Browsing by Subject "Viral Load"
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Item Open Access Activity of Galidesivir in a Hamster Model of SARS-CoV-2.(Viruses, 2021-12-21) Taylor, Ray; Bowen, Richard; Demarest, James F; DeSpirito, Michael; Hartwig, Airn; Bielefeldt-Ohmann, Helle; Walling, Dennis M; Mathis, Amanda; Babu, Yarlagadda SCoronavirus disease 2019 (COVID-19) has claimed the lives of millions of people worldwide since it first emerged. The impact of the COVID-19 pandemic on public health and the global economy has highlighted the medical need for the development of broadly acting interventions against emerging viral threats. Galidesivir is a broad-spectrum antiviral compound with demonstrated in vitro and in vivo efficacy against several RNA viruses of public health concern, including those causing yellow fever, Ebola, Marburg, and Rift Valley fever. In vitro studies have shown that the antiviral activity of galidesivir also extends to coronaviruses. Herein, we describe the efficacy of galidesivir in the Syrian golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Treatment with galidesivir reduced lung pathology in infected animals compared with untreated controls when treatment was initiated 24 h prior to infection. These results add to the evidence of the applicability of galidesivir as a potential medical intervention for a range of acute viral illnesses, including coronaviruses.Item Open Access Common genetic variation and the control of HIV-1 in humans.(PLoS Genet, 2009-12) Fellay, Jacques; Ge, Dongliang; Shianna, Kevin V; Colombo, Sara; Ledergerber, Bruno; Cirulli, Elizabeth T; Urban, Thomas J; Zhang, Kunlin; Gumbs, Curtis E; Smith, Jason P; Castagna, Antonella; Cozzi-Lepri, Alessandro; De Luca, Andrea; Easterbrook, Philippa; Günthard, Huldrych F; Mallal, Simon; Mussini, Cristina; Dalmau, Judith; Martinez-Picado, Javier; Miro, José M; Obel, Niels; Wolinsky, Steven M; Martinson, Jeremy J; Detels, Roger; Margolick, Joseph B; Jacobson, Lisa P; Descombes, Patrick; Antonarakis, Stylianos E; Beckmann, Jacques S; O'Brien, Stephen J; Letvin, Norman L; McMichael, Andrew J; Haynes, Barton F; Carrington, Mary; Feng, Sheng; Telenti, Amalio; Goldstein, David B; NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.Item Open Access Comparison of Detection Limits of Fourth- and Fifth-Generation Combination HIV Antigen-Antibody, p24 Antigen, and Viral Load Assays on Diverse HIV Isolates.(Journal of clinical microbiology, 2018-08) Stone, Mars; Bainbridge, John; Sanchez, Ana M; Keating, Sheila M; Pappas, Andrea; Rountree, Wes; Todd, Chris; Bakkour, Sonia; Manak, Mark; Peel, Sheila A; Coombs, Robert W; Ramos, Eric M; Shriver, M Kathleen; Contestable, Paul; Nair, Sangeetha Vijaysri; Wilson, David H; Stengelin, Martin; Murphy, Gary; Hewlett, Indira; Denny, Thomas N; Busch, Michael PDetection of acute HIV infection is critical for HIV public health and diagnostics. Clinical fourth-generation antigen (Ag)/antibody (Ab) combination (combo) and p24 Ag immunoassays have enhanced detection of acute infection compared to Ab-alone assays but require ongoing evaluation with currently circulating diverse subtypes. Genetically and geographically diverse HIV clinical isolates were used to assess clinical HIV diagnostic, blood screening, and next-generation assays. Three-hundred-member panels of 20 serially diluted well-characterized antibody-negative HIV isolates for which the researchers were blind to the results (blind panels) were distributed to manufacturers and end-user labs to assess the relative analytic sensitivity of currently approved and preapproved clinical HIV fourth-generation Ag/Ab combo or p24 Ag-alone immunoassays for the detection of diverse subtypes. The limits of detection (LODs) of virus were estimated for different subtypes relative to confirmed viral loads. Analysis of immunoassay sensitivity was benchmarked against confirmed viral load measurements on the blind panel. On the basis of the proportion of positive results on 300 observations, all Ag/Ab combo and standard sensitivity p24 Ag assays performed similarly and within half-log LODs, illustrating the similar breadth of reactivity and diagnostic utility. Ultrasensitive p24 Ag assays achieved dramatically increased sensitivities, while the rapid combo assays performed poorly. The similar performance of the different commercially available fourth-generation assays on diverse subtypes supports their use in broad geographic settings with locally circulating HIV clades and recombinant strains. Next-generation preclinical ultrasensitive p24 Ag assays achieved dramatically improved sensitivity, while rapid fourth-generation assays performed poorly for p24 Ag detection.Item Open Access COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets.(Nature, 2021-07) Delorey, Toni M; Ziegler, Carly GK; Heimberg, Graham; Normand, Rachelly; Yang, Yiming; Segerstolpe, Åsa; Abbondanza, Domenic; Fleming, Stephen J; Subramanian, Ayshwarya; Montoro, Daniel T; Jagadeesh, Karthik A; Dey, Kushal K; Sen, Pritha; Slyper, Michal; Pita-Juárez, Yered H; Phillips, Devan; Biermann, Jana; Bloom-Ackermann, Zohar; Barkas, Nikolaos; Ganna, Andrea; Gomez, James; Melms, Johannes C; Katsyv, Igor; Normandin, Erica; Naderi, Pourya; Popov, Yury V; Raju, Siddharth S; Niezen, Sebastian; Tsai, Linus T-Y; Siddle, Katherine J; Sud, Malika; Tran, Victoria M; Vellarikkal, Shamsudheen K; Wang, Yiping; Amir-Zilberstein, Liat; Atri, Deepak S; Beechem, Joseph; Brook, Olga R; Chen, Jonathan; Divakar, Prajan; Dorceus, Phylicia; Engreitz, Jesse M; Essene, Adam; Fitzgerald, Donna M; Fropf, Robin; Gazal, Steven; Gould, Joshua; Grzyb, John; Harvey, Tyler; Hecht, Jonathan; Hether, Tyler; Jané-Valbuena, Judit; Leney-Greene, Michael; Ma, Hui; McCabe, Cristin; McLoughlin, Daniel E; Miller, Eric M; Muus, Christoph; Niemi, Mari; Padera, Robert; Pan, Liuliu; Pant, Deepti; Pe'er, Carmel; Pfiffner-Borges, Jenna; Pinto, Christopher J; Plaisted, Jacob; Reeves, Jason; Ross, Marty; Rudy, Melissa; Rueckert, Erroll H; Siciliano, Michelle; Sturm, Alexander; Todres, Ellen; Waghray, Avinash; Warren, Sarah; Zhang, Shuting; Zollinger, Daniel R; Cosimi, Lisa; Gupta, Rajat M; Hacohen, Nir; Hibshoosh, Hanina; Hide, Winston; Price, Alkes L; Rajagopal, Jayaraj; Tata, Purushothama Rao; Riedel, Stefan; Szabo, Gyongyi; Tickle, Timothy L; Ellinor, Patrick T; Hung, Deborah; Sabeti, Pardis C; Novak, Richard; Rogers, Robert; Ingber, Donald E; Jiang, Z Gordon; Juric, Dejan; Babadi, Mehrtash; Farhi, Samouil L; Izar, Benjamin; Stone, James R; Vlachos, Ioannis S; Solomon, Isaac H; Ashenberg, Orr; Porter, Caroline BM; Li, Bo; Shalek, Alex K; Villani, Alexandra-Chloé; Rozenblatt-Rosen, Orit; Regev, AvivCOVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure1-4, but little is known about its pathophysiology. Here we generated single-cell atlases of 24 lung, 16 kidney, 16 liver and 19 heart autopsy tissue samples and spatial atlases of 14 lung samples from donors who died of COVID-19. Integrated computational analysis uncovered substantial remodelling in the lung epithelial, immune and stromal compartments, with evidence of multiple paths of failed tissue regeneration, including defective alveolar type 2 differentiation and expansion of fibroblasts and putative TP63+ intrapulmonary basal-like progenitor cells. Viral RNAs were enriched in mononuclear phagocytic and endothelial lung cells, which induced specific host programs. Spatial analysis in lung distinguished inflammatory host responses in lung regions with and without viral RNA. Analysis of the other tissue atlases showed transcriptional alterations in multiple cell types in heart tissue from donors with COVID-19, and mapped cell types and genes implicated with disease severity based on COVID-19 genome-wide association studies. Our foundational dataset elucidates the biological effect of severe SARS-CoV-2 infection across the body, a key step towards new treatments.Item Open Access Cross-platform analysis of HIV-1 RNA data generated by a multicenter assay validation study with wide geographic representation.(J Clin Microbiol, 2012-08) Jennings, Cheryl; Harty, Brian; Granger, Suzanne; Wager, Carrie; Crump, John A; Fiscus, Susan A; Bremer, James WHIV-1 RNA quantitation continues to be extremely important for monitoring patients infected with HIV-1, and a number of assays have been utilized for this purpose. Differences in assay performance with respect to log(10) recovery and HIV-1 subtype specificity have been well documented for commercially available assays, although comparisons are usually limited to one or two assay platforms. Two new FDA-approved assays, the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test (RT) and the Abbott RealTime HIV-1 