1,110 results on '"Mullins, James I."'
Search Results
2. Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition
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Seaton, Kelly E, Huang, Yunda, Karuna, Shelly, Heptinstall, Jack R, Brackett, Caroline, Chiong, Kelvin, Zhang, Lily, Yates, Nicole L, Sampson, Mark, Rudnicki, Erika, Juraska, Michal, deCamp, Allan C, Edlefsen, Paul T, Mullins, James I, Williamson, Carolyn, Rossenkhan, Raabya, Giorgi, Elena E, Kenny, Avi, Angier, Heather, Randhawa, April, Weiner, Joshua A, Rojas, Michelle, Sarzotti-Kelsoe, Marcella, Zhang, Lu, Sawant, Sheetal, Ackerman, Margaret E, McDermott, Adrian B, Mascola, John R, Hural, John, McElrath, M Julianna, Andrew, Philip, Hidalgo, Jose A, Clark, Jesse, Laher, Fatima, Orrell, Catherine, Frank, Ian, Gonzales, Pedro, Edupuganti, Srilatha, Mgodi, Nyaradzo, Corey, Lawrence, Morris, Lynn, Montefiori, David, Cohen, Myron S, Gilbert, Peter B, and Tomaras, Georgia D
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Biomedical and Clinical Sciences ,Immunology ,Vaccine Related ,Pediatric AIDS ,Infectious Diseases ,Pediatric ,Vaccine Related (AIDS) ,Prevention ,Immunization ,Sexually Transmitted Infections ,Biotechnology ,Clinical Research ,HIV/AIDS ,Clinical Trials and Supportive Activities ,Infection ,Good Health and Well Being ,Humans ,Broadly Neutralizing Antibodies ,Antibodies ,Neutralizing ,Acquired Immunodeficiency Syndrome ,HIV Infections ,HIV Seropositivity ,HIV Antibodies ,HIV-1 ,AIDS Vaccines ,Body weight-based dosing ,HIV ,Broadly neutralising antibodies ,body weight ,prevention ,broadly neutralizing antibodies ,monoclonal antibody ,pharmacokinetics ,Clinical Sciences ,Public Health and Health Services ,Clinical sciences ,Epidemiology - Abstract
BackgroundThe phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data.MethodsThe case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations.FindingsEstimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy.InterpretationThese findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs.FundingWas provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.
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- 2023
3. Antigen specificities and proviral integration sites differ in HIV-infected cells by timing of antiretroviral treatment initiation
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Joy, Jaimy, Gervassi, Ana, Chen, Lennie, Kirshenbaum, Brent, Styrchak, Sheila, Ko, Daisy, McLaughlin, Sherry, Shao, Danica, Kosmider, Ewelina, Edlefsen, Paul T., Maenza, Janine, Collier, Ann C., Mullins, James I., Horton, Helen, and Frenkel, Lisa M.
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Viral antigens -- Health aspects ,Highly active antiretroviral therapy -- Methods ,CD4 lymphocytes -- Health aspects ,HIV infection -- Development and progression -- Drug therapy -- Genetic aspects ,Health care industry - Abstract
Despite effective antiretroviral therapy (ART), persons living with HIV harbor reservoirs of persistently infected [CD4.sup.+] cells, which constitute a barrier to cure. Initiation of ART during acute infection reduces the size of the HIV reservoir, and we hypothesized that in addition, it would favor integration of proviruses in HIV- specific [CD4.sup.+] T cells, while initiation of ART during chronic HIV infection would favor relatively more proviruses in herpesvirus-specific cells. We further hypothesized that proviruses in acute ART initiators would be integrated into antiviral genes, whereas integration sites (ISs) in chronic ART initiators would favor genes associated with cell proliferation and exhaustion. We found that the HIV DNA distribution across HIV-specific versus herpesvirus-specific [CD4.sup.+] T cells was as hypothesized. HIV ISs in acute ART initiators were significantly enriched in gene sets controlling lipid metabolism and HIF-1[alpha]-mediated hypoxia, both metabolic pathways active in early HIV infection. Persistence of these infected cells during prolonged ART suggests a survival advantage. ISs in chronic ART initiators were enriched in a gene set controlling EZH2 histone methylation, and methylation has been associated with diminished long terminal repeat transcription. These differences that we found in antigen specificities and IS distributions within HIV- infected cells might be leveraged in designing cure strategies tailored to the timing of ART initiation., Introduction Antiretroviral therapy (ART) can effectively suppress HIV replication, but maintenance of virologic suppression requires that persons living with HIV adhere to the prescribed medicines over their lifetime, as current [...]
