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Maple Leaf, Canada
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News Article | April 19, 2017

Researchers at Johns Hopkins and George Washington universities report new evidence that proteins created by defective forms of HIV long previously believed to be harmless actually interact with our immune systems and are actively monitored by a specific type of immune cell, called cytotoxic T cells. In a report on the study, conducted on laboratory-grown human cells and published April 12 in the journal Cell Host and Microbe, the investigators say their experiments show that while defective HIV proviruses -- the viral genetic material -- cannot create functional infectious HIVs, a specific subset called "hypermutated" HIV proviruses creates proteins that cytotoxic T cells recognize as HIV. HIV proviruses can outnumber functional HIV 1000 copies to one and the faulty proteins they create can complicate efforts to measure a patient's viral load, exhaust immune systems, shield functional HIV from attack by natural means or drugs, and seriously complicate the development of a cure. Researchers believe that if they can exploit the "hypermutated" form of these proviruses, it could help them eliminate more of the defective HIV proviruses and develop a cure for HIV infection. "The virus has a lot of ways, even in its defective forms, to distract our immune systems, and understanding how they do this is essential in finding a cure," says Ya Chi Ho, M.D., Ph.D., instructor of medicine at the Johns Hopkins University School of Medicine, and the lead study investigator. In the study, the scientists collected nine different defective HIV proviruses from six people infected with HIV, then transfected cultures of human immune cells with them in the laboratory. They grew and tested the transfected cells for markers of HIV proliferation -- such as RNA and proteins -- and found that all of them were capable of creating these components despite their mutations. "The fact that defective proviruses can contribute to viral RNA and protein production is concerning, because it means that the measurements of HIV load in infected patients may not be as accurate as we thought. Part of the count is coming from defective viruses," says Ho. After verifying that defective HIV proviruses created HIV proteins, the researchers then tested whether human immune system cells could biologically recognize and interact with those proteins. The group again transfected cells in the lab with 6 different types of defective HIV provirus taken from patients. In collaboration with Dr. R. Brad Jones, Ph.D., co-first author of the paper and assistant professor of microbiology, immunology and tropical medicine at the George Washington School of Medicine and Health Sciences, Ho's team matched cytotoxic T lymphocytes, the immune cells responsible for recognizing and destroying HIV, from the corresponding patient to the infected cells. The researchers observed that cells containing a the "hypermutated" HIV can be recognized by an infected patient's cytotoxic T cells. "If we identify and find a way to use the right protein, perhaps one of those expressed by the "hypermutated" HIV we found in this study, we could create a potent vaccine which could boost the immune system enough to eliminate HIV altogether," says Ho. However, defective HIV proviruses can distract the immune cells from attacking fully infectious normal HIV. "The cytotoxic T lymphocytes' ability to identify and target the real threat appears to be greatly impaired, because they may attack proteins from defective proviruses instead of the real thing," says Ho. Ho believes that further information about the mutant proviruses could give scientists the tools to target them, get around them, and create a cure for HIV -- a long elusive goal for virologists. Other researchers involved in this study include Ross A. Pollack, Mihaela Pertea, Katherine M. Bruner, Alyssa R. Martin, Adam A. Capoferri, Subul A. Beg and Robert F. Siliciano from the Johns Hopkins University School of Medicine; R. Brad Jones, Allison S. Thomas, Szu-Han Huang and Sara Karandish of the George Washington University; Eitan Halper-Stromberg of the University of Colorado; Patrick C. Young of the Icahn School of Medicine at Mount Sinai; Colin Kovacs of the University of Toronto & The Maple Leaf Medical Clinic; and Erika Benko of the Maple Leaf Medical Clinic. This work was supported by the National Institute of Allergy and Infectious Diseases Extramural Activities (1R21AI118402-01, AI096114, 1U1AI096109), The Martin Dulaney CARE and DARE Collaboratories, the ARCHE Collaborative Research Grant from the Foundations for AIDS Research Generature Cure initiative, the Johns Hopkins Center for AIDS Research, the W. Smith Charitable Trust AIDS Research Grant, Gilead Science HIV Cure Research Grant, the Howard Hughes Medical Institute and the Bill and Melinda Gates Foundation.

