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1. Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection

Author

Ahuja, Sunil K, Manoharan, Muthu Saravanan, Lee, Grace C, McKinnon, Lyle R, Meunier, Justin A, Steri, Maristella, Harper, Nathan, Fiorillo, Edoardo, Smith, Alisha M, Restrepo, Marcos I, Branum, Anne P, Bottomley, Matthew J, Orrù, Valeria, Jimenez, Fabio, Carrillo, Andrew, Pandranki, Lavanya, Winter, Caitlyn A, Winter, Lauryn A, Gaitan, Alvaro A, Moreira, Alvaro G, Walter, Elizabeth A, Silvestri, Guido, King, Christopher L, Zheng, Yong-Tang, Zheng, Hong-Yi, Kimani, Joshua, Blake Ball, T, Plummer, Francis A, Fowke, Keith R, Harden, Paul N, Wood, Kathryn J, Ferris, Martin T, Lund, Jennifer M, Heise, Mark T, Garrett, Nigel, Canady, Kristen R, Abdool Karim, Salim S, Little, Susan J, Gianella, Sara, Smith, Davey M, Letendre, Scott, Richman, Douglas D, Cucca, Francesco, Trinh, Hanh, Sanchez-Reilly, Sandra, Hecht, Joan M, Cadena Zuluaga, Jose A, Anzueto, Antonio, Pugh, Jacqueline A, Agan, Brian K, Root-Bernstein, Robert, Clark, Robert A, Okulicz, Jason F, and He, Weijing

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Biodefense, Infectious Diseases, Aging, Vaccine Related, Prevention, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Infection, Good Health and Well Being, Female, Humans, Longevity, COVID-19, Inflammation, Outcome Assessment, Health Care, South Texas Veterans Health Care System COVID-19 team
Abstract

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

Published
2023

2. Africa-specific human genetic variation near CHD1L associates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Published
2023
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4. Author Correction: Africa-specific human genetic variation near CHD1L associates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Published
2023
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5. Vaccine targeting SIVmac251 protease cleavage sites protects macaques against vaginal infection

Author

Li, Hongzhao, Omange, Robert W., Liang, Binhua, Toledo, Nikki, Hai, Yan, Liu, Lewis R., Schalk, Dane, Crecente-Campo, Jose, Dacoba, Tamara G., Lambe, Andrew B., Lim, So-Yon, Li, Lin, Kashem, Mohammad Abul, Wan, Yanmin, Correia-Pinto, Jorge F., Seaman, Michael S., Liu, Xiao Qing, Balshaw, Robert F., Li, Qingsheng, Schultz-Darken, Nancy, Alonso, Maria J., Plummer, Francis A., Whitney, James B., and Luo, Ma

Subjects
AIDS vaccines -- Physiological aspects, HIV infections -- Prevention, HIV -- Physiological aspects, Proteases -- Physiological aspects -- Chemical properties -- Health aspects, Vaginosis -- Prevention, Health care industry
Abstract

After over 3 decades of research, an effective anti-HIV vaccine remains elusive. The recently halted HVTN702 clinical trial not only further stresses the challenge to develop an effective HIV vaccine but also emphasizes that unconventional and novel vaccine strategies are urgently needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provided greater than 80% protection to Mauritian cynomolgus macaques against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses correlated with vaccine efficacy. The PCS vaccine did not induce immune activation or inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune microenvironment generated by the PCS vaccine was predictive of vaccine efficacy. Our study demonstrates, for the first time to our knowledge, that a vaccine which targets only viral maturation, but lacks full-length Env and Gag immunogens, can prevent intravaginal infection in a stringent macaque/SIV challenge model. Targeting HIV maturation thus offers a potentially novel approach to developing an effective HIV vaccine., Introduction HIV mutates rapidly and preferentially infects activated [CD4.sup.+] T cells. Inflammation activates and attracts HIV target cells, thereby enhancing the risk of infection (1-3). These inherent characteristics of HIV [...]

Published
2020
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6. The Genome Sequence of the SARS-Associated Coronavirus

Author

Marra, Marco A., Astell, Caroline R., Holt, Robert A., Brooks-Wilson, Angela, Khattra, Jaswinder, Asano, Jennifer K., Barber, Sarah A., Chan, Susanna Y., Cloutier, Alison, Coughlin, Shaun M., Freeman, Doug, Girn, Noreen, Griffith, Obi L., Leach, Stephen R., Mayo, Michael, McDonald, Helen, Montgomery, Stephen B., Pandoh, Pawan K., Petrescu, Anca S., Robertson, A. Gordon, Schein, Jacqueline E., Siddiqui, Asim, Smailus, Duane E., Stott, Jeff M., Yang, George S., Plummer, Francis, Andonov, Anton, Artsob, Harvey, Bastien, Nathalie, Bernard, Kathy, Booth, Timothy F., Bowness, Donnie, Czub, Martin, Drebot, Michael, Fernando, Lisa, Flick, Ramon, Garbutt, Michael, Gray, Michael, Grolla, Allen, Jones, Steven, Feldmann, Heinz, Meyers, Adrienne, Kabani, Amin, Li, Yan, Normand, Susan, Stroher, Ute, Tipples, Graham A., Tyler, Shaun, Vogrig, Robert, Ward, Diane, Watson, Brynn, Brunham, Robert C., Krajden, Mel, Petric, Martin, Skowronski, Danuta M., Upton, Chris, and Roper, Rachel L.

