Papers by Marianne Harris
Biochemical Pharmacology, 2021
While combination antiretroviral therapy (cART) durably suppresses HIV replication, virus persist... more While combination antiretroviral therapy (cART) durably suppresses HIV replication, virus persists in CD4+ T-cells that harbor latent but spontaneously inducible and replication-competent provirus. One strategy to inactivate these viral reservoirs involves the use of agents that continue to reinforce HIV latency even after their withdrawal. To identify new chemical leads with such properties, we investigated a series of naturally-occurring flavones (chrysin, apigenin, luteolin, and luteolin-7-glucoside (L7G)) and functionally-related cyclin dependent kinase 9 (CDK9) inhibitors (flavopiridol and atuveciclib) which are reported or presumed to suppress HIV replication in vitro. We found that, while all compounds inhibit provirus expression induced by latency-reversing agents in vitro, only aglycone flavonoids (chrysin, apigenin, luteolin, flavopiridol) and atuveciclib, but not the glycosylated flavonoid L7G, inhibit spontaneous latency reversal. Aglycone flavonoids and atuveciclib, but not L7G, also inhibit CDK9 and the HIV Tat protein. Aglycone flavonoids do not reinforce HIV latency following their in vitro withdrawal, which corresponds with their ability to also inhibit class I/II histone deacetylases (HDAC), a well-established mechanism of latency reversal. In contrast, atuveciclib and flavopiridol, which exhibit little or no HDAC inhibition, continue to reinforce latency for 9 to 14+ days, respectively, following their withdrawal in vitro. Finally, we show that flavopiridol also inhibits spontaneous ex vivo viral RNA production in CD4+ T cells from donors with HIV. These results implicate CDK9 inhibition (in the absence of HDAC inhibition) as a potentially favorable property in the search for compounds that durably reinforce HIV latency.
Nature Communications, 2021
Opening Paragraph (serves as abstract for submission) and BodyThe Intact Proviral DNA Assay (IPDA... more Opening Paragraph (serves as abstract for submission) and BodyThe Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a precise and scalable method for intact HIV reservoir quantification1. This duplexed droplet digital PCR (ddPCR) assay simultaneously targets the HIV Packaging Signal (Ψ) and the Rev Responsive Element (RRE) within Envelope (env) to distinguish genomically intact proviruses against a large background of defective ones2. The IPDA requires less time, resources, and biological material than the gold standard for replication-competent HIV reservoir measurement, the Quantitative Viral Outgrowth Assay (QVOA)3, and is being adopted in research and clinical studies4–7. In our cohort of HIV-1 subtype B-infected individuals from North America however, the IPDA yielded a 28% failure rate due to HIV polymorphism. We further demonstrate that within-host HIV diversity can lead the IPDA to underestimate intact HIV reservoir size, which could negatively ...
Viruses, 2019
Quantifying HIV Envelope (Env)-specific antibodies in HIV+ plasma is useful for interpreting anti... more Quantifying HIV Envelope (Env)-specific antibodies in HIV+ plasma is useful for interpreting antibody dependent cellular cytotoxicity assay results. HIV Env, the only viral protein expressed on the surface of infected cells, has a native trimeric closed conformation on cells infected with wild-type HIV. However, CD4+ uninfected bystander cells in HIV+ cell cultures bind gp120 shed from HIV+ cells exposing CD4-induced epitopes normally hidden in native Env. We used flow-cytometry based assays to quantify antibodies in HIV+ plasma specific for native trimeric Env or gp120/CD4 conjugates using CEM.NKr.CCR5 (CEM) cells infected with HIV (iCEM) or coated with recombinant gp120 (cCEM), as a surrogate for gp120+ HIV- bystander cells. Results from both assays were compared to those of a plate-based ELISA to monomeric gp120. The levels of Env-specific antibodies to cCEM and iCEM, measured by flow cytometry, and to gp120 by ELISA were positively correlated. More antibodies in HIV+ plasma reco...
Atherosclerosis Supplements, 2005
BMC Infectious Diseases, 2016
Background: Gay, bisexual and other men who have sex with men (MSM) are disproportionately affect... more Background: Gay, bisexual and other men who have sex with men (MSM) are disproportionately affected by HIV in Canada. Combination antiretroviral therapy has been shown to dramatically decrease progression to AIDS, premature death and HIV transmission. However, there are no comprehensive data regarding combination antiretroviral therapy outcomes among this population. We sought to identify socio-demographic and clinical correlates of viral suppression and rebound. Methods: Our analysis included MSM participants in the Canadian Observational Cohort, a multi-site cohort of HIV-positive adults from Canada's three most populous provinces, aged ≥18 years who first initiated combination antiretroviral therapy between 2000 and 2011. We used accelerated failure time models to identify factors predicting time to suppression (2 measures <50 copies/mL ≥30 days apart) and subsequent rebound (2 measures >200 copies/mL ≥30 days apart). Results: Of 2,858 participants, 2,448 (86 %) achieved viral suppression in a median time of 5 months (Q1-Q3: 3-7 months). Viral suppression was significantly associated with later calendar year of antiretroviral therapy initiation, no history of injection drug use, lower baseline viral load, being on an initial regimen consisting of non-nucleoside reverse-transcriptase inhibitors, and older age. Among those who suppressed, 295 (12 %) experienced viral rebound. This was associated with earlier calendar year of antiretroviral therapy initiation, injection drug use history, younger age, higher baseline CD4 cell count, and living in British Columbia. Conclusions: Further strategies are required to optimize combination antiretroviral therapy outcomes in men who have sex with men in Canada, specifically targeting younger MSM and those with a history of injection drug use.