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- 2024
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4. Droplet-microfluidics-assisted sequencing of HIV proviruses and their integration sites in cells from people on antiretroviral therapy
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Sun, Chen, Liu, Leqian, Pérez, Liliana, Li, Xiangpeng, Liu, Yifan, Xu, Peng, Boritz, Eli A, Mullins, James I, and Abate, Adam R
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Biotechnology ,Genetics ,Human Genome ,HIV/AIDS ,Infectious Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,DNA ,Viral ,HIV Infections ,HIV-1 ,Humans ,Microfluidics ,Proviruses - Abstract
The human immunodeficiency virus (HIV) integrates its genome into that of infected cells and may enter an inactive state of reversible latency that cannot be targeted using antiretroviral therapy. Sequencing such a provirus and the adjacent host junctions in individual cells may elucidate the mechanisms of the persistence of infected cells, but this is difficult owing to the 150-million-fold higher amount of background human DNA. Here we show that full-length proviruses connected to their contiguous HIV-host DNA junctions can be assembled via a high-throughput microfluidic assay where droplet-based whole-genome amplification of HIV DNA in its native context is followed by a polymerase chain reaction (PCR) to tag droplets containing proviruses for sequencing. We assayed infected cells from people with HIV receiving suppressive antiretroviral therapy, resulting in the detection and sequencing of paired proviral genomes and integration sites, 90% of which were not recovered by commonly used nested-PCR methods. The sequencing of individual proviral genomes with their integration sites could improve the genetic analysis of persistent HIV-infected cell reservoirs.
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- 2022
5. Africa-specific human genetic variation near CHD1L associates with HIV-1 load
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McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques
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- 2023
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6. The immunogenicity of an HIV-1 Gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy
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Jacobson, Jeffrey M., Felber, Barbara K., Chen, Huichao, Pavlakis, George N., Mullins, James I., De Rosa, Stephen C., Kuritzkes, Daniel R., Tomaras, Georgia D., Kinslow, Jennifer, Bao, Yajing, Olefsky, Maxine, Rosati, Margherita, Bear, Jenifer, Heptinstall, Jack R., Zhang, Lu, Sawant, Sheetal, Hannaman, Drew, Laird, Gregory M., Cyktor, Joshua C., Heath, Sonya L., Collier, Ann C., Koletar, Susan L., Taiwo, Babafemi O., Tebas, Pablo, Wohl, David A., Belaunzaran-Zamudio, Pablo F., McElrath, M. Juliana, and Landay, Alan L.
