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Principal Investigator: Thomas Quinn
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $778,661
Funding agency: National Institute of Allergy and Infectious Diseases
HIV/AIDS is a global pandemic with 38 million individuals living with HIV infection, and approximately 45 million have died from AIDS worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV and its co-infections in developing countries, to determine the viral kinetics associated with transmission, and to characterize the different molecular strains of HIV for infectiousness and progression of disease. This year we added investigations on SARS-CoV-2, which causes COVID-19. By the first week in August of 2020, SARS-CoV-2 has infected nearly 18 million people globally and killed over 700,000 individuals. The performance of diagnostic assays remains problematic and the burden of infection remains unclear in many populations, and we have initiated serologic epidemiologic and virologic studies to characterize the infection in the US and in Uganda.
Using a phage display assay, we characterized antibody binding to >3,300 HIV peptides in 57 HIV-1, subtype C infected women from 2 weeks to 8 years post infection. We found that the number of unique epitopes targeted ("antibody breadth") increased early in infection and then stabilized or declined. A decline in antibody breadth 9 months to 2 years after infection was associated more rapid disease progression. We identify 266 peptides with increasing antibody reactivity over time and 43 peptides with decreasing reactivity over time. These data were used to design a prototype four-peptide "serosignature" to predict duration of HIV infection. We also demonstrated that epitope engineering can be used to optimize peptide binding properties for applications such as cross-sectional HIV incidence estimation.
The major barrier to curing HIV infection is the persistence of HIV in latently infected resting memory CD4+ T cells. Previous work from our section and the ICER Uganda team found that the latent viral reservoir (LVR) in our Ugandan population is over 3-fold smaller than that of a previously reported American population. This represents the first quantification of latently infected resting CD4+ T cells with replication competent virus in an ART treated, virally suppressed sub-Saharan African population. We expanded on this work to further examine this Ugandan population and found that women have a significantly smaller replication-competent LVR compare to Ugandan men. In addition, we identified unique immunological and clinical characteristics between the two sexes of treated Ugandans. In particular we found that LVR size of men, but not women, was correlated with PD-1 expression. This work highlighted the need for expanded studies of women in HIV Cure work.
We have expanded our studies examining HIV superinfection and its effects on the pandemic by exploring the role of anti-HIV neutralizing antibodies (NAb) in the context of HIV superinfection. In collaboration with Dr. John Mascola and Dr. Nicole Doria-Rose from the NIAID VRC, we examined the longitudinal NAb, and non-neutralizing binding antibody, responses in a group of people who inject drugs who were infected with highly similar viral strains. Our findings supported other studies and found a small but significant viral genotypic effect on the resulting NAb response in these individuals suggesting that the infecting HIV viral strain at least in part influences the resulting humoral immune response.
South Africa has the largest HIV epidemic in the world, with 19% of the global number of people living with HIV, 15% of new infections and 11% of AIDS-related deaths. We completed our multiyear project examining HIV infections in emergency departments (ED) in the Eastern Cape of South Africa, and found that of 28.0% of ED patients were HIV positive, of which 28.9% were newly diagnosed. These data also found incredibly high HIV incidence in this population, and highlights the potential for ED to serve as a point-of-contact for previously underserved HIV-infected populations in South Africa.
We have also expanded on our work examining HIV-positive to HIV-positive (HIV+/HIV+) organ transplants in South Africa and the US. As part of this later collaboration with the HOPE in Action team we reported the initial results of our pilot trial comparing HIV+/HIV+ to HIV-/HIV+ recipients and found that there were no significant differences in deaths, oneyear graft survival (p=0.9), oneyear mean estimated glomerular filtration rate (p=0.31), HIV breakthrough (p=0.99), infectious hospitalizations (p=0.85), or opportunistic infections (p=0.72). We also found no evidence of HIV-superinfection in these patients, which supports our work in South Africa.