assay (AR), that utilize real-time PCR have replaced previous HIV-1 RNA platforms. Inadequate detection of some strains of HIV-1 resulted in the addition of a new primer/probe set and the introduction of a second version of the RT assay. In this study, comparisons of assay performance between the different FDA-approved HIV-1 RNA assay platforms (both new and existing) were performed by using validation data that included both well-characterized virus stock and locally collected clinical samples. Laboratories across diverse geographical regions performed the validation testing and submitted data to the Virology Quality Assurance program (VQA) for analysis. Correlation values for clinical sample testing varied across the assay platforms (r = 0.832 to 0.986), and average log(10) recoveries for HIV-1 RNA controls (compared to the nominal value) ranged from -0.215 to 0.181. These data demonstrate the need for use of one assay platform for longitudinal patient monitoring, but the data also reinforce the notion that no one assay is superior and that testing across platforms may be required for discordance reconciliation.Item Open Access Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up.(BMC Infect Dis, 2014-11-07) Dow, Dorothy E; Shayo, Aisa M; Cunningham, Coleen K; Reddy, Elizabeth ABACKGROUND: In Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up. METHODS: This was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained. RESULTS: 161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01). CONCLUSIONS: After viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.Item Open Access Early versus delayed fixed dose combination abacavir/lamivudine/zidovudine in patients with HIV and tuberculosis in Tanzania.(AIDS Res Hum Retroviruses, 2009-12) Shao, Humphrey J; Crump, John A; Ramadhani, Habib O; Uiso, Leonard O; Ole-Nguyaine, Sendui; Moon, Andrew M; Kiwera, Rehema A; Woods, Christopher W; Shao, John F; Bartlett, John A; Thielman, Nathan MFixed dose combination abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) among HIV-1 and tuberculosis (TB)-coinfected patients was evaluated and outcomes between early vs. delayed initiation were compared. In a randomized, pilot study conducted in the Kilimanjaro Region of Tanzania, HIV-infected inpatients with smear-positive TB and total lymphocyte count <1200/mm(3) were randomized to initiate ABC/3TC/ZDV either 2 (early) or 8 (delayed) weeks after commencing antituberculosis therapy and were followed for 104 weeks. Of 94 patients screened, 70 enrolled (41% female, median CD4 count 103 cells/mm(3)), and 33 in each group completed 104 weeks. Two deaths and 12 serious adverse events (SAEs) were observed in the early arm vs. one death, one clinical failure, and seven SAEs in the delayed arm (p = 0.6012 for time to first grade 3/4 event, SAE, or death). CD4 cell increases were +331 and +328 cells/mm(3), respectively. TB-immune reconstitution inflammatory syndromes (TB-IRIS) were not observed in any subject. Using intent-to-treat (ITT), missing = failure analyses, 74% (26/35) vs. 89% (31/35) randomized to early vs. delayed therapy had HIV RNA levels <400 copies/ml at 104 weeks (p = 0.2182) and 66% (23/35) vs. 74% (26/35), respectively, had HIV RNA levels <50 copies/ml (p = 0.6026). In an analysis in which switches from ABC/3TC/ZDV = failure, those receiving early therapy were less likely to be suppressed to <400 copies/ml [60% (21/35) vs. 86% (30/35), p = 0.030]. TB-IRIS was not observed among the 70 coinfected subjects beginning antiretroviral treatment. ABC/3TC/ZDV was well tolerated and resulted in steady immunologic improvement. Rates of virologic suppression were similar between early and delayed treatment strategies with triple nucleoside regimens when substitutions were allowed.Item Open Access Effective treatment of SIVcpz-induced immunodeficiency in a captive western chimpanzee.