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- 2024
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7. High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials
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Reeves, Daniel B., Mayer, Bryan T., deCamp, Allan C., Huang, Yunda, Zhang, Bo, Carpp, Lindsay N., Magaret, Craig A., Juraska, Michal, Gilbert, Peter B., Montefiori, David C., Bar, Katharine J., Cardozo-Ojeda, E. Fabian, Schiffer, Joshua T., Rossenkhan, Raabya, Edlefsen, Paul, Morris, Lynn, Mkhize, Nonhlanhla N., Williamson, Carolyn, Mullins, James I., Seaton, Kelly E., Tomaras, Georgia D., Andrew, Philip, Mgodi, Nyaradzo, Ledgerwood, Julie E., Cohen, Myron S., Corey, Lawrence, Naidoo, Logashvari, Orrell, Catherine, Goepfert, Paul A., Casapia, Martin, Sobieszczyk, Magdalena E., Karuna, Shelly T., and Edupuganti, Srilatha
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- 2023
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8. Comparative immunogenicity of an mRNA/LNP and a DNA vaccine targeting HIV gag conserved elements in macaques
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Valentin, Antonio, Bergamaschi, Cristina, Rosati, Margherita, Angel, Matthew, Burns, Robert, Agarwal, Mahesh, Gergen, Janina, Petsch, Benjamin, Oostvogels, Lidia, Loeliger, Edde, Chew, Kara W, Deeks, Steven G, Mullins, James I, Pavlakis, George N, and Felber, Barbara K
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Prevention ,Biotechnology ,Vaccine Related ,Infectious Diseases ,Vaccine Related (AIDS) ,Genetics ,HIV/AIDS ,Immunization ,Development of treatments and therapeutic interventions ,Prevention of disease and conditions ,and promotion of well-being ,3.4 Vaccines ,5.1 Pharmaceuticals ,Infection ,Inflammatory and immune system ,Good Health and Well Being ,AIDS Vaccines ,Animals ,CD8-Positive T-Lymphocytes ,HIV Infections ,HIV-1 ,Liposomes ,Macaca mulatta ,Nanoparticles ,RNA ,Messenger ,Vaccines ,DNA ,Vaccines ,Synthetic ,mRNA Vaccines ,mRNA ,LNP ,therapeutic immunization ,HIV ,T cell response ,antibody ,gag ,conserved sequences ,immune focusing ,mRNA/LNP ,Biochemistry and cell biology - Abstract
Immunogenicity of HIV-1 mRNA vaccine regimens was analyzed in a non-human primate animal model. Rhesus macaques immunized with mRNA in lipid nanoparticle (mRNA/LNP) formulation expressing HIV-1 Gag and Gag conserved regions (CE) as immunogens developed robust, durable antibody responses but low adaptive T-cell responses. Augmentation of the dose resulted in modest increases in vaccine-induced cellular immunity, with no difference in humoral responses. The gag mRNA/lipid nanoparticle (LNP) vaccine provided suboptimal priming of T cell responses for a heterologous DNA booster vaccination regimen. In contrast, a single immunization with gag mRNA/LNP efficiently boosted both humoral and cellular responses in macaques previously primed by a gag DNA-based vaccine. These anamnestic cellular responses were mediated by activated CD8+ T cells with a phenotype of differentiated T-bet+ cytotoxic memory T lymphocytes. The heterologous prime/boost regimens combining DNA and mRNA/LNP vaccine modalities maximized vaccine-induced cellular and humoral immune responses. Analysis of cytokine responses revealed a transient systemic signature characterized by the release of type I interferon, IL-15 and IFN-related chemokines. The pro-inflammatory status induced by the mRNA/LNP vaccine was also characterized by IL-23 and IL-6, concomitant with the release of IL-17 family of cytokines. Overall, the strong boost of cellular and humoral immunity induced by the mRNA/LNP vaccine suggests that it could be useful as a prophylactic vaccine in heterologous prime/boost modality and in immune therapeutic interventions against HIV infection or other chronic human diseases.