Accurate HCV incidence estimates are critical for help guide prevention and treatment programming, which is particularly important in the context of the US opioid epidemic. We developed and validated an evaluated an inexpensive HCV avidity assay, which was free from genotype effect, using 1,840 HCV antibody and RNA-positive samples from 875 individuals enrolled in 5 cohort studies in the US and India. An avidity index cut-off of <40% resulted in a mean duration of recent infection of 113 days (95% CI 84-146). The frequency of misclassification of known long term infected samples was 0.4% (95% CI 0.0-1.2), 4.6% (95% CI 2.2-8.3), and 9.5% (95% CI 3.6-19.6) among individuals who were HIV-uninfected, HIV-infected, and HIV-infected with a CD4 count <200/l, respectively. No variation was seen between HCV genotypes 1 and 3. In hypothetical scenarios of high-risk settings, a sample size of <1,000 individuals could reliably estimate primary HCV incidence. We demonstrated that our HCV antibody avidity assay can accurately estimate primary HCV incidence from a cross-sectional cohort, for the most common genotypes. This tool can serve as a valuable resource for program and policy planners seeking to monitor and reduce HCV burden.
We sought to understand the predictive value of the SARS-CoV-2 RT-PCR test by time from symptom onset. We analyzed data from seven published studies of results from the upper respiratory tract (n = 1330) from day of symptom onset. Before symptom onset (typically day 5 of infection), the probability of a false-negative result decreases from 100% on day 1 to 67% on day 4. On the day of symptom onset, the median false-negative rate was 38%. This decreased to 20% on day 8 and then began to increase again from 21% on day 9 to 66% on day 21. These results demonstrate that care must be taken in interpreting RT-PCR tests for SARS-CoV-2 infection. This is particularly true early in the course of infection, prior to symptom onset, when using these results as a basis for removing precautions intended to prevent onward transmission. Convalescent plasma from patients recovered from COVID-19 is currently one of the leading treatments for this infection. Among 126 potential convalescent plasma donors, the humoral immune response was evaluated by a SARS-CoV-2 virus neutralization assay. IgG titers were greater than either IgM or IgA for S1, full length S, and S-RBD. Of the 126 plasma samples, 101 (80%) had detectable neutralizing titers. Using neutralization titer as the reference, the sensitivity of the IgG ELISAs ranged between 95-98%, but specificity was only 20-32%. Male sex, older age, and hospitalization with COVID-19 were all consistently associated with increased antibody responses across the serological assays. Neutralizing antibody titers were reduced over time in contrast to overall antibody responses. There was substantial heterogeneity in the antibody response among potential convalescent plasma donors, but sex, age and hospitalization emerged as factors that can be used to identify individuals with a high likelihood of having strong antiviral antibody levels.
Terms: <19S Gamma Globulin><2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><AIDS><AIDS Virus><ARV resistance><ARV resistant><Accident and Emergency department><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Africa><African><Age><American><Anti-HCV Antibodies><Anti-HIV Positivity><Anti-Hepatitis C Virus Antibodies><Anti-Retroviral Agents><Antibodies><Antibody Avidity><Antibody Response><Antibody titer measurement><Antigenic Determinants><Antiretroviral Agents><Antiretroviral resistance><Antiretroviral resistant><Asia><Assay><Avidity><Behavioral><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological><Biological Assay><Blood Plasma><CD4 Cells><CD4 Lymphocyte Count><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ Cell Counts><CD4+ Counts><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID-19><COVID19><Caring><Cessation of life><Characteristics><Circumcision><Clinical><Clinical Virology><Cohort Studies><Collaborations><Concurrent Studies><Country><Data><Data Analyses><Data Analysis><Death><Developing