HIV/AIDS Research

Fred & A. Norman Drucker Laboratory for Virology Research

The basic research performed in the Fred and A. Norman Drucker Laboratory for Virology Research is focused on the evolutionary mechanisms underlying host-pathogen interactions, and their role in the emergence, spread and containment of infectious diseases. The overall goal of the laboratory is to study the nature and extent of viral genetic variation, the biological and evolutionary processes that affect viral populations, and the human genes and their relevant genetic variants that contribute to virus evolution and human disease.

Wolinksy Research Group

Steven Wolinsky, MD, the Samuel J. Sackett Professor of Infectious Diseases and Director of the Fred and A. Norman Drucker Laboratory, is an international leader in HIV molecular biology and pathogenesis research, with experience in leading and directing large, multicenter projects. Wolinsky has over 25 years of experience in studying the virus-host interaction and has been the leader of successful NIAID and NIDA-funded programs.

The research interests of the laboratory include:

• Understanding the host determinants of RNA virus pathogenesis and evolution at the molecular and population levels.
• Investigating the factors that drive the evolution of the virus and influence infection or disease severity.
• Utilizing systems biology approaches to unveil the innate immune responses against HIV-1 and other viruses (Influenza, Dengue, Chikungunya, ZIKA) infections.
• Identifying commonly known RNA modifications to human and viral RNA and discover others that may affect HIV infection.
• Characterizing and examining genetic variants that influence the human response to infection and host susceptibility in the Multicenter AIDS Cohort Study (MACS) and applying to antiviral strategies.
• Employing computational biology and bioinformatics to investigate human responses to viral infections and virus-host interactions. 

Active investigators in the Wolinsky research group:  Steven Wolinsky, MD;  Eun-Young Kim, PhD;  Ramon Lorenzo-Redondo, PhD

HIV-1 Translational Research Center

The Drucker Lab also houses the HIV-1 Translational Research Center. This center works to discover ways to sustain remission of HIV after stopping antiretroviral therapy (ART, also called “functional cure”) and prevent HIV infection. It is led by Richard D’Aquila, MD, The Howard Taylor Ricketts Professor of Medicine - Infectious Diseases, who has been translating mechanistic insights into initial and improved therapies for HIV infection for over 25 years. 

Projects include:

There are seven members of cellular A3s cytidine deaminases (A3A to A3H) in humans. Some of them are in the cytoplasm (A3D, -F, -G and -H haplotype II). Those A3s can potently inhibit HIV replication via mutagenesis of viral genomes, and are targeted for destruction by HIV to enable its replication. Other members of the A3 family are localized only to the cell nucleus (A3B and A3H haplotype I). A3B and -A are often up-regulated in cancers, inducing mutations into human chromosomal DNA that enhance cancer progression. Understanding mechanisms of regulation of levels of these proteins in cells can suggest innovative strategies for the functional cure of HIV-1 infection, as well as for cancer therapeutics.

Investigation of cellular mechanisms involved in regulations of A3 proteins: This project is to study underlying biological mechanisms for family of A3 proteins. Since A3 proteins play critical roles for inhibiting viral replication as cellular restriction factors (in the case of A3F, -G and -H) as well as are strongly implicated in promoting cancer evolution, drug-resistance and metastasis (in the case of A3B and -A), understanding mechanisms for biological regulations of these proteins would provide critical insights into functional cure strategy for HIV and novel therapeutic targets for cancer therapy.

Studying mechanism(s) for LMM to HMM transition of A3 proteins: A3 proteins are present in Low Molecular Mass (LMM) or High Molecular Mass (HMM) in the cell. Only LMM form of A3 proteins can actively either inhibit viral replication or introduce mutations into chromosomal DNA in the case of human cancer while HMM of A3s are enzymatically inactive. We are actively investigating biological regulations for LMM to HMM transition of the A3 proteins.

Investigation of cellular target(s) and mechanisms of patent-granted small molecule compounds: Patent-granted small molecule compounds for increasing cellular levels of A3 proteins were identified for their ability to strongly inhibit HIV-1 replication. The compounds discovered in collaboration with Gary Schiltz, PhD, and Meejeon Roh, PhD, and have been patented by Northwestern. This project is to identify cellular target(s) for the compounds and to investigate mechanisms for their effects on increasing all A3 proteins including A3G protein.  Understanding cellular target(s) and mechanisms of these compounds may provide novel candidate compounds for functional cure of HIV.   

