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2. 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

3. Immunologic resilience and COVID-19 survival advantage.

Author

Lee, Grace C, Restrepo, Marcos I, Harper, Nathan, Manoharan, Muthu Saravanan, Smith, Alisha M, Meunier, Justin A, Sanchez-Reilly, Sandra, Ehsan, Aamir, Branum, Anne P, Winter, Caitlyn, Winter, Lauryn, Jimenez, Fabio, Pandranki, Lavanya, Carrillo, Andrew, Perez, Graciela L, Anzueto, Antonio, Trinh, Hanh, Lee, Monica, Hecht, Joan M, Martinez-Vargas, Celida, Sehgal, Raj T, Cadena, Jose, Walter, Elizabeth A, Oakman, Kimberly, Benavides, Raymond, Pugh, Jacqueline A, South Texas Veterans Health Care System COVID-19 Team, Letendre, Scott, Steri, Maristella, Orrù, Valeria, Fiorillo, Edoardo, Cucca, Francesco, Moreira, Alvaro G, Zhang, Nu, Leadbetter, Elizabeth, Agan, Brian K, Richman, Douglas D, He, Weijing, Clark, Robert A, Okulicz, Jason F, and Ahuja, Sunil K

Subjects
South Texas Veterans Health Care System COVID-19 Team, AIDS, Aging, COVID-19, HIV, SARS-CoV-2, biomarkers, immune, inflammation, influenza, Infectious Diseases, Biodefense, Lung, Prevention, Emerging Infectious Diseases, Vaccine Related, Clinical Research, Pneumonia & Influenza, Pneumonia, 2.4 Surveillance and distribution, 2.1 Biological and endogenous factors, Infection, Allergy, Immunology
Abstract

BackgroundThe risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR).ObjectiveWe sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality.MethodsIR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes.ResultsIHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females.ConclusionsPreservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

Published
2021

4. Alcohol Consumption and Risk of Coronary Artery Disease (from the Million Veteran Program)

Author

Song, Rebecca J, Nguyen, Xuan-Mai T, Quaden, Rachel, Ho, Yuk-Lam, Justice, Amy C, Gagnon, David R, Cho, Kelly, O'Donnell, Christopher J, Concato, John, Gaziano, J Michael, Djoussé, Luc, Program, VA Million Veteran, Halasz, Ildiko, Federman, Daniel, Beckham, Jean, Sherman, Scott E, Sriram, Peruvemba, Tsao, Philip S, Boyko, Edward J, Xu, Junzhe, Lederle, Frank, Dellitalia, Louis J, McArdle, Rachel, Kaminsky, Laurence, Swann, Alan C, Hamner, Mark B, Florez, Hermes J, Pandya, Prashant, Villarreal, Gerardo, Wilson, Peter, Morgan, Timothy R, Davis, Lori, Hurley, Robin A, Meyer, Laurence, Ahuja, Sunil K, Konicki, Eric P, Cohen, David, Lichy, Jack, Whittle, Jeffrey, Haddock, Kathlyn Sue, Straub, Karl D, Callaghan, John T, Aguayo, Samuel M, Gupta, Samir, Washburn, Ronald G, Oehlert, Mary E, Hung, Adriana M, Wallbom, Agnes, Keith, Robert, Sonel, Elif, Schifman, Ronald B, Childress, Richard D, Godschalk, Michael F, Shuldiner, Alan R, Rastogi, Padmashri, Gutierrez, Salvador, Fernando, Ronald, Iruvanti, Pran R, Jhala, Darshana, Rosado-Rodriguez, Carlos, Mastorides, Stephen M, Harley, John B, Mattocks, Kristin, Robey, Brooks, Striker, Robert T, Rauchman, Michael, Wells, John, Ballas, Zuhair K, Woods, Susan S, Yeh, Shing Shing, Ratcliffe, Nora R, Klein, Jon B, Golden, Adam G, Ginzburg, Harold M, Sharma, Satish, Oursler, Kris Ann K, Whooley, Mary A, Gibson, Gretchen, and Heinz

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Substance Misuse, Brain Disorders, Heart Disease - Coronary Heart Disease, Alcoholism, Alcohol Use and Health, Heart Disease, Cardiovascular, Clinical Research, Atherosclerosis, Stroke, Oral and gastrointestinal, Good Health and Well Being, Aged, Alcohol Drinking, Alcoholic Beverages, Alcoholism, Coronary Artery Disease, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Protective Factors, Risk Factors, Self Report, United States, Veterans, VA Million Veteran Program, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