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- 2022
9. CD101 genetic variants modify regulatory and conventional T cell phenotypes and functions
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Richert-Spuhler, Laura E, Mar, Corinne M, Shinde, Paurvi, Wu, Feinan, Hong, Ting, Greene, Evan, Hou, Sharon, Thomas, Katherine, Gottardo, Raphael, Mugo, Nelly, de Bruyn, Guy, Celum, Connie, Baeten, Jared M, Lingappa, Jairam R, Lund, Jennifer M, Wald, Anna, Campbell, Mary S, Corey, Lawrence, Coombs, Robert W, Hughes, James P, Magaret, Amalia, McElrath, M Juliana, Morrow, Rhoda, Mullins, James I, Coetzee, David, Fife, Kenneth, Were, Edwin, Essex, Max, Makhema, Joseph, Katabira, Elly, Ronald, Allan, Bukusi, Elizabeth, Cohen, Craig, Kapiga, Saidi, Manongi, Rachel, Farquhar, Carey, John-Stewart, Grace, Kiarie, James, Delany-Moretlwe, Sinead, Rees, Helen, Gray, Glenda, McIntyre, James, Mugo, Nelly Rwamba, Donnell, Deborah, Frenkel, Lisa, Hendrix, Craig W, Tumwesigye, Elioda, Ndase, Patrick, Bukusi, Eliabeth, Wangisi, Jonathan, Campbell, James, and Tappero, Jordan
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Clinical Research ,HIV/AIDS ,Prevention ,Genetics ,Infectious Diseases ,Aetiology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Underpinning research ,Inflammatory and immune system ,Adult ,Antigens ,CD ,B-Lymphocytes ,Cell Lineage ,Dendritic Cells ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Genetic Predisposition to Disease ,HIV Infections ,HIV-1 ,Humans ,Immunity ,Innate ,Immunophenotyping ,Male ,Monocytes ,Mutation ,Phenotype ,Receptors ,CCR5 ,Receptors ,CXCR4 ,T-Lymphocytes ,Regulatory ,Partners in Prevention HSV/HIV Transmission Study ,and the Partners PrEP Study Teams ,CD101 ,HIV acquisition ,T cell ,host genetic variation ,immune quiescence ,inflammation ,inflammatory homeostasis - Abstract
We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.
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- 2021
10. Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition
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Seaton, Kelly E., Huang, Yunda, Karuna, Shelly, Heptinstall, Jack R., Brackett, Caroline, Chiong, Kelvin, Zhang, Lily, Yates, Nicole L., Sampson, Mark, Rudnicki, Erika, Juraska, Michal, deCamp, Allan C., Edlefsen, Paul T., Mullins, James I., Williamson, Carolyn, Rossenkhan, Raabya, Giorgi, Elena E., Kenny, Avi, Angier, Heather, Randhawa, April, Weiner, Joshua A., Rojas, Michelle, Sarzotti-Kelsoe, Marcella, Zhang, Lu, Sawant, Sheetal, Ackerman, Margaret E., McDermott, Adrian B., Mascola, John R., Hural, John, McElrath, M. Julianna, Andrew, Philip, Hidalgo, Jose A., Clark, Jesse, Laher, Fatima, Orrell, Catherine, Frank, Ian, Gonzales, Pedro, Edupuganti, Srilatha, Mgodi, Nyaradzo, Corey, Lawrence, Morris, Lynn, Montefiori, David, Cohen, Myron S., Gilbert, Peter B., and Tomaras, Georgia D.
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- 2023
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11. Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition
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Gilbert, Peter B., Huang, Yunda, deCamp, Allan C., Karuna, Shelly, Zhang, Yuanyuan, Magaret, Craig A., Giorgi, Elena E., Korber, Bette, Edlefsen, Paul T., Rossenkhan, Raabya, Juraska, Michal, Rudnicki, Erika, Kochar, Nidhi, Huang, Ying, Carpp, Lindsay N., Barouch, Dan H., Mkhize, Nonhlanhla N., Hermanus, Tandile, Kgagudi, Prudence, Bekker, Valerie, Kaldine, Haajira, Mapengo, Rutendo E., Eaton, Amanda, Domin, Elize, West, Carley, Feng, Wenhong, Tang, Haili, Seaton, Kelly E., Heptinstall, Jack, Brackett, Caroline, Chiong, Kelvin, Tomaras, Georgia D., Andrew, Philip, Mayer, Bryan T., Reeves, Daniel B., Sobieszczyk, Magdalena E., Garrett, Nigel, Sanchez, Jorge, Gay, Cynthia, Makhema, Joseph, Williamson, Carolyn, Mullins, James I., Hural, John, Cohen, Myron S., Corey, Lawrence, Montefiori, David C., and Morris, Lynn
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- 2022
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12. Author Correction: Africa-specific human genetic variation near CHD1L associates with HIV-1 load
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McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques
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- 2023
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13. Comparisons of Human Immunodeficiency Virus Type 1 Envelope Variants in Blood and Genital Fluids near the Time of Male-to-Female Transmission.