Effects of neddylation inhibition on HIV-1 reactivation from latently infected reservoirs: This project is to investigate mechanisms of neddylation inhibition on HIV reactivation from hard to eliminate viral reservoir. Our data strongly indicated that neddylation inhibition led to reduce HIV reactivation coupled with cell death of reactivated cells. Understanding biological mechanisms will provide new novel intervention tool for eliminating latently infected HIV reservoir for functional HIV cure strategy.

Studying effects of increased A3B on cancer metabolism and cancer stem cell maintenance:  More than 70 % of human cancer displayed A3B-mediated mutations with increased expression of the protein. We have data strongly implicating A3B up-regulation to altered metabolism and increased cancer stemness. Understand how increased A3B protein affect these critical steps for cancer maintenance will provide in-depth knowledge of biological regulation of these critical steps.

Other active investigators in the D'Aquila group: Chisu Song, PhD; Isabelle Clerc, PhD; Aubrey Sawyer; Cristina Vaca; Hannah Hudson; Joshua Craft, MD

Clinical HIV research in the Division of Infectious Diseases is largely conducted through the AIDS Clinical Trials Group (ACTG), which has been funded by the National Institute of Allergy and Infectious Diseases since 1987. The ACTG is the largest network of expert clinical and translational investigators and therapeutic clinical trials units in the world, including sites in low- and middle-income countries. The mission of the ACTG is to cure HIV infection, reduce immune dysfunction/inflammation, and lower the burden of disease due to HIV infection and related complications or co-infections, such as tuberculosis and viral hepatitis. Babafemi Taiwo, MBBS, is the principal investigator of the Chicago Clinical Trials Unit (CCTU) and also leads investigator-initiated HIV clinical research studies.

Clinical Research Interests

• Novel antiretroviral treatment strategies to optimize virologic control, including two-drug regimens and injectable long-acting antiretroviral therapy (ART)
• Optimizing ART adherence and assessment of predictors of non-adherence
• HIV and treatment of chronic viral hepatitis B and C co-infection
• Effect of ART on neurocognitive impairment, frailty and age-related complications (cancer, bone, renal, cardiovascular, pulmonary and liver diseases)
• Pathways of molecular aging including telomere biology, mitochondrial dysfunction and epigenetic modification among individuals aging with HIV
• Immunologic mechanisms and interventions to decrease residual inflammation/immune activation
• Safe and effective contraception for HIV-infected women on ART
• Diagnosis and rapid ART during acute HIV infection

Active investigators: Babafemi Taiwo, MBBS;  Frank Palella, MD;  Chad Achenbach, MD, MPH;  Claudia Hawkins, MD, MPH;  Shannon Galvin, MD

Investigator-Initiated Studies

AIDS Clinical Trial Group (ACTG) 5322: HIV Infection, Aging & Inflammation Longitudinal Observational Study (HAILO)

HAILO is a prospective, observational, multicenter cohort study involving participants from over 20 AIDS Clinical Trial Units (ACTUs) across the U.S. Approximately 1,000 participants have been enrolled, all of whom received first HAART while ART-naive through an ACTG interventional parent clinical trial. Topics at the heart of HAILO’s research mission include the evaluation of the roles that inflammation and immune dysregulation play among aging ART-treated persons living with HIV infection.
 
At Northwestern, Frank Palella, MD, serves as HAILO’s co-chair and Babafemi Taiwo, MBBS, as vice-chair. 

Multicenter AIDS Cohort Study (MACS)

Founded in 1983 by the NIH and conducted by investigators in Chicago, Pittsburgh, Los Angeles and Baltimore, the MACS is the longest ongoing natural and treated history cohort study of HIV-infected persons in the world. In this study, over 7,000 HIV infected and uninfected men who have sex with men (MSM) undergo semiannual clinical interviews and examinations and sera and cells are collected and stored at each visit. The HIV sero-negative participants serve as a unique control group to compare with men living with HIV. Visits are comprehensive and include multiple components, such as interviews/questionnaires, physical exams and a functional status assessment.
 
MACS participants are seen semiannually. The MACS is a fixed cohort (enrollment has occurred only at specific calendar periods since 1984 in order to expand/replenish the cohort. In Chicago, participants are seen at Northwestern and at the CORE center.
 
Steven Wolinsky, MD, the principal investigator, leads the Chicago site (where over 400 men are followed) and directs the cutting-edge genetics work that involves all MACS participants nationwide.
 
The initial goal of MACS was to define incident infection and establish the natural history of HIV infection. However, with the development of effective therapies for HIV, the aims of the study have evolved to investigate the health of men living with HIV and to better understand clinical and subclinical predictors, biomarkers, and the pathogenesis of cardiac, pulmonary, renal, hepatic, bone and central nervous system disease. Additionally, the MACS project explores the functional status and frailty among ART-treated, HIV-infected men compared to otherwise similar uninfected MSM.
 
