A5057319380- HIV Research and Treatment
- Immune Cell Function and Interaction
- HIV/AIDS Research and Interventions
- HIV/AIDS drug development and treatment
- T-cell and B-cell Immunology
- Cytomegalovirus and herpesvirus research
- SARS-CoV-2 and COVID-19 Research
- HIV-related health complications and treatments
- Hepatitis C virus research
- Galectins and Cancer Biology
- COVID-19 Impact on Reproduction
- Vaccine Coverage and Hesitancy
- Immunotherapy and Immune Responses
- Immunodeficiency and Autoimmune Disorders
- Toxin Mechanisms and Immunotoxins
- Blood groups and transfusion
- interferon and immune responses
- Reproductive tract infections research
- Chemokine receptors and signaling
- Gut microbiota and health
- HIV, Drug Use, Sexual Risk
- IL-33, ST2, and ILC Pathways
- Phagocytosis and Immune Regulation
- COVID-19 Clinical Research Studies
- Mathematical and Theoretical Epidemiology and Ecology Models
Maple Leaf Medical Clinic
2015-2024
University of Toronto
2012-2019
University of North Carolina at Chapel Hill
2017
The presence of persistent, latent HIV reservoirs in CD4+ T cells obstructs current efforts to cure infection. so-called kick-and-kill paradigm proposes purge these by combining latency-reversing agents with immune effectors such as cytotoxic lymphocytes. Support for this approach is largely based on success latency models, which do not fully reflect the makeup individuals long-term antiretroviral therapy (ART). Recent studies have shown that CD8+ potential recognize defective proviruses,...
HIV-1 persists in a latent reservoir resting CD4+ T cells despite antiretroviral therapy (ART). The decays slowly over the first seven years of ART (t1/2 = 44 months). However, whether decay continues with long-term is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades might allow treatment interruption without viral rebound. Therefore, we measured 42 people on (mean 22 years) using quantitative outgrowth...
Resting CD4+ T-cells harboring inducible HIV proviruses are a critical reservoir in antiretroviral therapy (ART)-treated subjects. These cells express little to no viral protein, and thus neither die by cytopathic effects, nor efficiently cleared immune effectors. Elimination of this is theoretically possible combining latency-reversing agents (LRAs) with effectors, such as CD8+ T-cells. However, the relative efficacy different LRAs sensitizing latently-infected for recognition HIV-specific...
Despite lack of vaccine efficacy, the kinetics and magnitude HIV rebound in early-treated patients affect future clinical trial design.
Abstract Mucosal Th17 cells maintain the gut epithelial barrier and prevent invasion by luminal bacteria through a delicate balance of immunosuppressive proinflammatory functions. HIV infection is characterized mucosal depletion, microbial translocation, immune activation. Therefore, we assessed function blood sigmoid during both early chronic infection, as well impact short- long-term antiretroviral therapy. were defined IL-17a+ CD4 T cells, their functional capacity was coproduction...
Curing HIV infection will require the elimination of a reservoir infected CD4+ T cells that persists despite HIV-specific cytotoxic cell (CTL) responses. Although viral latency is critical factor in this persistence, recent evidence also suggests role for intrinsic resistance reservoir-harboring to CTL killing. This may have contributed negative outcomes clinical trials, where pharmacologic reversal has thus far failed drive reductions reservoirs. Through transcriptional profiling, we herein...
Abstract The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two regions distinguish genomically proviruses against large background of defective ones, and its application has yielded insights into persistence. Reports failures however, attributed polymorphism, have recently emerged. Here, we describe diverse North American cohort people with...
We examined the role of CD4(+) T cell IL-21 production in viral control HIV infection. HIV-infected individuals had greater circulating IL-21-producing cells blood compared with uninfected volunteers. HIV-specific were detected during untreated acute and chronic infection, elevated frequencies these correlated relative control. These an effector memory or end phenotype expressed CXCR5. CD8(+) exhibited high levels IL-21R, indicating sensitivity to IL-21. Low aviremic long-term...
Co-infection of HCV with HIV has been associated more rapid progression HCV-related disease. HCV-specific T-cell immune responses, which are essential for disease control, attenuated in co-infection HIV. exhaustion recently implicated the deficient control chronic viral infections. In current study, we investigated role programmed death-1 (PD-1) and immunoglobulin mucin domain-containing molecule-3 (Tim-3) expression during HCV/HIV co-infection. We show that co-infection, both total T cells...
The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we establish rationale for eliminating HIV-1–infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences the genome represent remnants ancient infectious retroviruses. We show that infection CD4+ T with resulted transcription HML-2 lineage type K [HERV-K(HML-2)] and expression Gag Env proteins. HERV-K(HML-2)–specific CD8+...