Moderate alcohol consumption has been associated with a lower risk of coronary artery disease (CAD) in the general population but has not been well studied in US veterans. We obtained self-reported alcohol consumption from Million Veteran Program participants. Using electronic health records, CAD events were defined as 1 inpatient or 2 outpatient diagnosis codes for CAD, or 1 code for a coronary procedure. We excluded participants with prevalent CAD (n = 69,995) or incomplete alcohol information (n = 8,449). We used a Cox proportional hazards model to estimate hazard ratios and 95% confidence intervals for CAD, adjusting for age, gender, body mass index, race, smoking, education, and exercise. Among 156,728 participants, the mean age was 65.3 years (standard deviation = 12.1) and 91% were men. There were 6,153 CAD events during a mean follow-up of 2.9 years. Adjusted hazard ratios (95% confidence intervals) for CAD were 1.00 (reference), 1.02 (0.92 to 1.13), 0.83 (0.74 to 0.93), 0.77 (0.67 to 0.87), 0.71 (0.62 to 0.81), 0.62 (0.51 to 0.76), 0.58 (0.46 to 0.74), and 0.95 (0.85 to 1.06) for categories of never drinker; former drinker; current drinkers of ≤0.5 drink/day, >0.5 to 1 drink/day, >1 to 2 drinks/day, >2 to 3 drinks/day, and >3 to 4 drinks/day; and heavy drinkers (>4 drinks/day) or alcohol use disorder, respectively. For a fixed amount of ethanol, intake at ≥3 days/week was associated with lower CAD risk compared with ≤1 day/week. Beverage preference (beer, wine, or liquor) did not influence the alcohol-CAD relation. Our data show a lower risk of CAD with light-to-moderate alcohol consumption among US veterans, and drinking frequency may provide a further reduction in risk.

Published
2018

5. DASH Score and Subsequent Risk of Coronary Artery Disease: The Findings From Million Veteran Program

Author

Djoussé, Luc, Ho, Yuk‐Lam, Nguyen, Xuan‐Mai T, Gagnon, David R, Wilson, Peter WF, Cho, Kelly, Gaziano, J Michael, Program, the VA Million Veteran, Halasz, Ildiko, Federman, Daniel, Beckham, Jean, Sherman, Scott E, Sriram, Peruvemba, Tsao, Philip S, Boyko, Edward J, Xu, Junzhe, Lederle, Frank, Dellitalia, Louis J, McArdle, Rachel, Kaminsky, Laurence, Swann, Alan C, Hamner, Mark B, Florez, Hermes J, Pandya, Prashant, Villarreal, Gerardo, Wilson, Peter, Morgan, Timothy R, Davis, Lori, Hurley, Robin A, Meyer, Laurence, Ahuja, Sunil K, Konicki, Eric P, Cohen, David, Lichy, Jack, Whittle, Jeffrey, Haddock, Kathlyn Sue, Straub, Karl D, Callaghan, John T, Aguayo, Samuel M, Gupta, Samir, Washburn, Ronald G, Oehlert, Mary E, Hung, Adriana M, Wallbom, Agnes, Keith, Robert, Sonel, Elif, Schifman, Ronald B, Childress, Richard D, Godschalk, Michael F, Shuldiner, Alan R, Rastogi, Padmashri, Gutierrez, Salvador, Fernando, Ronald, Iruvanti, Pran R, Jhala, Darshana, Rosado‐Rodriguez, Carlos, Mastorides, Stephen M, Harley, John B, Mattocks, Kristin, Striker, Robert T, Rauchman, Michael, Wells, John, Ballas, Zuhair K, Woods, Susan S, Yeh, Shing, Ratcliffe, Nora R, Klein, Jon B, Golden, Adam G, Ginzburg, Harold M, Sharma, Satish, Oursler, Kris Ann K, Whooley, Mary A, and Gibson, Gretchen

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Nutrition, Hypertension, Atherosclerosis, Clinical Research, Cardiovascular, Prevention, Good Health and Well Being, Aged, Coronary Artery Disease, Diet, Healthy, Dietary Approaches To Stop Hypertension, Female, Humans, Incidence, Male, Middle Aged, Patient Compliance, Prognosis, Prospective Studies, Protective Factors, Risk Assessment, Risk Factors, Risk Reduction Behavior, Time Factors, United States, Veterans Health, VA Million Veteran Program, coronary artery disease, epidemiology, nutrition, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract

While adherence to healthful dietary patterns has been associated with a lower risk of coronary artery disease (CAD) in the general population, limited data are available among US veterans. We tested the hypothesis that adherence to Dietary Approach to Stop Hypertension (DASH) food pattern is associated with a lower risk of developing CAD among veterans. We analyzed data on 153 802 participants of the Million Veteran Program enrolled between 2011 and 2016. Information on dietary habits was obtained using a food frequency questionnaire at enrollment. We used electronic health records to assess the development of CAD during follow-up. Of the 153 802 veterans who provided information on diet and were free of CAD at baseline, the mean age was 64.0 (SD=11.8) years and 90.4% were men. During a mean follow-up of 2.8 years, 5451 CAD cases occurred. The crude incidence rate of CAD was 14.0, 13.1, 12.6, 12.3, and 11.1 cases per 1000 person-years across consecutive quintiles of Dietary Approach to Stop Hypertension score. Hazard ratios (95% confidence interval) for CAD were 1.0 (ref), 0.91 (0.84-0.99), 0.87 (0.80-0.95), 0.86 (0.79-0.94), and 0.80 (0.73-0.87) from the lowest to highest quintile of Dietary Approach to Stop Hypertension score controlling for age, sex, body mass index, race, smoking, exercise, alcohol intake, and statin use (P linear trend,

Published
2018

6. Immunologic resilience and COVID-19 survival advantage

Author

Abdalla, Mohamed I., Adams, Sandra G., Agnew, Joseph, Ali, Saleem, Barker, Jennifer, Birdwell, Angela, Bradford, Stephen, Briggs, Heather, Marin Corral, Judith, Dacus, Jennifer J., Danaher, Patrick J., DePaul, Scott A., Dickerson, Jill, Doanne, Jollynn, Elbel, Samantha, Escamilla, Corina, Farrar, Robert, Feldman, David, Flynn, Julianne, Ford, Delvina, Foy, Joanna D., Freeman, Megan, Galley, Samantha, Garza, Maritza, Gilman, Sherraine, Gomez, Jennifer, Goyal, Varun K., Grassmuck, Sally, Hanson, Joshua, Harris, Brande, Hastings, Gabrielyd, Haywood, Audrey, Hinojosa, Cecilia, Ho, Tony T., Hopkins, Teri, Jewell, Pamela, Johnson, Thomas B., Kotogiannes, Vasiliki, Lawler, Austin C., Lester, Chadwick S., Levine, Stephanie M., Lewis, Haidee V., Louder, Angel, Mainor, Charmaine, Maldonado, Rachel, Martinez, Yvette, McElligott, Neil, Medlin, Laura, Mireles, Myra, Morneau, Kathleen, Munro, Samuel B., Nambiar, Anoop, Nassery, Daniel, Nathanson, Robert, O’Rorke, Jane, Padgett, Cheryl, Pascual-Guardia, Sergi, Patterson, Marisa, Perez, Rogelio, Phillips, Robert E., Polk, Patrick B., Pomager, Michael A., Preston, Kristy J., Proud, Kevin C., Rangel, Michelle, Ratcliffe, Temple A., Reichelderfer, Renee L., Renz, Evan M., Ross, Jeanette, Rudd, Teresa, Sanchez, Maria E., Sanders, Tammy, Schindler, Kevin C., Schmit, David, Solorzano, Claudio, Soni, Nilam, Tam, Win S., Tovar, Edward J., Tyler, Anna R., Vasquez, Anjuli, Veloso, Maria C., Venticinque, Steven G., Villalpando, Jorge A., Villanueva, Melissa, Villegas, Lauren, Wallace, Andrew, Wang, Emily, Williamson, Andreia, Trammell Velasquez, Sadie A., Yunes, Andrea, Zentner, Katharine H., Lee, Grace C., Restrepo, Marcos I., Harper, Nathan, Manoharan, Muthu Saravanan, Smith, Alisha M., Meunier, Justin A., Sanchez-Reilly, Sandra, Ehsan, Aamir, Branum, Anne P., Winter, Caitlyn, Winter, Lauryn, Jimenez, Fabio, Pandranki, Lavanya, Carrillo, Andrew, Perez, Graciela L., Anzueto, Antonio, Trinh, Hanh, Lee, Monica, Hecht, Joan M., Martinez-Vargas, Celida, Sehgal, Raj T., Cadena, Jose, Walter, Elizabeth A., Oakman, Kimberly, Benavides, Raymond, Pugh, Jacqueline A., Letendre, Scott, Steri, Maristella, Orrù, Valeria, Fiorillo, Edoardo, Cucca, Francesco, Moreira, Alvaro G., Zhang, Nu, Leadbetter, Elizabeth, Agan, Brian K., Richman, Douglas D., He, Weijing, Clark, Robert A., Okulicz, Jason F., and Ahuja, Sunil K.

