection and antiretroviral therapy in nonhuman primates

Gabriela M Webb  1 , Kristin A Sauter  2 , Diana Takahashi  2 , Melissa Kirigiti  2 , Lindsay Bader  2 , Sarah R Lindsley  2 , Hannah Blomenkamp  2 , Cicely Zaro  2 , Molly Shallman  2 , Casey McGuire  2 , Heather Hofmeister  2 , Uriel Avila  2 , Cleiton Pessoa  1 , Joseph M Hwang  1 , Allyson McCullen  1 , Matthew Humkey  1 , Jason Reed  1 , Lina Gao  3 , Lee Winchester  4 , Courtney V Fletcher  4 , Oleg Varlamov  2 , Todd T Brown  5 , Jonah B Sacha  1 , Paul Kievit  2 , Charles T Roberts  2   6
Affiliations

Effect of metabolic status on response to SIV infection and antiretroviral therapy in nonhuman primates

Gabriela M Webb et al. JCI Insight. .

Abstract

Current antiretroviral therapy (ART) regimens efficiently limit HIV replication, thereby improving the life expectancy of people living with HIV; however, they also cause metabolic side effects. The ongoing obesity epidemic has resulted in more people with metabolic comorbidities at the time of HIV infection, yet the effect of preexisting metabolic dysregulation on infection sequelae and response to ART is unclear. Here, to investigate the impact of preexisting obesity and insulin resistance on acute infection and subsequent long-term ART, we infected a cohort of lean and obese adult male macaques with SIV and administered ART. The responses of lean and obese macaques to SIV and ART were similar with respect to plasma and cell-associated viral loads, ART drug levels in plasma and tissues, SIV-specific immune responses, adipose tissue and islet morphology, and colon inflammation, with baseline differences between lean and obese groups largely maintained. Both groups exhibited a striking depletion of CD4+ T cells from adipose tissue that did not recover with ART. However, differential responses to SIV and ART were observed for body weight, omental adipocyte size, and the adiponectin/leptin ratio, a marker of cardiometabolic risk. Thus, obesity and insulin resistance had limited effects on multiple responses to acute SIV infection and ART, while several factors that underlie long-term metabolic comorbidities were influenced by prior obesity and insulin resistance. These studies provide the foundation for future investigations into the efficacy of adjunct therapies such as metformin and glucagon-like peptide-1 receptor agonists in the prevention of metabolic comorbidities in people living with HIV.

Keywords: AIDS/HIV; Adipose tissue; Glucose metabolism; Metabolism; Obesity.

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Figures

Figure 1
Figure 1. Experimental timeline, BW changes, and plasma RNA and cell-associated viral DNA dynamics during SIV infection and ART suppression.
(A) Schedule of experimental procedures and assessments. (B) BW in lean (n = 12) and obese (n = 10) groups over the study time course. Horizontal dotted lines indicate average baseline BW. Insert shows difference in baseline average BW. (C) SIV plasma RNA copies per mL over the study time course. Limit of quantification (LOQ) is denoted by the horizontal dotted line. (D) Cell-associated SIV DNA in peripheral lymph node, colon, and the SVF of OM and SC WAT over the study time course. In all figures, data points for lean animals are in blue and those for obese animals are in red. Significance was determined by ordinary 1-way ANOVA with Tukey’s multiple comparison test. ****P < 0.0001. All data are means ± SEM.
Figure 2
Figure 2. ART drug concentrations in tissues.
(A) Average levels of dolutegravir (DTG), tenofovir diphosphate (TFV-DP), and emtricitabine triphosphate (FTC-TP) in peripheral blood mononuclear cells (PBMCs), dissociated cells from mesenteric lymph node (MesLN), inguinal lymph node (IngLN), spleen, and OM and SC WAT SVF cells (SC and OM SVF) at necropsy (week 72) (cohort 1 only). (B) DTG, TFV-DP, and FTC-TP levels in PBMCs and the lipid fraction of OM and SC WAT. Conversion of the levels of DTG, TFV-DP, and FTC-TP in fmol/1 × 106 PBMCs to fmol/mL in panel B employed the average PBMC volume described by Simiele et al. (104). Data points for lean animals are in blue and those for obese animals are in red. Significance was determined by mixed-effects analysis with Tukey’s multiple comparison test. *P < 0.05; **P < 0.01. All data are means ± SEM.
Figure 3
Figure 3. Effect of SIV infection and ART suppression on CD4+ and CD8+ T cell frequencies in whole blood and OM and SC WAT.
Whole blood monocytes (A) and the stromovascular fraction of OM (B) and SC (C) WAT were analyzed by flow cytometry using the gating strategy and antibodies described in Supplemental Figure 12 and Supplemental Table 1. Data points for lean animals are in blue and those for obese animals are in red. Significance was determined by mixed-effects analysis with Tukey’s multiple comparison test. *P < 0.05; **P < 0.01; ***P < 0.001. All data are means ± SEM.
Figure 4
Figure 4. Effect of SIV infection and long-term ART on adipocyte size and pericellular extracellular matrix thickness.
(A) Representative images of OM and SC WAT from lean and obese animals stained with picosirius red; scale bar: 100 μm. (B) Average adipocyte size in individual lean and obese animals over the study time course. (C) Average interadipocyte/pericellular extracellular matrix thickness in lean and obese animals over the study time course. Data points for lean animals are in blue and those for obese animals are in red. Significance was determined by mixed-effects analysis with Tukey’s multiple comparison test. *P < 0.05; **P < 0.01; ****P < 0.0001. All data are means ± SEM.
Figure 5
Figure 5. Effect of SIV infection and ART on circulating adiponectin and leptin levels.
Total plasma adiponectin (A) levels were determined by ELISA and serum leptin (B) levels were determined by RIA. P values for longitudinal within-group (Time), between-group (Group), and time by group (Time × Group) interaction changes are indicated. (C) Adiponectin/leptin ratio (ALR) calculated from data of panels A and B. Data points for lean animals are in blue and those for obese animals are in red. Significance determined by mixed-effects analysis with Tukey’s multiple comparison test. ***P < 0.001; ****P < 0.0001. All data are means ± SEM.
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