Kamya P.,McGill University | Boulet S.,McGill University | Tsoukas C.M.,McGill University | Routy J.-P.,McGill University | And 11 more authors.
Journal of Virology | Year: 2011

Carriage of the natural killer (NK) receptor genotype KIR3DL1*h/*y with its HLA-B*57 ligand (*h/*y+B*57) is associated with slow time to AIDS and low viral load (VL). To provide a functional basis for these epidemiological observations, we assessed whether HIV-1-infected slow progressors (SP) carrying the *h/ *y+B*57 compound genotype would have increased NK cell polyfunctional potential in comparison to SP with other killer immunoglobulin-like receptor (KIR)/HLA compound genotypes and whether this enhanced polyfunctionality was dependent upon the coexpression of both KIR3DL1*h/*y and HLA-B*57. The functional potential of NK cells was investigated by stimulating peripheral blood mononuclear cells with HLA-devoid targets or single HLA transfectants. Multiparametric flow cytometry was used to detect NK cells with seven functional profiles representing all permutations of CD107a expression and gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) secretion. NK cells from individuals carrying KIR3DL1 receptor-HLABw4 ligand pairs had greater trifunctional responses than those from KIR3DL1 homozygotes (hmz), who were Bw6 homozygotes. NK cells from subjects carrying the *h/*y+B*57 genotypes exhibited the highest trifunctional potential, and this was dependent on cocarriage of the NK receptor and its ligand. Trifunctional cells secreted more of each function tested on a per-cell basis than each corresponding monofunctional NK subset. Although VL influenced NK functionality, individuals with defined KIR/HLA genotypes exhibited differences in NK cell polyfunctionality that could not be accounted for by VL alone. The protective effect of HLA-B*57 on slow progression to AIDS and low VL may be mediated through its interaction with KIR3DL1 alleles to educate NK cells for potent activity upon stimulation. © 2011, American Society for Microbiology. All Rights Reserved.

Margolis D.A.,Glaxosmithkline | Brinson C.C.,Central Texas Clinical Research | Smith G.H.R.,Maple Leaf Medical Clinic | de Vente J.,Living Hope Foundation | And 11 more authors.
The Lancet Infectious Diseases | Year: 2015

Background: In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals. Methods: In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with, NCT01641809. Findings: Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 [87%] of 60, 51 [85%] of 60, and 53 [87%] of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24, 149 (82%; 95% CI 77-88) patients in the cabotegravir groups (48 [80%; 70-90], 48 [80%; 70-90], and 53 [87%; 78-95] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60-82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69-82) receiving cabotegravir (41 [68%; 57-80], 45 [75%; 64-86], and 51 [84%; 74-93] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51-75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 [47%], 32 [53%], and 33 [54%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one [2%], one [2%], and four [7%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group. Interpretation: Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection. Funding: ViiV Healthcare and Janssen Research and Development. © 2015 Elsevier Ltd.

Chun T.-W.,U.S. National Institutes of Health | Murray D.,U.S. National Institutes of Health | Justement J.S.,U.S. National Institutes of Health | Blazkova J.,U.S. National Institutes of Health | And 8 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Several highly potent and broadly neutralizing monoclonal antibodies against HIV have recently been isolated from B cells of infected individuals. However, the effects of these antibodies on the persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We show that several HIV-specific monoclonal antibodies - in particular, PGT121, VRC01, and VRC03 - potently inhibited entry into CD4+T cells of HIV isolated from the latent viral reservoir of infected individuals whose plasma viremia was well controlled by ART. In addition, we demonstrate that HIV replication in autologous CD4+T cells derived from infected individuals receiving ART was profoundly suppressed by three aforementioned and other HIV-specific monoclonal antibodies. These findings have implications for passive immunotherapy as an approach toward controlling plasma viral rebound in patients whose ART is withdrawn.

Kim C.J.,University of Toronto | Nazli A.,McMaster University | Rojas O.L.,University of Toronto | Chege D.,University of Toronto | And 17 more authors.
Mucosal Immunology | Year: 2012

Interleukin-22 (IL-22) is a cytokine with epithelial reparative and regenerative properties that is produced by Th22 cells and by other immune cell subsets. Therefore, we explored the hypothesis that disruption of the gut barrier during HIV infection involves dysregulation of these cells in the gastrointestinal mucosa. Sigmoid IL-22-producing T cell and Th22 cells were dramatically depleted during chronic HIV infection, epithelial integrity was compromised, and microbial translocation was increased. These alterations were reversed after long-term antiretroviral therapy. While all mucosal IL-22-producing T-cell subsets were also depleted very early during HIV infection, at these early stages IL-22 production by non-T-cell populations (including NKp44 cells) was increased and gut epithelial integrity was maintained. Circulating Th22 cells expressed a higher level of the HIV co-receptor/binding molecules CCR5 and α4β7 than CD4+ T-cell subsets in HIV-uninfected participants, but this was not the case after HIV infection. Finally, recombinant IL-22 was protective against HIV and tumor necrosis factor-α-induced gut epithelial damage in a validated in vitro gut epithelial system. We conclude that reduced IL-22 production and Th22 depletion in the gut mucosa are important factors in HIV mucosal immunopathogenesis. © 2012 Society for Mucosal Immunology.