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Williams-Wietzikoski, Corey A, Campbell, Mary S, Payant, Rachel, Lam, Airin, Zhao, Hong, Huang, Hannah, Wald, Anna, Stevens, Wendy, Gray, Glenda, Farquhar, Carey, Rees, Helen, Celum, Connie, Mullins, James I, Lingappa, Jairam R, and Frenkel, Lisa M
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Vaccine Related ,Immunization ,HIV/AIDS ,Prevention ,Clinical Research ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Good Health and Well Being ,Adult ,Female ,Genitalia ,HIV Envelope Protein gp160 ,HIV Infections ,HIV-1 ,Heterosexuality ,Humans ,Male ,Phylogeny ,RNA ,Viral ,Receptors ,CCR5 ,Receptors ,CXCR4 ,Semen ,Sequence Analysis ,Young Adult ,coreceptor usage ,genetic bottleneck ,HIV ,heterosexual transmission ,N-linked glycosylation ,viral compartmentalization ,Biological Sciences ,Agricultural and Veterinary Sciences ,Medical and Health Sciences ,Virology ,Agricultural ,veterinary and food sciences ,Biological sciences ,Biomedical and clinical sciences - Abstract
To better understand the transmission of human immunodeficiency virus type 1 (HIV-1), the genetic characteristics of blood and genital viruses from males were compared to those of the imputed founding virus population in their female partners. Initially serodiscordant heterosexual African couples with sequence-confirmed male-to-female HIV-1 transmission and blood and genital specimens collected near the time of transmission were studied. Single viral templates from blood plasma and genital tract RNA and DNA were sequenced across HIV-1 env gp160. Eight of 29 couples examined yielded viral sequences from both tissues. Analysis of these couples' sequences demonstrated, with one exception, that the women's founding viral populations arose from a single viral variant and were CCR5 tropic, even though CXCR4 variants were detected within four males. The median genetic distance of the imputed most recent common ancestor of the women's founder viruses showed that they were closer to the semen viruses than to the blood viruses of their transmitting male partner, but this finding was biased by detection of a greater number of viral clades in the blood. Using multiple assays, the blood and genital viruses were consistently found to be compartmentalized in only two of eight men. No distinct amino acid signatures in the men's viruses were found to link to the women's founders, nor did the women's env sequences have shorter variable loops or fewer N-linked glycosylation sites. The lack of selective factors, except for coreceptor tropism, is consistent with others' findings in male-to-female and high-risk transmissions. The infrequent compartmentalization between the transmitters' blood and semen viruses suggests that cell-free blood virus likely includes HIV-1 sequences representative of those of viruses in semen.IMPORTANCE Mucosal transmissions account for the majority of HIV-1 infections. Identification of the viral characteristics associated with transmission would facilitate vaccine design. This study of HIV strains from transmitting males and their seroconverting female partners found that the males' genital tract viruses were rarely distinct from the blood variants. The imputed founder viruses in women were genetically similar to both the blood and genital tract variants of their male partners, indicating a lack of evidence for genital tract-specific lineages. These findings suggest that targeting vaccine responses to variants found in blood are likely to also protect from genital tract variants.
