Mark Brockman

Mark Brockman
Simon Fraser University · Faculty of Health Sciences

PhD, Virology, Harvard University

About

425
Publications
27,972
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
6,916
Citations
Citations since 2017
100 Research Items
2927 Citations
20172018201920202021202220230100200300400500600
20172018201920202021202220230100200300400500600
20172018201920202021202220230100200300400500600
20172018201920202021202220230100200300400500600
Introduction
My laboratory at Simon Fraser University (Vancouver/Burnaby, Canada) uses molecular and cellular biology approaches to investigate HIV virology, pathogenesis, and the host immune response to infection. Current studies focus on understanding the impact of HIV immune escape mutations on viral fitness and the ability of cytotoxic T lymphocytes (CTL) to recognize virus-infected cells.
Additional affiliations
March 2015 - present
Simon Fraser University
Position
  • Managing Director
December 2011 - present
Simon Fraser University
Position
  • Principal Investigator
September 2011 - December 2011
Simon Fraser University
Position
  • MBB322: Molecular Physiology
Education
September 1995 - June 2001
Harvard University
Field of study
  • Virology
September 1991 - May 1995
Beloit College
Field of study
  • Biochemistry and Philosopy

Publications

Publications (425)
Article
Background: Limited data exist regarding longer term antibody responses following three-dose coronavirus disease 2019 (COVID-19) vaccination, and the impact of a first SARS-CoV-2 infection during this time, in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART). We quantified wild-type-specific, Omicron BA.1-specific and Omicr...
Article
Full-text available
Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely characterized. We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain (RBD), ACE2 displacement and viral neutralization activities one month following the first and second COVID-19 vaccine doses, and again 3 months fo...
Article
Objectives: Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Our objective was to compare COVID-19 vaccine immunogenicity in PWH to HIV-negative individuals. Design: In a Canadian multi-center prospective, observational cohort of PWH receiving at least two COVID-19 vaccinations,...
Preprint
Full-text available
Background: Limited data exist regarding longer-term antibody responses following three-dose COVID-19 vaccination, and the impact of a first SARS-CoV-2 infection during this time, in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). We quantified wild-type-(WT), Omicron BA.1- and Omicron BA.5-specific responses up to...
Article
Full-text available
SARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have immunologically assessed serial Omicron infections. We characterized SARS-CoV-2 humoral responses in an individual who acquired laboratory-confirmed Omicron BA.1.15 ten weeks after a third dose of BNT162...
Preprint
Full-text available
Background Longer-term immune response data after three doses of COVID-19 mRNA vaccine remain limited, particularly among older adults and following Omicron breakthrough infection. Methods We quantified wild-type- and Omicron-specific serum IgG levels, ACE2 displacement activities and live virus neutralization up to six months post-third dose in 1...
Article
Full-text available
Background Longer-term humoral responses to two-dose COVID-19 vaccines remain incompletely characterized in people living with HIV (PLWH), as do initial responses to a third dose. Methods We measured antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement and viral neutralization against wild-type and Omicron str...
Article
Full-text available
HIV-1 accessory proteins Nef and Vpu enhance viral pathogenesis through partially overlapping immune evasion activities. Attenuated Nef or Vpu functions have been reported in individuals who display slower disease progression, but few studies have assessed the relative impact of these proteins in non-B HIV-1 subtypes or examined paired proteins fro...
Preprint
Full-text available
SARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have documented serial Omicron infections. We characterized SARS-CoV-2 humoral responses in a healthy young person who acquired laboratory-confirmed Omicron BA.1.15 ten weeks after a third dose of BNT162b2, a...
Article
Full-text available
Background Third COVID-19 vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults. Methods We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement, and virus neutralization against ancestral and Omicron (BA.1) strains from pre-vaccine up...
Preprint
Full-text available
Background: Longer-term humoral responses to two-dose COVID-19 vaccines remain incompletely characterized in people living with HIV (PLWH), as do initial responses to a third dose. Methods: We measured antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement and viral neutralization against wild-type and Omicron...