Vali B.,University of Toronto | Jones R.B.,University of Toronto | Sakhdari A.,University of Toronto | Sheth P.M.,University of Toronto | And 11 more authors.
European Journal of Immunology | Year: 2010

Co-infection of HCV with HIV has been associated with more rapid progression of HCV-related disease. HCV-specific T-cell immune responses, which are essential for disease control, are attenuated in co-infection with HIV. T-cell exhaustion has recently been implicated in the deficient control of chronic viral infections. In the current study, we investigated the role of programmed death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) expression in T-cell exhaustion during HCV/HIV co-infection. We show that in HCV/HIV co-infection, both total and HCV-specific T cells co-express Tim-3 and PD-1 in significantly higher frequencies, compared with HCV mono-infection. Co-expression of these two markers on HCV-specific CD8 + T cells positively correlated with a clinical parameter of liver disease progression. HCV-specific CD8+ T cells showed greater frequencies of Tim-3/PD-1 co-expression than HIV-specific CD8+ T cells, which may indicate a greater degree of exhaustion in the former. Blocking Tim-3 or PD-1 pathways restored both HIV- and HCV-specific CD8+ T-cell expansion in the blood of co-infected individuals. These data demonstrate that co-expression of Tim-3 and PD-1 may play a significant role in HCV-specific T-cell dysfunction, especially in the setting of HIV co-infection. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Yue F.Y.,University of Toronto | Lo C.,University of Toronto | Sakhdari A.,University of Toronto | Lee E.Y.,University of Toronto | And 10 more authors.
Journal of Immunology | Year: 2010

We examined the role of CD4+ T cell IL-21 production in viral control of HIV infection. HIV-infected individuals had greater circulating IL-21-producing CD4+ T cells in blood compared with uninfected volunteers. HIV-specific IL-21-producing CD4+ T cells were detected in blood during untreated acute and chronic HIV infection, and elevated frequencies of these cells correlated with relative viral control. These cells had an effector memory or end effector phenotype and expressed CXCR5. HIV-specific CD8+ T cells exhibited high levels of IL-21R, indicating sensitivity to IL-21. Low or aviremic long-term nonprogressors, however, showed absent or low HIV-specific IL-21 CD4+ T cells, but more easily detectable HIV-specific IL-2-producing CD4+ T cells, suggesting changing requirements for particular γ-chain cytokines depending on Ag abundance. Thus, IL-21-producing CD4+ T cells are induced in viremic HIV infection and likely contribute to viral control by affecting CD8 + T cell maintenance. Copyright © 2010 by The American Association of Immunologists, Inc.

Naccarato M.,St Michaels Hospital | Yoong D.,St Michaels Hospital | Kovacs C.,Maple Leaf Medical Clinic | Gough K.,St Michaels Hospital | Gough K.,University of Toronto
Antiviral Therapy | Year: 2012

The cytochrome P450 isoforms primarily involved in clobazam metabolism are CYP3A4 and 2C19. Drugs that modulate these enzymes would then be expected to alter the exposure of clobazam and its major metabolites. Etravirine, a second-generation non-nucleoside reverse transcriptase inhibitor has been shown to induce CYP3A4, while inhibiting CYP2C9 and CYP2C19. We report a case in which a potential drug interaction between clobazam and etravirine may have led to increased concentrations of clobazam and its pharmacologically active metabolite, N-desmethylclobazam, causing neurotoxic symptoms. ©2012 International Medical Press.

Antoniou T.,St Michaels Hospital | Antoniou T.,University of Toronto | Loutfy M.R.,University of Toronto | Brunetta J.,Maple Leaf Medical Clinic | And 4 more authors.
Antiviral Therapy | Year: 2014

Methods: We conducted a pharmacokinetic study using a staggered sampling approach. A total of 16 HIV-infected men receiving raltegravir-based therapy were recruited into the study. Each participant provided six blood plasma and six seminal plasma samples for quantification of drug concentrations in both compartments. Blood and semen samples were obtained within 1 h of each other and were collected prior to the morning dose and at 1, 2, 4, 8 and 12 h post-ingestion. Drug concentrations were determined by liquid chromatography tandem mass spectrometry.Results: A total of 96 semen samples and 96 blood samples were obtained from all participants during the study period. The median age and baseline CD4+ T-cell count of the study participants were 48 years (IQR 42-53) and 450 cells/mm3 (IQR 289-585). Virological suppression to <50 copies/ml had been maintained for a median of 21 months (IQR 7-35) at the time of study enrolment. The median seminal plasma-to-blood plasma ratios and AUC0-12 h seminal plasma-to-blood plasma ratios of raltegravir were 3.25 (IQR 1.46-5.37) and 2.26 (IQR 1.05-4.45), respectively. Conclusions: Concentrations of raltegravir in seminal plasma are several fold higher than those attained in blood plasma and those required to inhibit viral replication in this compartment. Further research examining the therapeutic and prophylactic implications of these findings is warranted..Background: We sought to determine the pharmacokinetic disposition of raltegravir in the blood and seminal plasma of HIV-infected men. © 2014 International Medical Press 1359-6535 (print) 2040-2058 (online).

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