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- 2019
14. HIV transmission patterns among transgender women, their cisgender male partners, and cisgender MSM in Lima, Peru: A molecular epidemiologic and phylodynamic analysis
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Long, Jessica E., Tordoff, Diana M., Reisner, Sari L., Dasgupta, Sayan, Mayer, Kenneth H., Mullins, James I., Lama, Javier R., Herbeck, Joshua T., and Duerr, Ann
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- 2022
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15. Breast milk and in utero transmission of HIV-1 select for envelope variants with unique molecular signatures
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Nakamura, Kyle J, Heath, Laura, Sobrera, Edwin R, Wilkinson, Thomas A, Semrau, Katherine, Kankasa, Chipepo, Tobin, Nicole H, Webb, Nicholas E, Lee, Benhur, Thea, Donald M, Kuhn, Louise, Mullins, James I, and Aldrovandi, Grace M
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Prevention ,Perinatal Period - Conditions Originating in Perinatal Period ,Biotechnology ,Infectious Diseases ,Vaccine Related ,Immunization ,Pediatric ,Pediatric AIDS ,HIV/AIDS ,Vaccine Related (AIDS) ,Aetiology ,2.2 Factors relating to the physical environment ,Infection ,Good Health and Well Being ,Breast Feeding ,Cohort Studies ,Female ,Genotype ,HIV Infections ,HIV-1 ,Humans ,Infant ,Infant ,Newborn ,Infectious Disease Transmission ,Vertical ,Male ,Maternal-Fetal Exchange ,Pregnancy ,Selection ,Genetic ,Sequence Analysis ,DNA ,env Gene Products ,Human Immunodeficiency Virus ,Mother-to-child transmission ,Envelope ,CD4 ,Glycosylation ,Broadly neutralizing antibodies ,Clinical Sciences ,Virology - Abstract
BackgroundMother-to-child transmission of human immunodeficiency virus-type 1 (HIV-1) poses a serious health threat in developing countries, and adequate interventions are as yet unrealized. HIV-1 infection is frequently initiated by a single founder viral variant, but the factors that influence particular variant selection are poorly understood.ResultsOur analysis of 647 full-length HIV-1 subtype C and G viral envelope sequences from 22 mother-infant pairs reveals unique genotypic and phenotypic signatures that depend upon transmission route. Relative to maternal strains, intrauterine HIV transmission selects infant variants that have shorter, less-glycosylated V1 loops that are more resistant to soluble CD4 (sCD4) neutralization. Transmission through breastfeeding selects for variants with fewer potential glycosylation sites in gp41, are more sensitive to the broadly neutralizing antibodies PG9 and PG16, and that bind sCD4 with reduced cooperativity. Furthermore, experiments with Affinofile cells indicate that infant viruses, regardless of transmission route, require increased levels of surface CD4 receptor for productive infection.ConclusionsThese data provide the first evidence for transmission route-specific selection of HIV-1 variants, potentially informing therapeutic strategies and vaccine designs that can be tailored to specific modes of vertical HIV transmission.
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- 2017
16. Development and Validation of a Genotypic Assay to Quantify CXCR4- and CCR5-Tropic Human Immunodeficiency Virus Type-1 (HIV-1) Populations and a Comparison to Trofile®
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Ko, Daisy, primary, McLaughlin, Sherry, additional, Deng, Wenjie, additional, Mullins, James I., additional, Dragavon, Joan, additional, Harb, Socorro, additional, Coombs, Robert W., additional, and Frenkel, Lisa M., additional
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- 2024
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17. CD101 genetic variants modify regulatory and conventional T cell phenotypes and functions
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Celum, Connie, Wald, Anna, Lingappa, Jairam R., Baeten, Jared M., Campbell, Mary S., Corey, Lawrence, Coombs, Robert W., Hughes, James P., Magaret, Amalia, McElrath, M. Juliana, Morrow, Rhoda, Mullins, James I., Coetzee, David, Fife, Kenneth, Were, Edwin, Essex, Max, Makhema, Joseph, Katabira, Elly, Ronald, Allan, Bukusi, Elizabeth, Cohen, Craig, Kapiga, Saidi, Manongi, Rachel, Farquhar, Carey, John-Stewart, Grace, Kiarie, James, Delany-Moretlwe, Sinead, Rees, Helen, de Bruyn, Guy, Gray, Glenda, McIntyre, James, Mugo, Nelly Rwamba, Donnell, Deborah, Frenkel, Lisa, Hendrix, Craig W., Tumwesigye, Elioda, Ndase, Patrick, Bukusi, Eliabeth, Wangisi, Jonathan, Campbell, James, Tappero, Jordan, Richert-Spuhler, Laura E., Mar, Corinne M., Shinde, Paurvi, Wu, Feinan, Hong, Ting, Greene, Evan, Hou, Sharon, Thomas, Katherine, Gottardo, Raphael, Mugo, Nelly, and Lund, Jennifer M.