Published
2021
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7. Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases

Author

Smith, Alisha M., Harper, Nathan, Meunier, Justin A., Branum, Anne P., Jimenez, Fabio, Pandranki, Lavanya, Carrillo, Andrew, Dela Cruz, Charles S., Restrepo, Marcos I., Maselli, Diego J., Rather, Cynthia G., Heisser, Anna H., Ramirez, Daniel A., He, Weijing, Clark, Robert A., Andrews, Charles P., Evans, Scott E., Pugh, Jacqueline A., Zhang, Nu, Lee, Grace C., Moreira, Alvaro G., Segal, Leopoldo N., Ramirez, Robert M., Jacobs, Robert L., Manoharan, Muthu Saravanan, Okulicz, Jason F., and Ahuja, Sunil K.

Published
2021
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8. Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

Author

Gornalusse, German G, Mummidi, Srinivas, Gaitan, Alvaro A, Jimenez, Fabio, Ramsuran, Veron, Picton, Anabela, Rogers, Kristen, Manoharan, Muthu Saravanan, Avadhanam, Nymisha, Murthy, Krishna K, Martinez, Hernan, Murillo, Angela Molano, Chykarenko, Zoya A, Hutt, Richard, Daskalakis, Demetre, Shostakovich-Koretskaya, Ludmila, Karim, Salim Abdool, Martin, Jeffrey N, Deeks, Steven G, Hecht, Frederick, Sinclair, Elizabeth, Clark, Robert A, Okulicz, Jason, Valentine, Fred T, Martinson, Neil, Tiemessen, Caroline Tanya, Ndung’u, Thumbi, Hunt, Peter W, He, Weijing, and Ahuja, Sunil K

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Immunology, Medical Microbiology, Human Genome, Sexually Transmitted Infections, Infectious Diseases, HIV/AIDS, 2.1 Biological and endogenous factors, Aetiology, DNA Methylation, Epigenesis, Genetic, HIV-1, Humans, Lymphocyte Activation, Receptors, CCR5, Receptors, Virus, T-Lymphocytes, HIV, CCR5, methylation, T-cell activation, polymorphism
Abstract

T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG -41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naïve T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG -41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Δ32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Δ32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (≥800 cells per mm(3)) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes.

Published
2015

9. Influence of the Timing of Antiretroviral Therapy on the Potential for Normalization of Immune Status in Human Immunodeficiency Virus 1–Infected Individuals

Author

Okulicz, Jason F, Le, Tuan D, Agan, Brian K, Camargo, Jose F, Landrum, Michael L, Wright, Edwina, Dolan, Matthew J, Ganesan, Anuradha, Ferguson, Tomas M, Smith, Davey M, Richman, Douglas D, Little, Susan J, Clark, Robert A, He, Weijing, and Ahuja, Sunil K

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Clinical Research, Hepatitis, Digestive Diseases, Liver Disease, Infectious Diseases, Prevention, Vaccine Related, Immunization, HIV/AIDS, Hepatitis - B, 2.1 Biological and endogenous factors, Aetiology, Infection, Good Health and Well Being, Adult, Anti-HIV Agents, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes, Female, HIV Infections, Humans, Male, RNA, Viral, Time Factors, Treatment Outcome, Young Adult, Clinical Sciences, Opthalmology and Optometry, Public Health and Health Services, Clinical sciences, Health services and systems
Abstract

ImportanceIn individuals with human immunodeficiency virus 1 (HIV-1) infection who are receiving antiretroviral therapy (ART), factors that promote full immune recovery are not well characterized.ObjectiveTo investigate the influence of the timing of ART relative to HIV-1 infection on normalization of CD4+ T-cell counts, AIDS risk, and immune function.Design, setting, and participantsParticipants in the observational US Military HIV Natural History Study with documented estimated dates of seroconversion (EDS) who achieved virologic suppression with ART were evaluated. Markers indicative of immune activation, dysfunction, and responsiveness were determined. Responses to hepatitis B virus (HBV) vaccine, an indicator of in vivo immune function, were also assessed. The timing of ART was indexed to the EDS and/or entry into the cohort. The CD4+ counts in HIV-1-uninfected populations were surveyed.Main outcomes and measuresNormalization of CD4+ counts to 900 cells/μL or higher, AIDS development, HBV vaccine response, as well as T-cell activation, dysfunction, and responsiveness.ResultsThe median CD4+ count in HIV-1-uninfected populations was approximately 900 cells/μL. Among 1119 HIV-1-infected participants, CD4+ normalization was achieved in 38.4% vs 28.3% of those initiating ART within 12 months vs after 12 months from the EDS (P = .001). Incrementally higher CD4+ recovery (