Countries><Developing Nations><Disease><Disease Progression><Disorder><Drugs><ED patient><ELISA><ER patient><Emergency Department><Emergency Department patient><Emergency Room patient><Emergency room><Engineering><Enrollment><Enzyme-Linked Immunosorbent Assay><Epidemic><Epidemiology><Epitopes><Frequencies><Genotype><Glomerular Filtration Rate><Graft Survival><Grafting Procedure><Guide prevention><HCV><HCV Antibodies><HCV Incidence><HIV><HIV Infections><HIV Positive><HIV Positivity><HIV Seroconversion><HIV Seropositivity><HIV antibody positive><HIV-1><HIV-I><HIV/STD><HIV/STI><HIV1><HTLV-III Infections><HTLV-III Seroconversion><HTLV-III Seropositivity><HTLV-III-LAV Infections><Health><Hepatitis C Antibodies><Hepatitis C Incidence><Hepatitis C Virus Antibodies><Hepatitis C virus><Heterogeneity><Heterosexuals><Hospital Admission><Hospitalization><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><IgA><IgG><IgM><Immune response><Immunochemical Immunologic><Immunoglobulin A><Immunoglobulin G><Immunoglobulin M><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Incidence><India><Individual><Infection><Injecting drug user><Injection Drug User><Institutes><International><Intervention><Intervention Strategies><Investigation><Kinetics><LAV-HTLV-III><Laboratories><Latin America><Length><Less-Developed Countries><Less-Developed Nations><Lymphadenopathy-Associated Virus><Maintenance><Male Circumcision><Medication><Microbial Superinvasion><Molecular><Molecular Interaction><Monitor><NIAID><National Institute of Allergy and Infectious Disease><Newly Diagnosed><Non-Polyadenylated RNA><Opportunistic Infections><Organ Transplantation><Organ Transplants><PD 1><PD-1><PD1><PWID><Patients><Peptides><Performance><Perinatal><Peripartum><Phage Display><Pharmaceutic Preparations><Pharmaceutical Preparations><Plasma><Plasma Serum><Policies><Population><Predictive Value><Probability><Property><Publishing><RNA><RNA Gene Products><RT-PCR><RTPCR><Reporting><Research Resources><Resources><Rest><Reticuloendothelial System, Serum, Plasma><Reverse Transcriptase Polymerase Chain Reaction><Ribonucleic Acid><Role><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><STD/HIV><STI/HIV><Sample Size><Sampling><Serologic><Serological><Severe acute respiratory syndrome coronavirus 2><Solid><South Africa><Specificity><Symptoms><T4 Cells><T4 Lymphocyte Count><T4 Lymphocytes><Testing><Third-World Countries><Third-World Nations><Time><Transmission><Transplant Recipients><Uganda><Under-Developed Countries><Under-Developed Nations><Upper respiratory tract><Vaccines><Validation><Variant><Variation><Viral><Viral Antibodies><Viral Diseases><Viral Latency><Viral reservoir><Virus><Virus Diseases><Virus Latency><Virus reservoir><Virus-HIV><Woman><Work><Wuhan coronavirus><ages><anti-retroviral><anti-retroviral resistance><anti-retroviral resistant><anti-viral antibody><antibody titering><antiretroviral><antiviral antibody><burden of infection><co-infection><cohort><coinfection><corona virus disease 2019><coronavirus disease 2019><data interpretation><design><designing><developing country><developing nation><diagnostic assay><drug/agent><enroll><epidemiologic><epidemiological><hepatitis C virus incidence><high risk><host response><immunoresponse><indexing><infection burden><interventional strategy><male><memory CD4 T cell><memory CD4 T lymphocyte><men><men's><microbicidal><microbicide><neutralizing antibody><novel><opiate crisis><opioid crisis><opioid epidemic><organ allograft><organ graft><organ xenograft><pandemic><pandemic disease><people who inject drugs><people who inject illicit drugs><persons who inject drugs><pilot trial><prevent><preventing><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><prototype><resistance to ARV><resistance to anti-retroviral><resistance to antiretroviral><resistant to ARV><resistant to anti-retroviral><resistant to antiretroviral><reverse transcriptase PCR><sex><sle2><social role><super infection><superinfection><systemic lupus erythematosus susceptibility 2><tool><transmission process><transplant patient><trial comparing><viral infection><virology><virus infection><virus-induced disease>