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- 2021
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18. High-Sequence Diversity and Rapid Virus Turnover Contribute to Higher Rates of Coreceptor Switching in Treatment-Experienced Subjects with HIV-1 Viremia
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Nedellec, Rebecca, Herbeck, Joshua T, Hunt, Peter W, Deeks, Steven G, Mullins, James I, Anton, Elizabeth D, Reeves, Jacqueline D, and Mosier, Donald E
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Genetics ,HIV/AIDS ,Infectious Diseases ,Sexually Transmitted Infections ,Clinical Research ,Infection ,Anti-HIV Agents ,Evolution ,Molecular ,Genetic Variation ,HIV Infections ,HIV-1 ,Humans ,Mutation ,Receptors ,CCR5 ,Receptors ,CXCR4 ,Receptors ,HIV ,Recombination ,Genetic ,Viral Tropism ,Viremia ,Virus Attachment ,env Gene Products ,Human Immunodeficiency Virus ,HIV-1 coreceptor switching ,sequence diversity ,sequence evolution ,Clinical Sciences ,Virology ,Clinical sciences - Abstract
Coreceptor switching from CCR5 to CXCR4 is common during chronic HIV-1 infection, but is even more common in individuals who have failed antiretroviral therapy (ART). Prior studies have suggested rapid mutation and/or recombination of HIV-1 envelope (env) genes during coreceptor switching. We compared the functional and genotypic changes in env of viruses from viremic subjects who had failed ART just before and after coreceptor switching and compared those to viruses from matched subjects without coreceptor switching. Analysis of multiple unique functional env clones from each subject revealed extensive diversity at both sample time points and rapid diversification of sequences during the 4-month interval in viruses from both 9 subjects with coreceptor switching and 15 control subjects. Only two subjects had envs with evidence of recombination. Three findings distinguished env clones from subjects with coreceptor switching from controls: (1) lower entry efficiency via CCR5; (2) longer V1/V2 regions; and (3), lower nadir CD4 T cell counts during prior years of infection. Most of these subjects harbored virus with lower replicative capacity associated with protease (PR) and/or reverse transcriptase inhibitor resistance mutations, and the extensive diversification tended to lead either to improved entry efficiency via CCR5 or the gain of entry function via CXCR4. These results suggest that R5X4 or X4 variants emerge from a diverse, low-fitness landscape shaped by chronic infection, multiple ART resistance mutations, the availability of target cells, and reduced entry efficiency via CCR5.
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- 2017
19. Patterns and rates of viral evolution in HIV-1 subtype B infected females and males.
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Dapp, Michael J, Kober, Kord M, Chen, Lennie, Westfall, Dylan H, Wong, Kim, Zhao, Hong, Hall, Breana M, Deng, Wenjie, Sibley, Thomas, Ghorai, Suvankar, Kim, Katie, Chen, Natalie, McHugh, Sarah, Au, Lily, Cohen, Mardge, Anastos, Kathryn, and Mullins, James I
- Subjects
Humans ,HIV-1 ,HIV Infections ,Disease Progression ,Nucleotides ,HIV Envelope Protein gp120 ,Likelihood Functions ,Cohort Studies ,Evolution ,Molecular ,Phylogeny ,Glycosylation ,Sex Characteristics ,Time Factors ,Female ,Male ,gag Gene Products ,Human Immunodeficiency Virus ,Evolution ,Molecular ,gag Gene Products ,Human Immunodeficiency Virus ,General Science & Technology - Abstract
Biological sex differences affect the course of HIV infection, with untreated women having lower viral loads compared to their male counterparts but, for a given viral load, women have a higher rate of progression to AIDS. However, the vast majority of data on viral evolution, a process that is clearly impacted by host immunity and could be impacted by sex differences, has been derived from men. We conducted an intensive analysis of HIV-1 gag and env-gp120 evolution taken over the first 6-11 years of infection from 8 Women's Interagency HIV Study (WIHS) participants who had not received combination antiretroviral therapy (ART). This was compared to similar data previously collected from men, with both groups infected with HIV-1 subtype B. Early virus populations in men and women were generally homogenous with no differences in diversity between sexes. No differences in ensuing nucleotide substitution rates were found between the female and male cohorts studied herein. As previously reported for men, time to peak diversity in env-gp120 in women was positively associated with time to CD4+ cell count below 200 (P = 0.017), and the number of predicted N-linked glycosylation sites generally increased over time, followed by a plateau or decline, with the majority of changes localized to the V1-V2 region. These findings strongly suggest that the sex differences in HIV-1 disease progression attributed to immune system composition and sensitivities are not revealed by, nor do they impact, global patterns of viral evolution, the latter of which proceeds similarly in women and men.