Published
2015

12. Alcohol Consumption and Risk of Coronary Artery Disease (from the Million Veteran Program)

Author

Halasz, Ildiko, Federman, Daniel, Beckham, Jean, Sherman, Scott E., Sriram, Peruvemba, Tsao, Philip S., Boyko, Edward J., Xu, Junzhe, Lederle, Frank, Dellitalia, Louis J., McArdle, Rachel, Kaminsky, Laurence, Swann, Alan C., Hamner, Mark B., Florez, Hermes J., Pandya, Prashant, Villarreal, Gerardo, Wilson, Peter, Morgan, Timothy R., Davis, Lori, Hurley, Robin A., Meyer, Laurence, Ahuja, Sunil K., Konicki, Eric P., Cohen, David, Lichy, Jack, Whittle, Jeffrey, Haddock, Kathlyn Sue, Straub, Karl D., Callaghan, John T., Aguayo, Samuel M., Gupta, Samir, Washburn, Ronald G., Oehlert, Mary E., Hung, Adriana M., Wallbom, Agnes, Keith, Robert, Sonel, Elif, Schifman, Ronald B., Childress, Richard D., Godschalk, Michael F., Shuldiner, Alan R., Rastogi, Padmashri, Gutierrez, Salvador, Fernando, Ronald, Iruvanti, Pran R., Jhala, Darshana, Rosado-Rodriguez, Carlos, Mastorides, Stephen M., Harley, John B., Mattocks, Kristin, Robey, Brooks, Striker, Robert T., Rauchman, Michael, Wells, John, Ballas, Zuhair K., Woods, Susan S., Yeh, Shing Shing, Ratcliffe, Nora R., Klein, Jon B., Golden, Adam G., Ginzburg, Harold M., Sharma, Satish, Oursler, Kris Ann K., Whooley, Mary A., Gibson, Gretchen, Heinz, Song, Rebecca J., Nguyen, Xuan-Mai T., Quaden, Rachel, Ho, Yuk-Lam, Justice, Amy C., Gagnon, David R., Cho, Kelly, O'Donnell, Christopher J., Concato, John, Gaziano, J. Michael, and Djoussé, Luc

Published
2018
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13. The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility

Author

Gonzalez, Enrique, Kulkarni, Hemant, Bolivar, Hector, Mangano, Andrea, Sanchez, Racquel, Catano, Gabriel, Nibbs, Robert J., Freedman, Barry I., Quinones, Marlon P., Bamshad, Michael J., Murthy, Krishna K., Rovin, Brad H., Bradley, William, Clark, Robert A., Anderson, Stephanie A., O'Connell, Robert J., Agan, Brian K., Ahuja, Seema S., Bologna, Rosa, Sen, Luisa, Dolan, Matthew J., and Ahuja, Sunil K.

Published
2005

14. Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease

Author

Shimizu, Chisato, Matsubara, Tomoyo, Onouchi, Yoshihiro, Jain, Sonia, Sun, Shelly, Nievergelt, Caroline M, Shike, Hiroko, Brophy, Victoria H, Takegawa, Tsuyoshi, Furukawa, Susumu, Akagi, Teiji, Newburger, Jane W, Baker, Annette L, Burgner, David, Hibberd, Martin L, Davila, Sonia, Levin, Michael, Mamtani, Manju, He, Weijing, Ahuja, Sunil K, and Burns, Jane C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Heart Disease, Heart Disease - Coronary Heart Disease, Autoimmune Disease, Cardiovascular, Clinical Research, Atherosclerosis, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Child, Coronary Aneurysm, Female, Haplotypes, Humans, Male, Matrix Metalloproteinases, Mucocutaneous Lymph Node Syndrome, Multigene Family, Polymorphism, Single Nucleotide, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes, including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease (KD) is an acute, self-limited vasculitis in children and the leading cause of acquired coronary artery aneurysms. We sought to identify shared molecular mechanisms of aneurysm formation by genotyping eight polymorphisms in matrix metalloproteinase (MMP)-1, 3, 7, 12 and 13 in the gene cluster on Chr.11q22, whose gene products have been implicated in aneurysm formation or are known to have elastase activity. We genotyped 482 US-UK KD patients (aneurysm+: n=111, aneurysm-: n=371) and tested our findings in an independent cohort of 200 Japanese KD patients (aneurysm+: n=58, aneurysm-: n=142). Analysis of the five MMP genes identified modest trends in allele and genotype frequencies for MMP-3 rs3025058 (-/T) and haplotypes containing MMP-3 rs3025058 (-/T) and MMP-12 rs2276109 (A/G) (nominal P=2 to 4 × 10(-5)) that conferred increased risk of aneurysm formation in US-UK subjects. This finding was validated in Japanese subjects and suggests the importance of this locus in aneurysm formation in children with KD. The region encompassing these risk haplotypes is a prime candidate for resequencing to look for rare genetic variation that may influence aneurysm formation.