(Retrovirology, 2017-06-02) Barbian, Hannah J; Jackson-Jewett, Raven; Brown, Corrine S; Bibollet-Ruche, Frederic; Learn, Gerald H; Decker, Timothy; Kreider, Edward F; Li, Yingying; Denny, Thomas N; Sharp, Paul M; Shaw, George M; Lifson, Jeffrey; Acosta, Edward P; Saag, Michael S; Bar, Katharine J; Hahn, Beatrice HSimian immunodeficiency virus of chimpanzees (SIVcpz), the progenitor of human immunodeficiency virus type 1 (HIV-1), is associated with increased mortality and AIDS-like immunopathology in wild-living chimpanzees (Pan troglodytes). Surprisingly, however, similar findings have not been reported for chimpanzees experimentally infected with SIVcpz in captivity, raising questions about the intrinsic pathogenicity of this lentivirus.Here, we report progressive immunodeficiency and clinical disease in a captive western chimpanzee (P. t. verus) infected twenty years ago by intrarectal inoculation with an SIVcpz strain (ANT) from a wild-caught eastern chimpanzee (P. t. schweinfurthii). With sustained plasma viral loads of 105 to 106 RNA copies/ml for the past 15 years, this chimpanzee developed CD4+ T cell depletion (220 cells/μl), thrombocytopenia (90,000 platelets/μl), and persistent soft tissue infections refractory to antibacterial therapy. Combination antiretroviral therapy consisting of emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and dolutegravir (DTG) decreased plasma viremia to undetectable levels (<200 copies/ml), improved CD4+ T cell counts (509 cell/μl), and resulted in the rapid resolution of all soft tissue infections. However, initial lack of adherence and/or differences in pharmacokinetics led to low plasma drug concentrations, which resulted in transient rebound viremia and the emergence of FTC resistance mutations (M184V/I) identical to those observed in HIV-1 infected humans.These data demonstrate that SIVcpz can cause immunodeficiency and other hallmarks of AIDS in captive chimpanzees, including P. t. verus apes that are not naturally infected with this virus. Moreover, SIVcpz-associated immunodeficiency can be effectively treated with antiretroviral therapy, although sufficiently high plasma concentrations must be maintained to prevent the emergence of drug resistance. These findings extend a growing body of evidence documenting the immunopathogenicity of SIVcpz and suggest that experimentally infected chimpanzees may benefit from clinical monitoring and therapeutic intervention.Item Open Access Genome-wide mRNA expression correlates of viral control in CD4+ T-cells from HIV-1-infected individuals.(PLoS Pathog, 2010-02-26) Rotger, Margalida; Dang, Kristen K; Fellay, Jacques; Heinzen, Erin L; Feng, Sheng; Descombes, Patrick; Shianna, Kevin V; Ge, Dongliang; Günthard, Huldrych F; Goldstein, David B; Telenti, Amalio; Swiss HIV Cohort Study; Center for HIV/AIDS Vaccine ImmunologyThere is great interindividual variability in HIV-1 viral setpoint after seroconversion, some of which is known to be due to genetic differences among infected individuals. Here, our focus is on determining, genome-wide, the contribution of variable gene expression to viral control, and to relate it to genomic DNA polymorphism. RNA was extracted from purified CD4+ T-cells from 137 HIV-1 seroconverters, 16 elite controllers, and 3 healthy blood donors. Expression levels of more than 48,000 mRNA transcripts were assessed by the Human-6 v3 Expression BeadChips (Illumina). Genome-wide SNP data was generated from genomic DNA using the HumanHap550 Genotyping BeadChip (Illumina). We observed two distinct profiles with 260 genes differentially expressed depending on HIV-1 viral load. There was significant upregulation of expression of interferon stimulated genes with increasing viral load, including genes of the intrinsic antiretroviral defense. Upon successful antiretroviral treatment, the transcriptome profile of previously viremic individuals reverted to a pattern comparable to that of elite controllers and of uninfected individuals. Genome-wide evaluation of cis-acting SNPs identified genetic variants modulating expression of 190 genes. Those were compared to the genes whose expression was found associated with viral load: expression of one interferon stimulated gene, OAS1, was found to be regulated by a SNP (rs3177979, p = 4.9E-12); however, we could not detect an independent association of the SNP with viral setpoint. Thus, this study represents an attempt to integrate genome-wide SNP signals with genome-wide expression profiles in the search for biological correlates of HIV-1 control. It underscores the paradox of the association between increasing levels of viral load and greater expression of antiviral defense pathways. It also shows that elite controllers do not have a fully distinctive mRNA expression pattern in CD4+ T cells. Overall, changes in global RNA expression reflect responses to viral replication rather than a mechanism that might explain viral control.Item Open Access HLA class II-Restricted CD8+ T cells in HIV-1 Virus Controllers.