Article
Background: Routine HIV drug resistance genotyping identified an integrase sequence harbouring T97A, E138K, G140S and Q148H, with high predicted resistance to all integrase strand transfer inhibitors (INSTIs). Objectives: To assess the impact of these substitutions alone and together on phenotypic INSTI susceptibility. Methods: We constructed rec...
Preprint
Full-text available
Background: Third COVID-19 vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults. Methods: We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement, and virus neutralization against ancestral and Omicron (BA.1) strains from pre-vaccine...
Article
Full-text available
Background The magnitude and durability of immune responses to COVID-19 mRNA vaccines remain incompletely characterized in the elderly. Methods Anti-spike RBD antibodies, ACE2 competition and virus neutralizing activities were assessed in plasma from 151 healthcare workers and older adults (range 24-98 years of age) one month following the first v...
Article
Full-text available
Introduction Most existing vaccines require higher or additional doses or adjuvants to provide similar protection for people living with HIV (PLWH) compared with HIV-uninfected individuals. Additional research is necessary to inform COVID-19 vaccine use in PLWH. Methods and analysis This multicentred observational Canadian cohort study will enrol...
Article
Full-text available
HIV therapy is lifelong because integrated, replication-competent viral copies persist within long-lived cells. To cure HIV, we need to understand when these viral reservoirs form, how large and genetically diverse they are, and how long they endure.
Preprint
Full-text available
Background. Our understanding of COVID-19 vaccine immune responses in people living with HIV (PLWH) remains incomplete. Methods. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and ACE2 displacement activities after one and two COVID-19 vaccine doses in 100 adult PLWH and 152 controls. Re...
Preprint
Full-text available
Background mRNA vaccines reduce COVID-19 incidence and severity, but the durability of vaccine-induced immune responses, particularly among the elderly, remains incompletely characterized. Methods Anti-spike RBD antibody titers, ACE2 competition and virus neutralizing activities were longitudinally assessed in 151 healthcare workers and older adult...
Article
Full-text available
Background The ubiquity of cellular phone (cellphone) use in young people’s daily lives has emerged as a priority area of concern for youth mental health. Objective This study measured the prevalence of depression and its association with high cellphone use among youth in Soweto and Durban, South Africa. Methods We analysed cross-sectional, basel...
Article
MHC-E, a non-classical MHC molecule, restricted CD8 T-cell responses have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E restricted CD8 T-cell responses in HIV infection however remains unknown. In this study, CD8 T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in-v...
Preprint
Full-text available
Background High rates of adolescent pregnancies in South Africa continues to be a pressing public health concern. This study examines (1) the prevalence of current contraceptive use; and (2) the independent association between adolescent pregnancy and effective contraception use. Methods This study uses baseline cross-sectional data from a youth-c...
Article
Full-text available
Background: Understanding young women and men's perceived barriers and facilitators to participation in biomedical HIV prevention research is important for designing youth friendly services (YFS) and acceptable technologies, which are necessary for preventing high sustained HIV incidence in South Africa. This study explores the multileveled barrier...
Preprint
Full-text available
Curing HIV will require eliminating the reservoir of integrated, replication-competent proviruses that persist despite antiretroviral therapy (ART). Understanding the burden, genetic diversity and longevity of persisting proviruses in diverse individuals with HIV is critical to this goal, but these characteristics remain understudied in some groups...
Article
Full-text available
Objectives: Psychological stress is an important determinant of health, including for mental well-being and sexual health. However, little is known about the prevalence and psychosocial and sexual health correlates of perceived stress among young people in South Africa, where elevated life-stressors are an important driver of health inequities. Thi...
Preprint
Full-text available
Background. Several Canadian provinces are extending the interval between COVID-19 vaccine doses to increase population vaccine coverage more rapidly. However, immunogenicity of these vaccines after one dose is incompletely characterized, particularly among the elderly, who are at greatest risk of severe COVID-19. Methods. We assessed SARS-CoV-2 hu...