Published
2010

15. Association of CCR2-CCR5 haplotypes and CCL3L1 copy number with Kawasaki Disease, coronary artery lesions, and IVIG responses in Japanese children.

Author

Mamtani, Manju, Matsubara, Tomoyo, Shimizu, Chisato, Furukawa, Susumu, Akagi, Teiji, Onouchi, Yoshihiro, Hata, Akira, Fujino, Akihiro, He, Weijing, Ahuja, Sunil K, and Burns, Jane C

Subjects
Coronary Vessels, Humans, Mucocutaneous Lymph Node Syndrome, Genetic Predisposition to Disease, Immunoglobulins, Intravenous, Receptors, CCR5, Chemokines, CC, Logistic Models, Drug Resistance, Haplotypes, Adolescent, Adult, Child, Child, Preschool, Infant, Asian Continental Ancestry Group, Female, Male, Young Adult, DNA Copy Number Variations, Immunoglobulins, Intravenous, Receptors, CCR5, Chemokines, CC, Preschool, General Science & Technology
Abstract

BackgroundThe etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown.Methodology/principal findingsWe used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR)=2.25, p=0.004 and OR=6.26, p=0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR=0.21, p=0.026) and CAL development (OR=0.44, p=0.071).Conclusions/significanceThe CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.

Published
2010

18. Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge

Author

Ahuja, Sunil K., Manoharan, Muthu Saravanan, Harper, Nathan L., Jimenez, Fabio, Hobson, Benjamin D., Martinez, Hernan, Ingale, Puraskar, Liu, Ya-Guang, Carrillo, Andrew, Lou, Zheng, Kellog, Dean L., Ahuja, Seema S., Rather, Cynthia G., Esch, Robert E., Ramirez, Daniel A., Clark, Robert A., Nadeau, Kari, Andrews, Charles P., Jacobs, Robert L., and He, Weijing

Published
2017
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20. Race-Specific HIV-1 Disease-Modifying Effects Associated with CCR5 Haplotypes

Author

Gonzalez, Enrique, Bamshad, Mike, Sato, Naoko, Mummidi, Srinivas, Dhanda, Rahul, Catano, Gabriel, Cabrera, Sonia, McBride, Megan, Cao, Xuan-Hien, Merrill, Gerald, O'Connell, Peter, Bowden, Donald W., Freedman, Barry I., Anderson, Stephanie A., Walter, Elizabeth A., Evans, James S., Stephan, Kevin T., Clark, Robert A., Tyagi, Sanjay, Ahuja, Seema S., Dolan, Matthew J., and Ahuja, Sunil K.

Published
1999

21. Development of a peripheral blood transcriptomic gene signature to predict bronchopulmonary dysplasia

Author

Moreira, Alvaro, primary, Tovar, Miriam, additional, Smith, Alisha M., additional, Lee, Grace C., additional, Meunier, Justin A., additional, Cheema, Zoya, additional, Moreira, Axel, additional, Winter, Caitlyn, additional, Mustafa, Shamimunisa B., additional, Seidner, Steven, additional, Findley, Tina, additional, Garcia, Joe G. N., additional, Thébaud, Bernard, additional, Kwinta, Przemko, additional, and Ahuja, Sunil K., additional

Published
2023
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24. Antiretroviral initiation at ≥800 CD4+ cells/ mm 3 associated with lower HIV reservoir size

Author

Rasmussen, Thomas A, Ahuja, Sunil K, Kuwanda, Locadiah, Vjecha, Michael J, Hudson, Fleur, Lal, Luxshimi, Rhodes, Ajantha, Chang, Judy, Palmer, Sarah, Auberson-Munderi, Paula, Mugerwa, Henry, Wood, Robin, Badal-Faesen, Sharlaa, Pillay, Sandy, Mngqibisa, Rosie, LaRosa, Alberto, Hildago, Jose, Petoumenos, Kathy, Chiu, Chris, Lutaakome, Joseph, Kitonsa, Jonathan, Kabaswaga, Esther, Pala, Pietro, Ganoza, Carmela, Fisher, Katie, Chang, Christina, Lewin, Sharon R, and Wright, Edwina J