Nephron Clinical Practice, 2008
MDRD formula than for all other methods. The performance of 24-hour urine creatinine clearance wa... more MDRD formula than for all other methods. The performance of 24-hour urine creatinine clearance was similar to that of the MDRD formula for patients with GFR ! 90 ml/min/1.73 m 2 , although it performed less well at higher GFR. The performance of cystatin C GFR was inferior to that of all the creatinine-based methods. Conclusions: While no method of kidney function estimation performed highly, both 24-hour urine creatinine clearance and the MDRD formula performed with a level of precision and accuracy sufficient for clinical decision making. Our findings support the preferential use of the MDRD formula in the treated HIV population and suggest that there are no HIV-specific factors that limit equation applicability. Larger validation studies are needed to confirm our findings and allow generalization to the HIV population at large.
Nephrology Dialysis Transplantation, 2007
We present a case of renal impairment in an emaciated HIV-infected male that initially went unrec... more We present a case of renal impairment in an emaciated HIV-infected male that initially went unrecognized because of reliance on serum creatinine and estimated glomerular filtration rate (eGFR). Inaccurate vancomycin dosing led to toxic drug levels (66 mg/l), associated with acute and severe worsening of kidney function. This occurred in the context of escalating We support ongoing efforts to develop or refine equations for specific unique and easily identifiable populations.
Quality of Life Research
The purpose of this study is to estimate the extent to which people aging with HIV meet criteria ... more The purpose of this study is to estimate the extent to which people aging with HIV meet criteria for successful aging as operationalized through HRQL and maintain this status over time. A second objective is to identify factors that place people at promise for continued successful aging, including environmental and resilience factors. Participants were members of the Positive Brain Health Now (BHN) cohort. People ≥ 50 years (n = 513) were classified as aging successfully if they were at or above norms on 7 or 8 of 8 health-related quality of life domains from the RAND-36. Group-based trajectory analysis, regression tree analysis, a form of machine learning, and logistic regression were applied to identify factors predicting successful aging. 73 (14·2%) met criteria for successful aging at entry and did not change status over time. The most influential factor was loneliness which split the sample into two groups with the prevalence of successful aging 28·4% in the “almost never” lonely compared to 4·6% in the “sometimes/often” lonely group. Other influential factors were feeling safe, social network, motivation, stigma, and socioeconomic status. These factors identified 17 sub-groups with at least 30 members with the proportions classified as aging successfully ranging from 0 to 79·4%. The nine variables important to classifying successful aging had a predictive accuracy of 0.862. Self-reported cognition but not cognitive test performance improved this accuracy to 0.895. The two groups defined by successful aging status did not differ on age, sex or viral load, nadir and current. The results indicate the important role of social determinants of health in successful aging among people living with HIV.
Results: 15 patients labeled as ABC HSR identified to-date returned for patch testing. 2/15 (13.3... more Results: 15 patients labeled as ABC HSR identified to-date returned for patch testing. 2/15 (13.3%) were patch test positive (PT+) and 13/15 (86.7%) were PT. 6/13 (46.1%) PTpatients were rechallenged with abacavir and 6/6 (100%) have tolerated ABC for a median of 12.5 (2-36) weeks. For 11 patients where genetic testing was available HLA-B*5701 was present in the 2/2 (100%) PT+ patients versus 0/9 patch PTpatients (p=0.018).
HIV Medicine, 2007
To determine the severity of injection site reactions (ISRs), patient quality of life (QoL) and p... more To determine the severity of injection site reactions (ISRs), patient quality of life (QoL) and preference when enfuvirtide is administered by the Biojector s (Bioject, Medical Technologies, Inc., Tualatin, OR, USA) relative to standard needles. A total of 201 HIV-positive patients on stable enfuvirtide-based therapy (n 5 184) or initiating such therapy (n 5 17) were evaluated prospectively after switching from standard needles to the Biojector s system. Patients used needles for a minimum of 2 weeks prior to switching to the Biojector s . Questionnaires to assess the incidence and severity of ISRs (31-item score) and QoL [Medical Outcomes Study HIV Health Survey (MOS-HIV)] were administered at baseline and following a minimum of 14 days of Biojector s use. The median changes in ISR score and number of ISRs following a median of 1.0 month [interquartile range (IQR) 0.9, 1.3] of Biojector s use were À 3 (IQR À 7, 1) and À 1 (IQR À 3, 1), respectively. The severity of pain (Po0.0001), induration (Po0.0001), pruritus (Po0.0001), nodules (Po0.0001) and erythema (Po0.0001) all decreased with the Biojector s . Administration of enfuvirtide with the Biojector s was associated with an improved patient QoL (Po0.0001), and was preferred by 72% of patients. Compared with needles, the Biojector s was associated with a decreased severity of ISRs and improved QoL in patients taking enfuvirtide.