Article
Objective To assess the prevalence of food insecurity and the independent association between depression and food insecurity among youth living in two urban settings in South Africa. Methods Baseline cross‐sectional survey data was analysed from a prospective cohort study conducted between 2014 and 2016 among youth (aged 16‐24 years) in Soweto and...
Article
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 iden...
Article
Full-text available
The HIV accessory protein Nef downregulates the viral entry receptor CD4, the Human Leukocyte Antigen (HLA)-A and -B molecules, the Serine incorporator 5 (SERINC5) protein and other molecules from the infected cell surface, thereby promoting viral infectivity, replication and immune evasion. The nef locus also represents one of the most genetically...
Article
Full-text available
HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We des...
Article
Full-text available
RESEARCH Cervical cancer is largely preventable, yet remains one of South African (SA) women's most significant health issues. Cervical cancer is the second leading cancer among women in SA, with 12 983 new cases diagnosed in 2018. It is one of the top contributors to cancer mortality, with an estimated 5 595 deaths. Specifically, it is the leading...
Article
Full-text available
A sterilizing or functional cure for HIV is currently precluded by resting CD4+ T cells that harbor latent but replication-competent provirus. The "shock-and-kill" pharmacological approach aims to reactivate provirus expression in the presence of antiretroviral therapy and target virus-expressing cells for elimination. However, no latency-reversal...
Article
Full-text available
Background: Africa bears a disproportionately high burden of globally significant disease but has lagged in knowledge production to address its health challenges. In this contribution, we discuss the challenges and approaches to health research capacity strengthening in sub-Saharan Africa and propose that the recent shift to an African-led approac...
Article
Partner notification and treatment are essential components of sexually transmitted infection (STI) management, but little is known about such practices among adolescents and young adults. Using data from a prospective cohort study (AYAZAZI) of youth aged 16–24 years in Durban, South Africa, we assessed the STI care cascade across participant diagn...
Article
Full-text available
The HIV-1 accessory protein Vpu enhances viral spread by downregulating CD4 and BST-2/tetherin on the surface of infected cells. Natural variability in these Vpu functions may contribute to HIV-1 pathogenesis, but this has not been investigated among the diverse viral subtypes that contribute to the HIV-1 pandemic. In this study, we found that Vpu...
Article
Full-text available
Identification of CD8+ T lymphocyte (CTL) escape mutations that compromise the pathogenic functions of the Nef protein may be relevant for an HIV‐1 attenuation‐based vaccine. Previously, HLA‐associated mutations 102H, 105R, 108D, and 199Y were individually statistically associated with decreased Nef‐mediated HLA‐I downregulation ability in a cohort...
Article
The main barrier to HIV cure is the ability of a genetically diverse pool of proviruses, integrated into the genomes of infected CD4 ⁺ T cells, to persist despite long-term suppressive combination antiretroviral therapy (cART). CD4 ⁺ T cells, however, constitute a heterogeneous population due to their maturation across a developmental continuum, an...
Article
Full-text available
HIV-1 Nef enhances virion infectivity by counteracting host restriction factor SERINC5; however, the impact of natural Nef polymorphisms on this function is largely unknown. We characterize SERINC5 downregulation activity of 91 primary HIV-1 subtype B nef alleles, including isolates from 45 elite controllers and 46 chronic progressors. Controller-d...
Article
Full-text available
Introduction: Measures used to assess equitable relationship dynamics, including the sexual relationship power scale (SRPS) have previously been associated with lower HIV-risk among young women, and reduced perpetration of intimate partner violence among men. However, few studies describe how the SRPS has been adapted and validated for use within...
Conference Paper
Background Women around the world use intra-vaginal practices (IVPs) for varying reasons. IVPs can disrupt the vaginal microbiome and induce inflammation, increasing susceptibility to bacterial vaginosis (BV), a risk for HIV acquisition. Limited research has focused on IVPs and their correlates among adolescent girls and young women (AGYW) in South...
Conference Paper
Background Psycho-social factors affect biological processes, including inflammation and immune response, yet their contribution to gender and socio-economic disparity of HIV is not well understood. In South Africa, 38% of new HIV infections occur in 15–24 year olds, with 3-times higher incidence among females. In this exploratory study, we examine...