Abstract

BACKGROUND: Identifying factors that determine the frequency of latently infected CD4+ T-cells on antiretroviral therapy (ART) may inform strategies for HIV cure. We investigated the role of CD4 count at ART initiation for HIV persistence on ART. METHODS: Among participants of the Strategic Timing of Antiretroviral Treatment (START) Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799 or ≥800 cells/mm 3. After 36-44 months on ART, we quantified levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA) and 2-long terminal repeat HIV-DNA in CD4+ T-cells and measured plasma HIV-RNA by single-copy assay. We measured T-cell expression of HLA-DR, programmed death-1, phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. RESULTS: We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799 and 50 in the ≥800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥800 cells/mm 3 at ART initiation compared to 600-799 or 500-599 cells/mm 3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥800 vs. 500-599 cells/mm 3 [median (IQR): 16.3 (7.0-117.6) vs. 68.4 (13.7-213.1) copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females.. CONCLUSION: Initiating ART with a CD4+ count ≥800 cells/mm 3 compared to 600-799 or 500-599 cells/mm 3 was associated with achieving a substantially smaller HIV reservoir on ART.

Published
2022

27. Metformin Attenuates Inflammatory Responses and Enhances Antibody Production in an Acute Pneumonia Model of Streptococcus pneumoniae

Author

Lee, Grace C., primary, Moreira, Alvaro G., additional, Hinojosa, Cecilia, additional, Benavides, Raymond, additional, Winter, Caitlyn, additional, Anderson, Audrey C., additional, Chen, Chang-Jui, additional, Borsa, Noemi, additional, Hastings, Gabrielyd, additional, Black, Cody A., additional, Bandy, Sarah M., additional, Shaffer, Alexander, additional, Restrepo, Marcos I., additional, and Ahuja, Sunil K., additional

Published
2022
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28. Antiretroviral Initiation at ≥800 CD4+ Cells/mm3 Associated With Lower Human Immunodeficiency Virus Reservoir Size

Author

Rasmussen, Thomas A, primary, Ahuja, Sunil K, additional, Kuwanda, Locadiah, additional, Vjecha, Michael J, additional, Hudson, Fleur, additional, Lal, Luxshimi, additional, Rhodes, Ajantha, additional, Chang, Judy, additional, Palmer, Sarah, additional, Auberson-Munderi, Paula, additional, Mugerwa, Henry, additional, Wood, Robin, additional, Badal-Faesen, Sharlaa, additional, Pillay, Sandy, additional, Mngqibisa, Rosie, additional, LaRosa, Alberto, additional, Hildago, Jose, additional, Petoumenos, Kathy, additional, Chiu, Chris, additional, Lutaakome, Joseph, additional, Kitonsa, Jonathan, additional, Kabaswaga, Esther, additional, Pala, Pietro, additional, Ganoza, Carmela, additional, Fisher, Katie, additional, Chang, Christina, additional, Lewin, Sharon R, additional, and Wright, Edwina J, additional

Published
2022
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37. A Plea for Justice for Jailed Medical Workers

Author

Ahuja, Sunil K., Aiuti, Fernando, Berkhout, Ben, Biberfeld, Peter, Burton, Dennis R., Colizzi, Vittorio, Deeks, Steven G., Desrosiers, Ronald C., Dierich, Manfred P., Doms, Robert W., Emerman, Michael, Gallo, Robert C., Girard, Marc, Greene, Warner C., Hoxie, James A., Hunter, Eric, Klein, George, Korber, Bette, Kuritzkes, Daniel R., Lederman, Michael M., Malim, Michael H., Marx, Preston A., McCune, Joseph M., McMichael, Andrew, Miller, Christopher, Miller, Veronica, Montagnier, Luc, Montefiori, David C., Moore, John P., Nixon, Douglas F., Overbaugh, Julie, Pauza, C. David, Richman, Douglas D., Saag, Michael S., Sattentau, Quentin, Schooley, Robert T., Shattock, Robin, Shaw, George M., Stevenson, Mario, Trkola, Alexandra, Wainberg, Mark A., Weiss, Robin A., Wolinsky, Steven, and Zack, Jerome A.

Published
2006
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39. Large‐scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma

Author

Smith, Alisha M., primary, Ramirez, Robert M., additional, Harper, Nathan, additional, Jimenez, Fabio, additional, Branum, Anne P., additional, Meunier, Justin A., additional, Pandranki, Lavanya, additional, Carrillo, Andrew, additional, Winter, Caitlyn, additional, Winter, Lauryn, additional, Rather, Cynthia G., additional, Ramirez, Daniel A., additional, Andrews, Charles P., additional, Restrepo, Marcos I., additional, Maselli, Diego J., additional, Pugh, Jacqueline A., additional, Clark, Robert A., additional, Lee, Grace C., additional, Moreira, Alvaro G., additional, Manoharan, Muthu Saravanan, additional, Okulicz, Jason F., additional, Jacobs, Robert L., additional, and Ahuja, Sunil K., additional