Published
2003

9. Toll-like Interleukin -1 Receptor Regulator (TILRR) Protein, a Major Modulator of Inflammation, is Expressed in Normal Human and Macaque Tissues and PBMCs

Author

Kashem,Mohammad Abul, Li,Lin, Yuan,Xin-Yong, Plummer,Francis A, Luo,Ma, Kashem,Mohammad Abul, Li,Lin, Yuan,Xin-Yong, Plummer,Francis A, and Luo,Ma

Abstract

Mohammad Abul Kashem,1– 3 Lin Li,2 Xin-Yong Yuan,2 Francis A Plummer1 ,†Ma Luo1,2 1Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada; 2JC Wilt Infectious Diseases Research Center, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada; 3Department of Microbiology and Veterinary Public Health, Chittagong Veterinary and Animal Sciences University, Chittagong, Bangladesh†Dr Francis A Plummer passed away on February 04, 2020Correspondence: Ma Luo, JC Wilt Infectious Diseases Research Center, National Microbiology Laboratory, 745 Logan Avenue, Winnipeg, MB, R3E 3L5, Canada, Tel +1 204-789-5072, Fax +1 204-789-2018, Email maluo@phac-aspc.gc.caPurpose: TILRR is a modulator of genes in the NF-κB inflammation pathway. It regulates inflammation-responsive genes, the secretion of inflammatory mediators, and the migration of immune cells. Because inflammation drives the pathogenesis of many infectious and inflammatory diseases, it is important to know the expression of TILRR protein in tissues and cells. This study examined TILRR protein expression in healthy adult human and macaques’ tissues and PBMCs (peripheral blood mononuclear cells).Methods and Results: Tissues (trachea, lungs, stomach, small intestine [ileum], cecum, colon, rectum, vagina, cervix, uterus, and penis) and PBMCs from humans and macaques were lysed in RIPA (radioimmunoprecipitation assay) lysis buffer. The TILRR protein was examined by fluorescent Western blot analysis. The relative fluorescence units (rfu) of TILRR protein expression were quantified by Image Studio software (LI-COR). The results showed that adult healthy female (n=1) rectal and cervicovaginal tissues expressed a higher level of TILRR protein than the other tissues (trachea, lungs, stomach, small intestine [ileum], cecum, colon, uterus, and penis) examined. Like humans, the lungs, colon, and rectal tissues of healthy adult female cynomolgus monke

Published
2022

13. The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans

Author

Abi-Rached, Laurent, Jobin, Matthew J., Kulkarni, Subhash, McWhinnie, Alasdair, Dalva, Klara, Gragert, Loren, Babrzadeh, Farbod, Gharizadeh, Baback, Luo, Ma, Plummer, Francis A., Kimani, Joshua, Carrington, Mary, Middleton, Derek, Rajalingam, Raja, Beksac, Meral, Marsh, Steven G. E., Maiers, Martin, Guethlein, Lisbeth A., Tavoularis, Sofia, Little, Ann-Margaret, Green, Richard E., Norman, Paul J., and Parham, Peter

Published
2011
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17. Africa-specific human genetic variation near CHD1Lassociates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Abstract

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1Lassociates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.

Published
2023
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22. Long-Term Survivors in Nairobi: Complete HIV-1 RNA Sequences and Immunogenetic Associations

Author

Fang, Guowei, Kuiken, Carla, Weiser, Barbara, Rowland-Jones, Sarah, Plummer, Francis, Chen, Chih-Hsiung, Kaul, Rupert, Anzala, Aggrey Omu, Bwayo, Job, Kimani, Joshua, Philpott, Sean M., Kitchen, Christina, Sinsheimer, Janet S., Gaschen, Brian, Lang, Dorothy, Shi, Binshan, Kemal, Kimdar Sherefa, Rostron, Tim, Brunner, Cheryl, Beddows, Simon, Sattenau, Quentin, Paxinos, Ellen, Oyugi, Julius, and Burger, Harold

Published
2004

36. TILRR (Toll-like Interleukin-1 Receptor Regulator), an Important Modulator of Inflammatory Responsive Genes, is Circulating in the Blood

Author

Kashem,Mohammad Abul, Yuan,Xin-Yong, Li,Lin, Kimani,Joshua, Plummer,Francis, Luo,Ma, Kashem,Mohammad Abul, Yuan,Xin-Yong, Li,Lin, Kimani,Joshua, Plummer,Francis, and Luo,Ma