Conference Paper
Background South African young women and other key populations have amongst the highest HIV incidence globally, and antiretroviral treatment (ART) initiation remains challenging. We measured HIV incidence, ART initiation, adherence, status disclosure and related support within 3 months from HIV diagnosis for youth who acquired HIV during follow-up...
Article
Sustained viremia after acute HIV infection is associated with profound CD4 ⁺ T cell loss and exhaustion of HIV-specific CD8 ⁺ T cell responses. To determine the impact of combination antiretroviral therapy (cART) on these processes, we examined the evolution of immune responses in acutely infected individuals initiating treatment before peak virem...
Article
HIV-1 Nef modulates the activation state of CD4 ⁺ T cells by altering signaling events elicited by the T cell receptor (TCR). Primary nef sequences exhibit extensive inter-individual diversity that influences their ability to downregulate CD4 and HLA class I; however, the impact of nef variation on modulation of T cell signaling is poorly character...
Article
Functional characterisation of different HIV-1 subtypes may improve understanding of viral pathogenesis and spread. Here, we evaluated the ability of 345 unique HIV-1 Nef clones representing subtypes A, B, C and D to inhibit NFAT signalling following TCR stimulation. The contribution of this Nef function to disease progression was also assessed in...
Article
Full-text available
While combination antiretroviral therapies (cART) have transformed HIV infection into a chronic manageable condition, they do not act upon the latent HIV reservoir and are therefore not curative. As HIV cure or remission should be more readily achievable in individuals with smaller HIV reservoirs, achieving a deeper understanding of the clinical, i...
Article
The identification of HIV polymorphisms reproducibly selected under pressure by specific HLA alleles and the elucidation of their impact on viral function can help identify immunogenic viral regions where immune escape incurs a fitness cost. However, our knowledge of HLA-driven escape pathways and their functional costs is largely limited to HIV su...
Article
Full-text available
Finding a cure for HIV is challenging because the virus is able to integrate itself into the host cell genome and establish a silent state, called latency, allowing it to evade antiviral drugs and the immune system. Various “shock and kill” strategies are being explored in attempts to eliminate latent HIV reservoirs. The goal of these approaches is...
Article
Full-text available
Some closely related human leukocyte antigen (HLA) alleles are associated with variable clinical outcomes following HIV-1 infection despite presenting the same viral epitopes. Mechanisms underlying these differences remain unclear but may be due to intrinsic characteristics of the HLA alleles or responding T cell repertoires. Here we examine CD8⁺ T...
Article
The production of nitric oxide (NO) by inducible NO synthase (iNOS) and the regulation of gene expression by hypoxia-inducible factors (HIFs) are important for many aspects of human cell biology. However, little is known about whether iNOS expression is controlled by HIFs in human cells. Stimulation of A549 human lung epithelial cells with cytokine...
Article
Full-text available
Background: Youth in southern Africa, particularly adolescent girls and young women, are a key population for HIV prevention interventions. Untreated genital tract infections (GTIs) increase both HIV transmission and acquisition risks. South African GTI treatment guidelines employ syndromic management, which relies on individuals to report GTI sig...
Article
Aim It was recently found that HIV can downregulate HLA-C on infected cells. This is mediated by the viral protein Vpu, and is in addition to the downregulation of HLA-A/B by Nef. The magnitude of HLA-C downregulation varies widely between primary HIV viruses, but the selection pressures resulting in either HLA-C downregulation or preservation are...
Article
Full-text available
Given that HIV evolution and latent reservoir establishment occur continually within-host, and that latently infected cells can persist long-term, the HIV reservoir should comprise a genetically heterogeneous archive recapitulating within-host HIV evolution. However, this has yet to be conclusively demonstrated, in part due to the challenges of rec...
Article
Full-text available
HIV-1 can downregulate HLA-C on infected cells, using the viral protein Vpu, and the magnitude of this downregulation varies widely between primary HIV-1 variants. The selection pressures that result in viral downregulation of HLA-C in some individuals, but preservation of surface HLA-C in others are not clear. To better understand viral immune eva...