AIDS, 2001
To provide population-based estimates of the prevalence of lipodystrophy syndrome and constituent... more To provide population-based estimates of the prevalence of lipodystrophy syndrome and constituent symptoms and to identify correlates of prevalent symptomology. Participants in a province-wide HIV/AIDS treatment programme reported morphological and metabolic abnormalities. Probable lipodystrophy was defined as self-report of at least one morphological abnormality or both high cholesterol and triglyceride levels. Explanatory variables investigated included: age; sex; ethnicity; transmission risk group; CD4 cell count; plasma viral load; AIDS diagnosis; duration of infection; alternative therapy use; past, current and duration of use of antiretroviral therapy (ART) by class and specific drug; total duration of ART; and current adherence. Stepwise logistic regression identified possible determinates of lipodystrophy. Of 1035 participants, 50% appeared to have probable lipodystrophy, with 36% reporting peripheral wasting, 33% abdominal weight gain, 6% buffalo hump, and 10 and 12% increased triglyceride or cholesterol levels, respectively. In multivariate analysis, lipodystrophy was associated with older age (per year) (AOR 1.03; 95% CI 1.01, 1.04), the use of ingested alternative therapies (AOR 1.46; 95% CI 1.06, 2.01), having ever used protease inhibitors (PI) (AOR 2.63; 95% CI 1.89, 3.66), and duration of stavudine treatment (per year) (AOR 1.35; 95% CI 1.15, 1.58). In analysis limited to participants exposed to PI, after similar adjustment, the duration of lamivudine rather than stavudine treatment was associated with lipodystrophy (AOR 1.32; 95% CI 1.13, 1.53). Increased risk of abnormalities is associated with the use of PI, and the duration of stavudine and lamivudine treatment after adjustment for personal characteristics, clinical disease stage, duration of infection and detailed treatment history.
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, Jan 20, 2004
Long-term remission of HIV-1 disease can be readily achieved by combinations of antiretroviral ag... more Long-term remission of HIV-1 disease can be readily achieved by combinations of antiretroviral agents. The suppression of plasma viral loads to less than the limit of quantification of the most sensitive commercially available assays (i.e., less than 50 copies/mL) and the coincident improvement in CD4 T cell counts is associated with resolution of established opportunistic infections and a decrease in the risk of new opportunistic infections. However, prolonged treatment with combination regimens can be difficult to sustain because of problems with adherence and toxic effects. All antiretroviral drugs can have both short-term and long-term adverse events. The risk of specific side effects varies from drug to drug, from drug class to drug class, and from patient to patient. A better understanding of the adverse effects of antiretroviral agents is of interest not only for HIV specialists as they try to optimize therapy, but also for other physicians who care for HIV-positive patients.
Journal of Biological Chemistry
Clinical Medicine. Therapeutics
Raltegravir is the first integrase strand transfer inhibitor to be approved for the treatment of ... more Raltegravir is the first integrase strand transfer inhibitor to be approved for the treatment of HIV infection. Administered orally in doses of 400 mg twice daily, it is well-tolerated and has minimal drug-drug interactions with coadministered antiretrovirals and other agents. In clinical trials including treatment-experienced and treatment-naïve HIV-infected adults, raltegravir in combination with other antiretroviral agents has demonstrated a rapid and potent virologic effect and a generally benign safety profile. Like other antiretrovirals, raltegravir should ideally be given with two additional agents to which the patient's virus is susceptible based on results of resistance testing. In this context, raltegravir offers a safe and effective option as a component of combination therapy in treatment-experienced patients who are infected with HIV-1 strains showing evidence of resistance to other antiretroviral agents. Pending the availability of longer-term efficacy and safety d...
International Journal of Gynecology & Obstetrics
Journal of Virology
The HIV reservoir, which comprises diverse proviruses integrated into the genomes of infected, pr... more The HIV reservoir, which comprises diverse proviruses integrated into the genomes of infected, primarily CD4+ T cells, is the main barrier to developing an effective HIV cure. Our understanding of the genetics and dynamics of proviruses persisting within distinct CD4+ T cell subsets, however, remains incomplete. Using single-genome amplification, we characterized subgenomic proviral sequences (nef region) from naive, central memory, transitional memory, and effector memory CD4+ T cells from five HIV-infected individuals on long-term combination antiretroviral therapy (cART) and compared these to HIV RNA sequences isolated longitudinally from archived plasma collected prior to cART initiation, yielding HIV data sets spanning a median of 19.5 years (range, 10 to 20 years) per participant. We inferred a distribution of within-host phylogenies for each participant, from which we characterized proviral ages, phylogenetic diversity, and genetic compartmentalization between CD4+ T cell sub...
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Papers by Marianne Harris