(Scientific reports, 2019-07-15) Nyanhete, Tinashe E; Frisbee, Alyse L; Bradley, Todd; Faison, William J; Robins, Elizabeth; Payne, Tamika; Freel, Stephanie A; Sawant, Sheetal; Weinhold, Kent J; Wiehe, Kevin; Haynes, Barton F; Ferrari, Guido; Li, Qi-Jing; Moody, M Anthony; Tomaras, Georgia DA paradigm shifting study demonstrated that induction of MHC class E and II-restricted CD8+ T cells was associated with the clearance of SIV infection in rhesus macaques. Another recent study highlighted the presence of HIV-1-specific class II-restricted CD8+ T cells in HIV-1 patients who naturally control infection (virus controllers; VCs). However, questions regarding class II-restricted CD8+ T cells ontogeny, distribution across different HIV-1 disease states and their role in viral control remain unclear. In this study, we investigated the distribution and anti-viral properties of HLA-DRB1*0701 and DQB1*0501 class II-restricted CD8+ T cells in different HIV-1 patient cohorts; and whether class II-restricted CD8+ T cells represent a unique T cell subset. We show that memory class II-restricted CD8+ T cell responses were more often detectable in VCs than in chronically infected patients, but not in healthy seronegative donors. We also demonstrate that VC CD8+ T cells inhibit virus replication in both a class I- and class II-dependent manner, and that in two VC patients the class II-restricted CD8+ T cells with an anti-viral gene signature expressed both CD4+ and CD8+ T cell lineage-specific genes. These data demonstrated that anti-viral memory class II-restricted CD8+ T cells with hybrid CD4+ and CD8+ features are present during natural HIV-1 infection.Item Open Access Host determinants of HIV-1 control in African Americans.(J Infect Dis, 2010-04-15) Pelak, Kimberly; Goldstein, David B; Walley, Nicole M; Fellay, Jacques; Ge, Dongliang; Shianna, Kevin V; Gumbs, Curtis; Gao, Xiaojiang; Maia, Jessica M; Cronin, Kenneth D; Hussain, Shehnaz K; Carrington, Mary; Michael, Nelson L; Weintrob, Amy C; Infectious Disease Clinical Research Program HIV Working Group; National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology (CHAVI)We performed a whole-genome association study of human immunodeficiency virus type 1 (HIV-1) set point among a cohort of African Americans (n = 515), and an intronic single-nucleotide polymorphism (SNP) in the HLA-B gene showed one of the strongest associations. We use a subset of patients to demonstrate that this SNP reflects the effect of the HLA-B*5703 allele, which shows a genome-wide statistically significant association with viral load set point (P = 5.6 x 10(-10)). These analyses therefore confirm a member of the HLA-B*57 group of alleles as the most important common variant that influences viral load variation in African Americans, which is consistent with what has been observed for individuals of European ancestry, among whom the most important common variant is HLA-B*5701.Item Open Access Human Herpes Virus 8 in HIV-1 infected individuals receiving cancer chemotherapy and stem cell transplantation.(PloS one, 2018-01) Hogan, Louise E; Hanhauser, Emily; Hobbs, Kristen S; Palmer, Christine D; Robles, Yvonne; Jost, Stephanie; LaCasce, Anne S; Abramson, Jeremy; Hamdan, Ayad; Marty, Francisco M; Kuritzkes, Daniel R; Henrich, Timothy JBackground
Human Herpes Virus 8 (HHV8) can cause Kaposi's Sarcoma (KS) in immunosuppressed individuals. However, little is known about the association between chemotherapy or hematopoietic stem cell transplantation (HSCT), circulating HHV8 DNA levels, and clinical KS in HIV-1-infected individuals with various malignancies. Therefore, we examined the associations between various malignancies, systemic cancer chemotherapy, T cell phenotypes, and circulating HHV8 DNA in 29 HIV-1-infected participants with concomitant KS or other cancer diagnoses.Methods
We quantified HHV8 plasma viral loads and cell-associated HHV8 DNA and determined the relationship between circulating HHV8 DNA and lymphocyte counts, and markers of early and late lymphocyte activation, proliferation and exhaustion.Results