Cytotoxic CD8+ T cells (CTLs) contain virus infections through the release of granules containing both perforin and granzymes. cell 'exhaustion' is a hallmark chronic persistent viral including HIV. The inhibitory regulatory molecule, Immunoglobulin Mucin domain 3 (Tim-3) induced on HIV-specific in progressive infection. These Tim-3 expressing are dysfunctional terms their capacities to proliferate or produce cytokines. In this study, we evaluated effect expression cytotoxic capabilities...
A rare subset of IL-10-producing B cells, named regulatory cells (Bregs), suppresses adaptive immune responses and inflammation in mice. In this study, we examined the role HIV-1 infection. Compared to uninfected controls, cell frequencies were elevated both blood sigmoid colon during early chronic phase untreated Ex vivo frequency infection directly correlated with viral load. from infected individuals enriched CD19+TIM-1+ for specificity trimeric envelope protein. Anti-retroviral therapy...
Abstract T cell Ig mucin domain-containing molecule 3 (Tim-3) is a glycoprotein found on the surface of subset CD8+ and Th1 CD4+ cells. Elevated expression Tim-3 virus-specific cells during chronic viral infections, such as HIV-1, hepatitis B virus, C positively correlates with load. Tim-3+ cytotoxic are dysfunctional unable to secrete effector cytokines, IFN-γ TNF-α. In this study, we examined potential inducers primary human Direct HIV-1 infection cells, or LPS, be elevated in infection,...
Semen is a major vector for HIV transmission, but the semen RNA viral load (VL) only correlates moderately with blood VL. Viral shedding can be enhanced by genital infections and associated inflammation, it also occur in absence of classical pathogens. Thus, we hypothesized that dysregulated microbiome local shedding. We analyzed samples from 49 men who have sex (MSM), including 22 HIV-uninfected 27 HIV-infected men, at baseline after starting antiretroviral therapy (ART) using 16S rRNA...
Several highly potent and broadly neutralizing monoclonal antibodies against HIV have recently been isolated from B cells of infected individuals. However, the effects these on persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We show that several HIV-specific antibodies--in particular, PGT121, VRC01, VRC03--potently inhibited entry into CD4(+) T latent reservoir whose plasma viremia was well controlled by ART. In addition, we...
The signaling adaptor TNFR-associated factor 1 (TRAF1) is specifically lost from virus-specific CD8 T cells during the chronic phase of infection with HIV in humans or lymphocytic choriomeningitis virus (LCMV) clone 13 mice. In contrast, TRAF1 maintained at higher levels controllers after acute LCMV infection. expression negatively correlates programmed death and load knockdown viral results decreased suppression ex vivo. Consistent desensitization TRAF1-binding co-stimulatory receptor...
Elite controllers suppress human immunodeficiency virus (HIV) viremia to below the limit of detection in absence antiretroviral therapy (ART). However, precise frequencies CD4+ T cells carrying replication-competent HIV and/or dynamics infectious viral reservoirs response initiation and discontinuation ART elite are unknown. We show that size pool harboring diminished significantly after rebounded baseline upon cessation therapy. Our data provide compelling evidence persistent replication...
HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these decay and infected cell population that remains is commonly considered to be invisible T-cells. We hypothesized HIV antigen recognition may persist ART-treated individuals due low-level or episodic protein expression. posited if persistent were occurring it would preferentially directed against early gene products Nef, Tat, Rev as compared late...
Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity these vaccines their effects on reservoirs are not available. Our study 68 PWH 23 HIV-negative participants aged 55 older post-three vaccine doses showed equally strong anti-spike IgG responses in serum saliva through week 48 from baseline, while salivary IgA low. had diminished live-virus neutralization after two doses, which 'rescued' post-booster....
Abstract In chronic diseases, such as HIV infection, plasmacytoid dendritic cells (pDCs) are rendered dysfunctional, measured by their decreased capacity to produce IFN-α. this study, we identified elevated levels of T cell Ig and mucin-domain containing molecule-3 (Tim-3)–expressing pDCs in the blood HIV-infected donors. The frequency Tim-3–expressing correlated inversely with CD4 counts positively viral loads. A lower expressing Tim-3 produced IFN-α or TNF-α response TLR7 agonists...
While combination antiretroviral therapies (cART) have transformed HIV infection into a chronic manageable condition, they do not act upon the latent reservoir and are therefore curative. As cure or remission should be more readily achievable in individuals with smaller reservoirs, achieving deeper understanding of clinical, immunological, virological determinants size is critical to eradication efforts. We performed post hoc analysis 30 participants clinical trial early cART who had...