Background Although some integrase strand transfer inhibitors (INSTIs) promote peripheral and central adipose tissue/weight gain in people with human immunodeficiency virus (PHIV), the underlying mechanism has not been identified. Here, we used human and simian models to assess the impact of INSTIs on adipose tissue phenotype and function. Methods Adipocyte size and fibrosis were determined in biopsies of subcutaneous and visceral adipose tissue (SCAT and VAT, respectively) from 14 noninfected macaques and 19 PHIV treated or not treated with an INSTI. Fibrosis, adipogenesis, oxidative stress, mitochondrial function, and insulin sensitivity were assessed in human proliferating or adipocyte-differentiated adipose stem cells after long-term exposure to dolutegravir or raltegravir. Results We observed elevated fibrosis, adipocyte size, and adipogenic marker expression in SCAT and VAT from INSTI-treated noninfected macaques. Adiponectin expression was low in SCAT. Accordingly, SCAT and VAT samples from INSTI-exposed patients displayed higher levels of fibrosis than those from nonexposed patients. In vitro, dolutegravir and, to a lesser extent, raltegravir were associated with greater extracellular matrix production and lipid accumulation in adipose stem cells and/or adipocytes as observed in vivo. Despite the INSTIs’ proadipogenic and prolipogenic effects, these drugs promoted oxidative stress, mitochondrial dysfunction, and insulin resistance. Conclusions Dolutegravir and raltegravir can directly impact adipocytes and adipose tissue. These INSTIs induced adipogenesis, lipogenesis, oxidative stress, fibrosis, and insulin resistance. The present study is the first to shed light on the fat modifications observed in INSTI-treated PHIV.

Although white AT can contribute to anti-infectious immune responses, it can also be targeted and perturbed by pathogens. The AT's immune involvement is primarily due to strong pro-inflammatory responses (with both local and paracrine effects), and the large number of fat-resident macrophages. Adipocytes also exert direct antimicrobial responses. In recent years, it has been found that memory T cells accumulate in AT, where they provide efficient secondary responses against viral pathogens. These observations have prompted researchers to re-evaluate the links between obesity and susceptibility to infections. In contrast, AT serves as a reservoir for several persistence pathogens, such as human adenovirus Ad-36, Trypanosoma gondii, Mycobacterium tuberculosis, influenza A virus, and cytomegalovirus (CMV). The presence and persistence of bacterial DNA in AT has led to the concept of a tissuespecific microbiota. The unexpected coexistence of immune cells and pathogens within the specific AT environment is intriguing, and its impact on anti-infectious immune responses requires further evaluation. AT has been recently identified as a site of HIV persistence. In the context of HIV infection, AT is targeted by both the virus and the antiretroviral drugs. AT's intrinsic metabolic features, large overall mass, and wide distribution make it a major tissue reservoir, and one that may contribute to the pathophysiology of chronic HIV infections. Here, we review the immune, metabolic, viral, and pharmacological aspects that contribute to HIV persistence in AT. We also evaluate the respective impacts of both intrinsic and HIV-induced factors on AT's involvement as a viral reservoir. Lastly, we examine the potential consequences of HIV persistence on the metabolic and immune activities of AT.

The diversity of the human immune repertoire and how it relates to a functional immune response has not yet been studied in detail in humanized NOD.SCID.cc À/À immunodeficient mice. Here, we used a multiplex PCR on genomic DNA to quantify the combinatorial diversity of all possible V-J rearrangements at the TCR-b chain and heavy chain Ig locus. We first show that the combinatorial diversity of the TCR-b chain generated in the thymus was well preserved in the periphery, suggesting that human T cells were not vastly activated in mice, in agreement with phenotypic studies. We then show that the combinatorial diversity in NOD.SCID.cc À/À mice reached 100% of human reference samples for both the TCR and the heavy chain of Ig. To document the functionality of this repertoire, we show that a detectable but weak HLA-restricted cellular immune response could be elicited in reconstituted mice after immunization with an adenoviral vector expressing HCV envelope glycoproteins. Altogether, our results suggest that humanized mice express a diversified repertoire and are able to mount antigen-specific immune responses.

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Objectives: Combination microbicide vaginal rings may be more effective than single microbicide rings at reducing/preventing sexual transmission of HIV. Here, we report the pre-clinical development and macaque pharmacokinetics of matrix-type silicone elastomer vaginal rings containing dapivirine and darunavir.Methods: Macaque rings containing 25 mg dapivirine, 100 mg dapivirine, 300 mg darunavir or 100 mg dapivirine + 300 mg darunavir were manufactured and characterized by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28 day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC 50 values were calculated.Results: Darunavir caused a concentration-dependent reduction in the dapivirine melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present and the release medium. In macaques, serum concentrations of both microbicides were maintained between 10 1 and 10 2 pg/mL. Vaginal fluid levels ranged between 10 3 and 10 4 ng/g and between 104 and 10 5 ng/g for dapivirine and darunavir, respectively. Both dapivirine and darunavir showed very similar concentrations in each tissue type; the range of drug tissue concentrations followed the general rank order: vagina (1.8×10 3 -3.8×10 3 ng/g) .cervix (9.4×10 1 -3.9×10 2 ng/g) . uterus (0 -108 ng/g) .rectum (0 -40 ng/g). Measured IC 50 values were .2 ng/mL for both compounds.Conclusions: Based on these results, and in light of recent clinical progress of the 25 mg dapivirine ring, a combination vaginal ring containing dapivirine and darunavir is a viable second-generation HIV microbicide candidate.

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Objective Antibody response to the messenger RNA (mRNA) COVID‐19 vaccine has been shown to be diminished in rituximab (RTX)–treated patients. We undertook this study to compare humoral and T cell responses between healthy controls, patients with autoimmune diseases treated with RTX, and those treated with other immunosuppressants, all of whom had been vaccinated with 2 doses of the mRNA COVID‐19 vaccine. Methods We performed anti‐spike IgG and neutralization assays just before and 28 days after the second BNT162b2 (Pfizer‐BioNTech) vaccine dose. The specific T cell response was assessed in activated CD4 and CD8 T cells using intracellular flow cytometry staining of cytokines (interferon‐γ, tumor necrosis factor, and interleukin‐2) after stimulation with SARS–CoV‐2 spike peptide pools. Results A lower proportion of responders with neutralizing antibodies to the vaccine was observed in the RTX group (29%; n = 24) compared to the other immunosuppressants group (80%; n = 35) (P = 0.0001) and the healthy control group (92%; n = 26) (P < 0.0001). No patients treated with RTX in the last 6 months showed a response. Time since last infusion was the main factor influencing humoral response in RTX‐treated patients. The functional CD4 and CD8 cellular responses to SARS–CoV‐2 peptides for each single cytokine or polyfunctionality were not different in the RTX group compared to the other immunosuppressants group or the control group. In RTX‐treated patients, the T cell response was not different between patients with and those without a humoral response. Conclusion RTX induced a diminished antibody response to the mRNA COVID‐19 vaccine, but the functional T cell response was not altered compared to healthy controls and autoimmune disease patients treated with other immunosuppressants. Further work is needed to assess the clinical protection granted by a functionally active T cell response in the absence of an anti‐spike antibody response.

Highlights d SIV-specific CD8 + T cells in acute infection show poor SIVsuppressive activity ex vivo d SIV-suppressive activity increases over time in SIV controllers preceding viral control d Controllers develop memory-like CD8 + T cells, which seems to favor protective immunity d Cells from non-controllers have a skewed phenotype and fail to gain antiviral potential