There were no significant differences in plasma HHV8 DNA levels between baseline and post-chemotherapy time points or with the presence or absence of clinical KS. However, in two participants circulating HHV8 DNA increased following treatment for KS or HSCT for lymphoma,. We observed an approximately 2-log10 reduction in plasma HHV8 DNA in an individual with KS and multicentric Castleman disease following rituximab monotherapy. Although individuals with clinical KS had lower mean CD4+ T cell counts and percentages as expected, there were no significant associations with these factors and plasma HHV8 levels. We identified increased proportions of CD8+ and CD4+ T cells expressing CD69 (P = 0.01 & P = 0.04 respectively), and increased CD57 expression on CD4+ T cells (P = 0.003) in participants with detectable HHV8.Conclusion
These results suggest there is a complex relationship between circulating HHV8 DNA and tissue-based disease in HIV-1 and HHV8 co-infected individuals with various malignancies.Item Open Access Human Immunodeficiency Virus Type 1 Persistence Following Systemic Chemotherapy for Malignancy.(The Journal of infectious diseases, 2017-07) Henrich, Timothy J; Hobbs, Kristen S; Hanhauser, Emily; Scully, Eileen; Hogan, Louise E; Robles, Yvonne P; Leadabrand, Kaitlyn S; Marty, Francisco M; Palmer, Christine D; Jost, Stephanie; Körner, Christian; Li, Jonathan Z; Gandhi, Rajesh T; Hamdan, Ayad; Abramson, Jeremy; LaCasce, Ann S; Kuritzkes, Daniel RBackground
Systemic chemotherapies for various malignancies have been shown to significantly, yet transiently, decrease numbers of CD4+ T lymphocytes, a major reservoir for human immunodeficiency virus type 1 (HIV-1) infection. However, little is known about the impact of cytoreductive chemotherapy on HIV-1 reservoir dynamics, persistence, and immune responses.Methods
We investigated the changes in peripheral CD4+ T-cell-associated HIV-1 DNA and RNA levels, lymphocyte activation, viral population structure, and virus-specific immune responses in a longitudinal cohort of 15 HIV-1-infected individuals receiving systemic chemotherapy or subsequent autologous stem cell transplantation for treatment of hematological malignancies and solid tumors.Results
Despite a transient reduction in CD4+ T cells capable of harboring HIV-1, a 1.7- and 3.3-fold increase in mean CD4+ T-cell-associated HIV-1 RNA and DNA, respectively, were observed months following completion of chemotherapy in individuals on antiretroviral therapy. We also observed changes in CD4+ T-cell population diversity and clonal viral sequence expansion during CD4+ T-cell reconstitution following chemotherapy cessation. Finally, HIV-1 DNA was preferentially, and in some cases exclusively, detected in cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-responsive CD4+ T cells following chemotherapy.Conclusions
Expansion of HIV-infected CMV/EBV-specific CD4 + T cells may contribute to maintenance of the HIV DNA reservoir following chemotherapy.Item Open Access Implementation of a Pooled Surveillance Testing Program for Asymptomatic SARS-CoV-2 Infections on a College Campus - Duke University, Durham, North Carolina, August 2-October 11, 2020.(MMWR. Morbidity and mortality weekly report, 2020-11-20) Denny, Thomas N; Andrews, Laura; Bonsignori, Mattia; Cavanaugh, Kyle; Datto, Michael B; Deckard, Anastasia; DeMarco, C Todd; DeNaeyer, Nicole; Epling, Carol A; Gurley, Thaddeus; Haase, Steven B; Hallberg, Chloe; Harer, John; Kneifel, Charles L; Lee, Mark J; Louzao, Raul; Moody, M Anthony; Moore, Zack; Polage, Christopher R; Puglin, Jamie; Spotts, P Hunter; Vaughn, John A; Wolfe, Cameron ROn university campuses and in similar congregate environments, surveillance testing of asymptomatic persons is a critical strategy (1,2) for preventing transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). All students at Duke University, a private research university in Durham, North Carolina, signed the Duke Compact (3), agreeing to observe mandatory masking, social distancing, and participation in entry and surveillance testing. The university implemented a five-to-one pooled testing program for SARS-CoV-2 using a quantitative, in-house, laboratory-developed, real-time reverse transcription-polymerase chain reaction (RT-PCR) test (4,5). Pooling of specimens to enable large-scale testing while minimizing use of reagents was pioneered during the human immunodeficiency virus pandemic (6). A similar