Other areas of active research include sexual and drug use behavior, neuro-cognition, responses to ART, co-infection with viral hepatitis and liver disease in general, HIV-associated cancer risk (including herpes virus effects on cancer pathogenesis), HIV- associated kidney disease, bone disease/fractures and frailty/functional status.
 
MACS investigators have authored over 1,400 manuscripts to date, published in every major peer-reviewed biomedical journal. These publications range widely in subject matter and include numerous reports concerning HIV transmission, natural history, pathogenesis, immune response, genetics, co-infections, and associated inflammation and immune dysregulation.
 
Much work has been accomplished through sub-studies over the past several years, especially those involving coronary Ca+ and overall plaque measurement via serial CT angiograms, cardiac MRI on a subset of participants serially measured GFR using iohexol, human papilloma virus and anal cytology, frailty/fracture risk/bone disease (BOSS Study), and neuroimaging
 
Current and planned sub-studies funded through special supplements made available through the National Heart, Lung, and Blood Institute (NHLBI) include:

1. Identification and characterization of cardiac arrhythmias and conduction abnormalities in HIV-infected compared to HIV-uninfected men using electrocardiograms and ambulatory cardiac monitoring.
2. Identification and characterization of clinical and subclinical structural cardiac abnormalities in HIV-infected compared to HIV-uninfected men by echocardiography.
3. Identification and characterization of chronic obstructive pulmonary disease in HIV-infected compared to HIV-uninfected men, including pulmonary function testing.
4. Characterization of sleep apnea and sleep quality, including home sleep testing and activity monitoring. This study is designed to identify associations between obstructive sleep apnea, insulin resistance, subclinical cardiovascular disease, autonomic function and neurobehavioral outcomes in men with and without HIV infection.

Active MACS investigators include: Steven Wolinsky, MD;  John Phair, MD;  Frank Palella, MD, Valentina Stosor, MD;  Eun-Young Kim, PhD;  Ramon Lorenzo-Redondo, PhD;  Claudia Hawkins, MD, MPH

The HIV Outpatient Study (HOPS)

HOPS was inaugurated in 1993 by the Centers for Disease Control and Prevention (CDC). It is a prospective, observational, nationwide (currently in six U.S. cities), dynamic cohort (participants can enter or leave observation depending on when they are seen clinically) of HIV-infected outpatients and their HIV-treating primary care clinicians. Comprehensive clinical data collected during routine outpatient care are entered into the HOPS database on-site and centrally aggregated and managed so they are available for investigative query. Over 10,000 participants have been enrolled since the study’s inception, and there are currently about 3,000 active participants. Currently, Frank Palella, MD, is the principal investigator of HOPS at Northwestern.

Comprehensive longitudinal data entered into the HOPS electronic database include HIV clinical parameters (T-cell subsets, HIV RNA levels, HIV resistance testing results), opportunistic events and information regarding all non-AIDS diagnoses. These non-AIDS diagnoses have become areas of increased investigative focus, as persons with HIV enjoy markedly extended survival consequent to successful treatment with antiretroviral therapy (ART).

HOPS has generated numerous research reports in peer-reviewed biomedical journals. These reports have evaluated outcomes and associated risks in diverse clinical areas. For example, a report on HIV-associated mortality was the first journal article (New England Journal of Medicine, 1998) that profiled the profound reductions in AIDS-related death and opportunistic disease consequent to HAART use. It remains among the most highly cited articles of the HAART era.

Other areas of research inquiry and publication have included opportunistic disease (AIDS, JAIDS), longterm CD4 and HIV RNA responses to ART (AIDS, JAIDS), durability of ART’s effectiveness (AIDS), optimal timing of ART initiation (Annals of Internal Medicine), longitudinal ART use patterns (AIDS), adherence to therapy, ability to safely d/c OI prophylaxis after immune reconstitution (Annals of Internal Medicine), comparison of efficacy/toxicity of various HAART regimens, use of HIV susceptibility testing and associations with survival, responses to therapy (Annals of Internal Medicine), sexual practices and STD co-infections, time spent viremic/cumulative viremia and implications for HIV transmission and mortality, metabolic outcomes including cardiovascular diseases, HIV-associated body habitus changes (lipoatrophy and lipoaccumulation), and other chronic non-AIDS comorbidities including bone disease, kidney disease, hyperlipidemia and ART-related toxicities, bone fractures, and chronic viral hepatitis co-infection.