Abstract

Mohammad Abul Kashem,1– 4 Xin-Yong Yuan,4 Lin Li,2 Joshua Kimani,5 Francis Plummer1 ,†Ma Luo1,2,4 1Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada; 2JC Wilt Infectious Diseases Research Centre, Winnipeg, Mb, Canada; 3Department of Microbiology and Veterinary Public Health, Chittagong Veterinary and Animal Sciences University, Chittagong, Bangladesh; 4National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada; 5Institute for Tropical and Infectious Diseases, University of Nairobi, Nairobi, Kenya†In memoriam (passed away on February 4, 2020).Correspondence: Ma LuoDepartment of Medical Microbiology, University of Manitoba, Winnipeg, MB, CanadaTel +204-789-5072Fax +204-789-2018Email maluo@canada.ca; Ma.Luo@umanitoba.caPurpose: TILRR (Toll-like interleukin-1 receptor regulator), a variant of FREM1 (Fras-related extracellular matrix 1), is a modulator of many genes in NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and inflammatory responses. It enhanced the expression of multiple genes in the NF-κB signaling pathway and promoted the production of multiple pro-inflammatory cytokines/chemokines. TILRR is an extracellular matrix protein and expressed in cells and tissues, and has never been considered to exist in the blood. The study aimed to identify circulating TILRR protein in human plasma as a biomarker of systemic inflammation.Methods and Results: We developed a multiplex bead array method (Bio-Plex) using 4 monoclonal antibodies targeting different protein domains of FREM1/TILRR to investigate whether TILRR can be detected in blood plasma. The results of the multiplex bead array method were validated by Western blot analysis of affinity-purified TILRR from patient plasma samples. We subsequently analyzed 640 plasma samples from women enrolled in the Pumwani Sex Worker cohort (PSWC) (Nairobi, Kenya). Our study showed that TILRR exists in all pa

Published
2021

44. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations

Author

Pillai, Nisha Esakimuthu, Okada, Yukinori, Saw, Woei-Yuh, Ong, Rick Twee-Hee, Wang, Xu, Tantoso, Erwin, Xu, Wenting, Peterson, Trevor A., Bielawny, Thomas, Ali, Mohammad, Tay, Koon-Yong, Poh, Wan-Ting, Tan, Linda Wei-Lin, Koo, Seok-Hwee, Lim, Wei-Yen, Soong, Richie, Wenk, Markus, Raychaudhuri, Soumya, Little, Peter, Plummer, Francis A., Lee, Edmund J. D., Chia, Kee-Seng, Luo, Ma, De Bakker, Paul I. W., and Teo, Yik-Ying

Published
2014
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47. Cross-clade HIV-1-specific neutralizing IgA in mucosal and systemic compartments of HIV-1-exposed, persistently seronegative subjects

Author

Devito, Claudia, Hinkula, Jorma, Kaul, Rupert, Kimani, Joshua, Kiama, Peter, Lopalco, Lucia, Barass, Claudia, Piconi, Stefania, Trabattoni, Daria, Bwayo, Job J., Plummer, Francis, Clerici, Mario, and Broliden, Kristina

Subjects
AIDS (Disease) -- Physiological aspects, HIV infection -- Physiological aspects, Cladistic analysis -- Usage, AIDS vaccines -- Research, Natural immunity -- Research, Health
Abstract

The ability of plasma and mucosal IgA purified from HIV-1-exposed, persistently seronegative (HEPS) subjects to neutralize HIV-1 primary isolates of different viral clades and phenotypes has been studied. IgA from two groups of HEPS persons, sex workers in Kenya, where clades A and D predominate, and from heterosexual partners of individuals infected by clade B virus was tested. Mucosal and plasma IgA from HEPS subjects was found to neutralize HIV-1 of different clades. This ability may be important in an effective HIV-1 vaccine. Whether a vaccine will be able to protect against HIV-1 of different clades is a significant concern.

Published
2002

48. Reduced HIV risk-taking and low HIV incidence after enrollment and risk-reduction counseling in a sexually transmitted disease prevention trial in Nairobi, Kenia

Author

Kaul, Rupert, Kimani, Joshua, Nagelkerke, Nico J., Fonck, Karoline, Keli, Florence, MacDonald, Kelly S., Ronald, Allan R., Plummer, Francis A., Bwayo, Job J., Ngugi, Elizabeth N., Temmerman, Marleen, and Moses, Stephen

Subjects
Epidemiology -- Statistics, Epidemiology -- Research, HIV patients -- Health aspects, HIV patients -- Care and treatment, HIV infection -- Demographic aspects, HIV infection -- Prevention, HIV infection -- Research, HIV infection -- Health aspects, Sexually transmitted diseases -- Demographic aspects, Sexually transmitted diseases -- Prevention, Sexually transmitted diseases -- Health aspects, Health
Abstract

Research has been conducted on HIV prevention. The development of the more effective methods of HIV and sexually transmitted infection prevention and the development of HIV vaccine are discussed.

Published
2002

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