methodology was adapted for Duke University's asymptomatic testing program. The baseline SARS-CoV-2 testing plan was to distribute tests geospatially and temporally across on- and off-campus student populations. By September 20, 2020, asymptomatic testing was scaled up to testing targets, which include testing for residential undergraduates twice weekly, off-campus undergraduates one to two times per week, and graduate students approximately once weekly. In addition, in response to newly identified positive test results, testing was focused in locations or within cohorts where data suggested an increased risk for transmission. Scale-up over 4 weeks entailed redeploying staff members to prepare 15 campus testing sites for specimen collection, developing information management tools, and repurposing laboratory automation to establish an asymptomatic surveillance system. During August 2-October 11, 68,913 specimens from 10,265 graduate and undergraduate students were tested. Eighty-four specimens were positive for SARS-CoV-2, and 51% were among persons with no symptoms. Testing as a result of contact tracing identified 27.4% of infections. A combination of risk-reduction strategies and frequent surveillance testing likely contributed to a prolonged period of low transmission on campus. These findings highlight the importance of combined testing and contact tracing strategies beyond symptomatic testing, in association with other preventive measures. Pooled testing balances resource availability with supply-chain disruptions, high throughput with high sensitivity, and rapid turnaround with an acceptable workload.Item Open Access ImPlementation REsearCh to DEvelop Interventions for People Living with HIV (the PRECluDE consortium): Combatting chronic disease comorbidities in HIV populations through implementation research.(Progress in cardiovascular diseases, 2020-03) Gamble-George, Joyonna Carrie; Longenecker, Christopher T; Webel, Allison R; Au, David H; Brown, Arleen F; Bosworth, Hayden; Crothers, Kristina; Cunningham, William E; Fiscella, Kevin A; Hamilton, Alison B; Helfrich, Christian D; Ladapo, Joseph A; Luque, Amneris; Tobin, Jonathan N; Wyatt, Gail E; Implementation Research to Develop Interventions for People Living with HIV (PRECluDE) ConsortiumAntiretroviral therapy (ART) prevented premature mortality and improved the quality of life among people living with the human immunodeficiency virus (PLWH), such that now more than half of PLWH in the United States are 50 years of age and older. Increased longevity among PLWH has resulted in a significant rise in chronic, comorbid diseases. However, the implementation of guideline-based interventions for preventing, treating, and managing such age-related, chronic conditions among the HIV population is lacking. The PRECluDE consortium supported by the Center for Translation Research and Implementation Science at the National Heart, Lung, and Blood Institute catalyzes implementation research on proven-effective interventions for co-occurring heart, lung, blood, and sleep diseases and conditions among PLWH. These collaborative research studies use novel implementation frameworks with HIV, mental health, cardiovascular, and pulmonary care to advance comprehensive HIV and chronic disease healthcare in a variety of settings and among diverse populations.Item Open Access In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies(Cell, 2021) Li, Dapeng; Edwards, Robert J; Manne, Kartik; Martinez, David R; Schäfer, Alexandra; Alam, S Munir; Wiehe, Kevin; Lu, Xiaozhi; Parks, Robert; Sutherland, Laura L; othersSARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques.Item Open Access Influence of HLA-C expression level on HIV control.(Science, 2013-04-05) Apps, Richard; Qi, Ying; Carlson, Jonathan M; Chen, Haoyan; Gao, Xiaojiang; Thomas, Rasmi; Yuki, Yuko; Del Prete, Greg Q; Goulder, Philip; Brumme, Zabrina L; Brumme, Chanson J; John, Mina; Mallal, Simon; Nelson, George; Bosch, Ronald; Heckerman, David; Stein, Judy L; Soderberg, Kelly A; Moody, M Anthony; Denny, Thomas N; Zeng, Xue; Fang, Jingyuan; Moffett, Ashley; Lifson, Jeffrey D; Goedert, James J; Buchbinder, Susan; Kirk, Gregory D; Fellay, Jacques; McLaren, Paul; Deeks, Steven G; Pereyra, Florencia; Walker, Bruce; Michael, Nelson L; Weintrob, Amy; Wolinsky, Steven; Liao, Wilson; Carrington, MaryA variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn's disease, suggesting a broader influence of HLA expression levels in human disease.Item Open Access Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated.(J Exp Med, 2011-10-24) Liao, Hua-Xin; Chen, Xi; Munshaw, Supriya; Zhang, Ruijun; Marshall, Dawn J; Vandergrift, Nathan; Whitesides, John F; Lu, Xiaozhi; Yu, Jae-Sung; Hwang, Kwan-Ki; Gao, Feng; Markowitz, Martin; Heath, Sonya L; Bar, Katharine J; Goepfert, Paul A; Montefiori, David C; Shaw, George C; Alam, S Munir; Margolis, David M; Denny, Thomas N; Boyd, Scott D; Marshal, Eleanor; Egholm, Michael; Simen, Birgitte B; Hanczaruk, Bozena; Fire, Andrew Z; Voss, Gerald; Kelsoe, Garnett; Tomaras, Georgia D; Moody, M Anthony; Kepler, Thomas B; Haynes, Barton FThe initial antibody response to HIV-1 is targeted to envelope (Env) gp41, and is nonneutralizing and ineffective in controlling viremia. To understand the origins and characteristics of gp41-binding antibodies produced shortly after HIV-1 transmission, we isolated and studied gp41-reactive plasma cells from subjects acutely infected with HIV-1. The frequencies of somatic mutations were relatively high in these gp41-reactive antibodies. Reverted unmutated ancestors of gp41-reactive antibodies derived from subjects acutely infected with HIV-1 frequently did not react with autologous HIV-1 Env; however, these antibodies were polyreactive and frequently bound to host or bacterial antigens. In one large clonal lineage of gp41-reactive antibodies, reactivity to HIV-1 Env was acquired only after somatic mutations. Polyreactive gp41-binding antibodies were also isolated from uninfected individuals. These data suggest that the majority of gp41-binding antibodies produced after acute HIV-1 infection are cross-reactive responses generated by stimulating memory B cells that have previously been activated by non-HIV-1 antigens.Item Open Access Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings.(AIDS, 2012-07-17) Bartlett, John A; Ribaudo, Heather J; Wallis, Carole L; Aga, Evgenia; Katzenstein, David A; Stevens, Wendy S; Norton, Michael R; Klingman, Karin L; Hosseinipour, Mina C; Crump, John A; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Kallungal, Beatrice A; Kumarasamy, NagalingeswaranOBJECTIVE: To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs). DESIGN: An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000 copies/ml. METHODS: Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100 mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r. RESULTS: Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400 copies/ml at week 24 (n=102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40 copies/ml and 30 had levels 40-200 copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400 copies/ml. CONCLUSION: In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity.Item Open Access Lopinavir/Ritonavir Monotherapy as Second-line Antiretroviral Treatment in Resource-Limited Settings: Week 104 Analysis of AIDS Clinical Trials Group (ACTG) A5230.(Clin Infect Dis, 2015-05-15) Kumarasamy, Nagalingeswaran; Aga, Evgenia; Ribaudo, Heather J; Wallis, Carole L; Katzenstein, David A; Stevens, Wendy S; Norton, Michael R; Klingman, Karin L; Hosseinipour, Mina C; Crump, John A; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Bartlett, John ABACKGROUND: The AIDS Clinical Trials Group (ACTG) A5230 study evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure (VF) on first-line human immunodeficiency virus (HIV) regimens in Africa and Asia. METHODS: Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200 000 copies/mL. All subjects received LPV/r 400/100 mg twice daily. VF was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models. RESULTS: One hundred twenty-three subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 of 123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39 of 41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400 copies/mL over 104 weeks on LPV/r monotherapy was 60% (95% CI, 50%-68%); 80%-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level <400 copies/mL at weeks 24, 48, and 104 revealed that 61%, 62%, and 65% were suppressed to <40 copies/mL, respectively. CONCLUSIONS: LPV/r monotherapy after first-line VF with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks. CLINICAL TRIALS REGISTRATION: NCT00357552.