The Chicago Women's Interagency HIV Study (WIHS)

Human immunodeficiency virus (HIV) has had a profound impact on the health of women. By the end of 2016, 52 percent of the more than 36.7 million people living with HIV infection were women. HIV infection and the resultant acquired immunodeficiency syndrome (AIDS) are the leading causes of death among women in their reproductive years (ages 15 to 49).

The WIHS is an ongoing prospective cohort study that was started in 1993 by the NIH to understand the development of HIV infections in both treated and untreated women in the United States. Northwestern University has been an active component of the Chicago WIHS clinical consortia, being one of the six initial WIHS sites.

Recently, there was an expansion of sites to better represent women with HIV or at risk of HIV in the southern United States. The core of the national study includes an in-depth structured interview, physical and gynecologic examinations, as well as laboratory testing twice a year. Participants are also invited to participate in various sub-studies related to HIV. After close to 25 years, the WIHS continues to investigate questions at the forefront of HIV research, spanning topics such as women’s reproductive health, clinical outcomes (for example, cardiovascular disease, neuro-cognition, diabetes and aging) and the effectiveness of antiretroviral therapy over time. 
 
For more information on WIHS and the research it has done over the years at the Chicago WIHS site, please visit the Chicago WIHS site.

Active investigator: Chad Achenbach, MD, MPH

With successes in combination antiretroviral therapy, end organ diseases such as liver and kidney failure have become more prevalent in persons living with HIV infection. Investigators from the Division of Infectious Diseases have established important multi-disciplinary collaborations with the medical center to study the outcomes of organ transplantation in HIV-infected persons. Valentina Stosor, MD, has served as the principal investigator for one of these multi-disciplinary collaborations: the NIH/NIAID supported Solid Organ Transplantation in HIV: Multi-Site Study. This observational study evaluated the safety and efficacy of kidney and liver transplantation in 275 HIV-infected patients from 20 high-volume transplant centers. Thanks to the contributions of this study, organ transplantation is now an accepted and important therapy for HIV-infected patients with end-stage kidney and liver disease. 

Active Investigator: Valentina Stosor, MD
 
Current areas of research in which Valentina Stosor, MD, is the Northwestern principal investigator include:

• Impact of CCR5 blockade on renal allograft function and HIV persistence in HIV-positive kidney transplant recipients (U01AI118594)
• Utilization of HIV-positive organs for kidney and liver transplantation in HIV-positive persons: Multicenter pilot (liver and kidney) and U01AI134591-01 (kidney) studies focus on safety and post-transplant clinical outcomes, HIV superinfection and changes in latent reservoirs.

Visit the Multicenter Aids Cohort Center to learn more.

Center for AIDS Research

The Third Coast Center for AIDS Research (CFAR) provides cutting-edge research, resources and services to faculty in the Division of Infectious Diseases, as well as all faculty throughout Northwestern University and nearby partner universities, health departments, clinics and community organizations. The Third Coast CFAR is competitively funded by the National Institutes of Health (NIH) as part of a national network of institutions with extensive NIH support for HIV-related research. CFAR’s mission is to support the advancement of the entire portfolio of NIH-funded HIV research, to enhance collaboration across all disciplines and to add both value and strategic growth to NIH’s priorities for HIV research.
 
The Third Coast CFAR leads citywide efforts to enhance the  collaborative research environment. These initiatives include scientific symposia, a seminar series and tailored workshops, featuring the work of world-class scientists striving to end the HIV epidemic from Chicago and around the globe.
 
Of relevance to our division, the Third Coast CFAR Clinical Sciences Core services include clinical research project development, regulatory consultation and navigation, participant recruitment, specimen procurement, clinical informatics and biostatistics and data analysis. The Clinical Sciences Core also provides HIV clinical research and HIV comorbidities forums.
 
The Third Coast CFAR Developmental Core funds pilot projects aimed at generating preliminary data for NIH applications through annual pilot competitions and other award programs. It also provides additional resources to support early-stage investigators as they prepare to submit applications to NIH.
 
Other CFAR cores support HIV researchers with services focused on virus and immune pathogenesis and behavioral, social and implementation sciences.
 
CFAR Leaders From the Division of Infectious Diseases: Richard D’Aquila, MD (PI and co-director of the Viral Pathogenesis Core), Brian Mustanski, PhD (PI), Elena Martinelli, PhD, MHSc, MPH (co-director of the Developmental Core) and Babafemi Taiwo, MBBS (director of the Clinical Sciences Core). Please contact them, or CFAR Associate Director Justin Schmandt, MPH, for further information.