Data
Vpu sequence information for the longitudinally sampled individual studied in Fig 2E. (A) A phylogenetic tree of 87 Vpu sequences previously obtained from this individual [48]. Sequences are shown from samples taken 1 (light blue), 4 (dark blue), or 10 (magenta) years after seroconversion. The tree is rooted using NL4.3 and a consensus subtype B se...
Data
Multiple linear regression model for viruses of each subtype. Using 191 primary Vpu clones from chronic infection a multiple linear regression model identified residues at 5 positions of Vpu affecting HLA-C downregulation (Fig 4B, shown on the left). This analysis was repeated separately for infections with viruses of different subtype (shown right...
Data
Amino acid sequences of the 35 Vpu clones analyzed from 6 individuals in Fig 2. (DOCX)
Data
HLA-C downregulation quantified for 14 primary viruses, comparing transfection of cloned Vpu molecules to in vitro infection of primary cells. (A) HeLa cells were transfected with Vpu cloned from NL4-3 or a primary virus that downregulates HLA-C. HeLa populations were then gated based on the expression of GFP, and the MFI of HLA-C staining compared...
Data
HIV-1 subtypes differ in their frequency of HLA-C downregulation. Data is shown for 195 individuals from which HLA-C downregulation by a single Vpu clone from chronic untreated infection was measured by transfection of Molt-4 cells. HLA-C downregulation is observed more frequently for Vpu molecules from viral subtypes A and B, compared to subtypes...
Data
Vpu sequence variation observed at positions identified as important in downregulation of HLA-C. 191 primary Vpu clones were analyzed in Fig 4 and identified residues at Vpu positions 3, 5, 15, 16 and 24 which associated independently with HLA-C downregulation. For each of these positions the frequency of all residues observed in this population of...
Data
Residuals plot for predicted HLA-C downregulation. In Fig 4E a multiple linear regression model was used to predict downregulation of HLA-C based on Vpu sequence at 5 positions. The residuals between observed and predicted HLA-C downregulation are shown for all 191 Vpu clones in this analysis. (TIF)
Data
Average expression level of HLA-C alleles. The average expression level for each 2-digit HLA-C allele is reported here, from previously described staining of peripheral blood CD3+ cells from healthy donors analyzed by flow cytometry using the monoclonal antibody DT9 [31]. MFI of DT9 staining was plotted twice for each donor, once for each 2-digit H...
Data
Multiple linear regression model for viruses of each cohort. Using 191 primary Vpu clones from chronic infection a multiple linear regression model identified residues at 5 positions of Vpu affecting HLA-C downregulation (Fig 4B, shown on the left). This analysis was repeated separately for individuals of each of the two cohorts used (shown right)....
Data
Stratification by cohort of analyses indicating HLA-C downregulation adapts to host HLA genotype. (A,B) Separately for BC HOMER and UARTO individuals, the proportion of Vpu clones that downregulate HLA-C strongly is shown for HLA-C alleles with n≥5 in both cohorts. The number of individuals in each group is shown above each plot. (C,D) HLA-C expres...
Data
Correlations between viral sequence adaptation to host HLA-C and the observed downregulation of HLA-C by Vpu. For 72 individuals with subtype B virus the extent of HIV-1 adaptation to each HLA-C could be quantified from the proportion of Nef sequence variants which associate with that HLA-C allele, which are observed in individual viral sequences....
Data
Sequences of HA-tagged HLA constructs. Black text indicates sequence from HLA-A, red indicates sequence from HLA-C, with green identifying the HA tag added at the N-terminus after the leader peptide. (TIF)
Data
Multiple linear regression model including virus subtype as a covariate. Using 191 primary Vpu clones from chronic infection a multiple linear regression model identified residues at 5 positions of Vpu affecting HLA-C downregulation (Fig 4B, shown on the left). This analysis was repeated including viral subtype as a covariate (subtype A, B, C, or D...