Deciphering HIV-associated inflammation: microbiome's influence and experimental insights.

Purpose Of Review: To review novel experimental approaches for studying host:microbe interactions and their role in intestinal and systemic inflammation in people living with HIV (PLWH).

Recent Findings: Inflammation in PLWH is impacted by interactions between the microbiome, the intestinal epithelium, and immune cells. This complex interplay is not fully understood and requires a variety of analytical techniques to study.

Differential effects of antiretroviral treatment on immunity and gut microbiome composition in people living with HIV in rural versus urban Zimbabwe.

Background: The widespread availability of antiretroviral therapy (ART) has dramatically reduced mortality and improved life expectancy for people living with HIV (PLWH). However, even with HIV-1 suppression, chronic immune activation and elevated inflammation persist and have been linked to a pro-inflammatory gut microbiome composition and compromised intestinal barrier integrity. PLWH in urban versus rural areas of sub-Saharan Africa experience differences in environmental factors that may impact the gut microbiome and immune system, in response to ART, yet this has not previously been investigated in these groups.

Autoantibodies elicited with SARS-CoV-2 infection are linked to alterations in double negative B cells.

Double negative (DN) B cells (CD27-IgD-) comprise a heterogenous population of DN1, DN2, and the recently described DN3 and DN4 subsets. In autoimmune disease, DN2 cells are reported to be precursors to autoreactive antibody secreting cells and expansion of DN2 cells is linked to elevated interferon levels. Severe SARS-CoV-2 infection is characterized by elevated systemic levels of pro-inflammatory cytokines and serum autoantibodies and expansion of the DN2 subset in severe SARS-CoV-2 infection has been reported.

SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2.

As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC).

Disruption of Genes Encoding Putative Zwitterionic Capsular Polysaccharides of Diverse Intestinal Bacteroides Reduces the Induction of Host Anti-Inflammatory Factors.

Bacterial zwitterionic capsular polysaccharides (ZPS), such as polysaccharide A (PSA) of the intestinal commensal Bacteroides fragilis, have been shown to modulate T cells, including inducing anti-inflammatory IL-10-secreting T regulatory cells (Tregs). We previously used a genomic screen to identify diverse host-associated bacteria with the predicted genetic capacity to produce ZPSs related to PSA of B. fragilis and hypothesized that genetic disruption (KO) of a key functional gene within these operons would reduce the anti-inflammatory activity of these bacteria.

SARS-CoV-2 infection relaxes peripheral B cell tolerance.

Severe SARS-CoV-2 infection is associated with strong inflammation and autoantibody production against diverse self-antigens, suggesting a system-wide defect in B cell tolerance. BND cells are a B cell subset in healthy individuals harboring autoreactive but anergic B lymphocytes. In vitro evidence suggests inflammatory stimuli can breach peripheral B cell tolerance in this subset.

Intestinal microbial communities and isolated from HIV+/- men who have sex with men increase frequencies of lamina propria CCR5 CD4 T cells.

Men who have sex with men (MSM), regardless of HIV infection status, have an intestinal microbiome that is compositionally distinct from men who have sex with women (MSW) and women. We recently showed HIV-negative MSM have elevated levels of intestinal CD4 T cells expressing CCR5, a critical co-receptor for HIV. Whether elevated expression of CCR5 is driven by the altered gut microbiome composition in MSM has not been explored.

Postinfectious Immunity After COVID-19 and Vaccination Against SARS-CoV-2.

Early results suggest that SARS-CoV-2 vaccines are highly effective for the prevention of COVID-19. Unfortunately, until we can safely, rapidly, and affordably vaccinate enough people to achieve collective immunity, we cannot afford to disregard the benefits of naturally acquired immunity in those, whose prior documented infections have already run their course. As long as the vaccine manufacturing, supply, or administration are limited in capacity, vaccination of individuals with naturally acquired immunity at the expense of others without any immune protection is inherently inequitable, and violates the principle of justice in biomedical ethics.

Systems Analysis of Gut Microbiome Influence on Metabolic Disease in HIV-Positive and High-Risk Populations.

Poor metabolic health, characterized by insulin resistance and dyslipidemia, is higher in people living with HIV and has been linked with inflammation, antiretroviral therapy (ART) drugs, and ART-associated lipodystrophy (LD). Metabolic disease is associated with gut microbiome composition outside the context of HIV but has not been deeply explored in HIV infection or in high-risk men who have sex with men (HR-MSM), who have a highly altered gut microbiome composition. Furthermore, the contribution of increased bacterial translocation and associated systemic inflammation that has been described in HIV-positive and HR-MSM individuals has not been explored.

Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion.

Interleukin-1β (IL-1β)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples ( = 469) compared to normal skin ( = 324), with a highly significant correlation between NLRP3 and IL-1β ( < 0.

Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression.

The oncogenic drivers and progression factors in multiple myeloma (MM) are heterogeneous and difficult to target therapeutically. Many different MM drugs have emerged, however, that attack various phenotypic aspects of malignant plasma cells. These drugs are administered in numerous, seemingly interchangeable combinations.

Correction to: An exploration of Prevotella-rich microbiomes in HIV and men who have sex with men.

Following publication of the original article [1], the authors reported an error in Fig. 2. The original Fig.

Can gut microbiota of men who have sex with men influence HIV transmission?

Gaining a complete understanding of transmission risk factors will assist in efforts to reduce new HIV infections, especially within the disproportionally affected population of men who have sex with men (MSM). We recently reported that the fecal microbiota of MSM elevates immune activation in gnotobiotic mice and enhances HIV infection over that of fecal microbiota from men who have sex with women. We also demonstrated elevation of the gut homing marker CD103 (integrin αE) on CD4 T cells by MSM-microbiota.

B Cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis.

Activated B cells modulate infection by differentiating into pathogen-specific antibody-producing effector plasmablasts/plasma cells, memory cells, and immune regulatory B cells. In this context, the B cell phenotypes that infiltrate the central nervous system during human immunodeficiency virus (HIV) and cryptococcal meningitis coinfection are ill defined. We characterized clinical parameters, mortality, and B cell phenotypes in blood and cerebrospinal fluid (CSF) by flow cytometry in HIV-infected adults with cryptococcal ( = 31) and noncryptococcal ( = 12) meningitis and in heathy control subjects with neither infection ( = 10).

VOLARE: visual analysis of disease-associated microbiome-immune system interplay.

Background: Relationships between specific microbes and proper immune system development, composition, and function have been reported in a number of studies. However, researchers have discovered only a fraction of the likely relationships. "Omic" methodologies such as 16S ribosomal RNA (rRNA) sequencing and time-of-flight mass cytometry (CyTOF) immunophenotyping generate data that support generation of hypotheses, with the potential to identify additional relationships at a level of granularity ripe for further experimentation.

Gut microbiota from high-risk men who have sex with men drive immune activation in gnotobiotic mice and in vitro HIV infection.

Men who have sex with men (MSM) have differences in immune activation and gut microbiome composition compared with men who have sex with women (MSW), even in the absence of HIV infection. Gut microbiome differences associated with HIV itself when controlling for MSM, as assessed by 16S rRNA sequencing, are relatively subtle. Understanding whether gut microbiome composition impacts immune activation in HIV-negative and HIV-positive MSM has important implications since immune activation has been associated with HIV acquisition risk and disease progression.

Varicella zoster virus productively infects human peripheral blood mononuclear cells to modulate expression of immunoinhibitory proteins and blocking PD-L1 enhances virus-specific CD8+ T cell effector function.

Varicella zoster virus (VZV) is a lymphotropic alpha-herpesvirinae subfamily member that produces varicella on primary infection and causes zoster, vascular disease and vision loss upon reactivation from latency. VZV-infected peripheral blood mononuclear cells (PBMCs) disseminate virus to distal organs to produce clinical disease. To assess immune evasion strategies elicited by VZV that may contribute to dissemination of infection, human PBMCs and VZV-specific CD8+ T cells (V-CD8+) were mock- or VZV-infected and analyzed for immunoinhibitory protein PD-1, PD-L1, PD-L2, CTLA-4, LAG-3 and TIM-3 expression using flow cytometry.

Role for nuclear interleukin-37 in the suppression of innate immunity.

The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1α and IL-33, IL-37 is a dual-function cytokine in that IL-37 translocates to the nucleus but also transmits a signal via surface membrane receptors. The role of nuclear IL-37 remains unknown on the ability of this cytokine to inhibit innate inflammation.

Early-onset autoimmune vitiligo associated with an enhancer variant haplotype that upregulates class II HLA expression.

Vitiligo is an autoimmune disease in which melanocyte destruction causes skin depigmentation, with 49 loci known from previous GWAS. Aiming to define vitiligo subtypes, we discovered that age-of-onset is bimodal; one-third of cases have early onset (mean 10.3 years) and two-thirds later onset (mean 34.