Published
2021
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44. Role of astrocytes and chemokine systems in acute TNFα induced demyelinating syndrome: CCR2-dependent signals promote astrocyte activation and survival via NF-κB and Akt

Author

Quinones, Marlon P., Kalkonde, Yogeshwar, Estrada, Carlos A., Jimenez, Fabio, Ramirez, Robert, Mahimainathan, Lenin, Mummidi, Srinivas, Choudhury, Goutam G., Martinez, Hernan, Adams, Lisa, Mack, Matthias, Reddick, Robert L., Maffi, Shivani, Haralambous, Sylva, Probert, Lesley, Ahuja, Sunil K., and Ahuja, Seema S.

Published
2008
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45. Episodic Aspiration with Oral Commensals Induces a MyD88-dependent, Pulmonary T-Helper Cell Type 17 Response that Mitigates Susceptibility to Streptococcus pneumoniae

Author

Wu, Benjamin G., primary, Sulaiman, Imran, additional, Tsay, Jun-Chieh J., additional, Perez, Luisanny, additional, Franca, Brendan, additional, Li, Yonghua, additional, Wang, Jing, additional, Gonzalez, Amber N., additional, El-Ashmawy, Mariam, additional, Carpenito, Joseph, additional, Olsen, Evan, additional, Sauthoff, Maya, additional, Yie, Kevin, additional, Liu, Xiuxiu, additional, Shen, Nan, additional, Clemente, Jose C., additional, Kapoor, Bianca, additional, Zangari, Tonia, additional, Mezzano, Valeria, additional, Loomis, Cynthia, additional, Weiden, Michael D., additional, Koralov, Sergei B., additional, D’Armiento, Jeanine, additional, Ahuja, Sunil K., additional, Wu, Xue-Ru, additional, Weiser, Jeffrey N., additional, and Segal, Leopoldo N., additional

Published
2021
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46. Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE [epsilon]4/[epsilon]4 genotype accelerates HIV disease progression

Author

Burt, Trevor D., Agan, Brian K., Marconi, Vincent C., He, Weijing, Kulkarni, Hemant, Mold, Jeffrey E., Cavrois, Marielle, Huang, Yadong, Mahley, Robert W., Dolan, Matthew J., McCune, Joseph M., and Ahuja, Sunil K.

Subjects
Apolipoproteins -- Physiological aspects, HIV infection -- Risk factors, HIV infection -- Prognosis, Alzheimer's disease -- Risk factors, Alzheimer's disease -- Care and treatment, Science and technology
Abstract

Originally recognized for their role in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E isoforms (apoE2, apoE3, and apoE4) have also been implicated to play a key role in several biological processes not directly related to their lipid transport function. For example, apoE4 contributes significantly to neurodegeneration in Alzheimer's disease. However, the role of apoE in infectious diseases is less well defined. Here, by examining a large cohort of [HIV.sup.+] European and African American subjects, we found that the APOE [epsilon]4/[epsilon]4 genotype is associated with an accelerated disease course and especially progression to death compared with the APOE [epsilon]3/[epsilon]3 genotype. However, an association between the [epsilon]4/[epsilon]4 genotype and HIV-associated dementia (HAD), a neurological condition with clinicopathological features similar to Alzheimer's disease, was not detected. Consistent with the genotype-phenotype relationships observed, compared with recombinant apoE3, apoE4 enhanced HIV fusion/cell entry of both R5 and X4 HIV strains in vitro. These findings establish apoE as a determinant of HIV-AIDS pathogenesis and raise the possibility that current efforts to convert apoE4 to an 'apoE3-like' molecule to treat Alzheimer's disease might also have clinical applicability in HIV disease. HIV/AIDS | fusion/cell entry | infectious diseases | apoE

Published
2008

47. CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals

Author

Ahuja, Sunil K., Kulkarni, Hemant, Catano, Gabriel, Agan, Brian, Camargo, Jose F., He, Weijing, O'Connel, Robert J., Marconi, Vincent C., Delmar, Judith, Eron, Joseph Clark, Robert A., Frost, Simon, Martin, Jeffrey, Ahuja, Seema S., Deeks, Steven G., Little, Susan, Richman, Douglas, Hecht, Frederick M., and Dolan, Matthew J.

Abstract

The basis for the extensive variability seen in the reconstitution of CD4+ T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at, HIV-1 infection is characterized by extensive variability in the degree of depletion or recovery in [CD4.sup.+] T cell (abbreviated as [CD4.sup.+]) counts before or after receipt of HAART, respectively. Variability [...]

Published
2008

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