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- 2017
20. Prevention efficacy of the broadly neutralizing antibody VRC01 depends on HIV-1 envelope sequence features
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Juraska, Michal, primary, Bai, Hongjun, additional, deCamp, Allan C., additional, Magaret, Craig A., additional, Li, Li, additional, Gillespie, Kevin, additional, Carpp, Lindsay N., additional, Giorgi, Elena E., additional, Ludwig, James, additional, Molitor, Cindy, additional, Hudson, Aaron, additional, Williamson, Brian D., additional, Espy, Nicole, additional, Simpkins, Brian, additional, Rudnicki, Erika, additional, Shao, Danica, additional, Rossenkhan, Raabya, additional, Edlefsen, Paul T., additional, Westfall, Dylan H., additional, Deng, Wenjie, additional, Chen, Lennie, additional, Zhao, Hong, additional, Bhattacharya, Tanmoy, additional, Pankow, Alec, additional, Murrell, Ben, additional, Yssel, Anna, additional, Matten, David, additional, York, Talita, additional, Beaume, Nicolas, additional, Gwashu-Nyangiwe, Asanda, additional, Ndabambi, Nonkululeko, additional, Thebus, Ruwayhida, additional, Karuna, Shelly T., additional, Morris, Lynn, additional, Montefiori, David C., additional, Hural, John A., additional, Cohen, Myron S., additional, Corey, Lawrence, additional, Rolland, Morgane, additional, Gilbert, Peter B., additional, Williamson, Carolyn, additional, and Mullins, James I., additional
- Published
- 2024
- Full Text
- View/download PDF
21. Transient Increase in Herpes Simplex Virus Type 2 (HSV-2)–Associated Genital Ulcers Following Initiation of Antiretroviral Therapy in HIV/HSV-2–Coinfected Individuals
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Fife, Kenneth H, Mugwanya, Kenneth, Thomas, Katherine K, Baeten, Jared M, Celum, Connie, Bukusi, Elizabeth, de Bruyn, Guy, Mujugira, Andrew, Vwalika, Bellington, Wald, Anna, Lingappa, Jairam R, Lingappa, Jairam, Campbell, Mary, Corey, Lawrence, Coombs, Robert W, Hughes, James P, Magaret, Amalia, McElrath, M Juliana, Morrow, Rhoda, Mullins, James I, Coetzee, David, Fife, Kenneth, Were, Edwin, Essex, Max, Makhema, Joseph, Katabira, Elly, Ronald, Allan, Allen, Susan, Kayitenkore, Kayitesi, Karita, Etienne, Cohen, Craig, Kanweka, William, Kapiga, Saidi, Manongi, Rachel, Farquhar, Carey, John-Stewart, Grace, Kiarie, James, Inambao, Mubiana, Delany-Moretlwe, Sinead, Rees, Helen, Gray, Glenda, McIntyre, James, and Mugo, Nelly Rwamba
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Clinical Research ,HIV/AIDS ,Sexually Transmitted Infections ,Infectious Diseases ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Infection ,Acyclovir ,Adult ,Antiretroviral Therapy ,Highly Active ,Coinfection ,Female ,HIV Infections ,Herpes Genitalis ,Herpesvirus 2 ,Human ,Humans ,Immune Reconstitution Inflammatory Syndrome ,Incidence ,Male ,Middle Aged ,Ulcer ,Partners in Prevention HSV/HIV Transmission Study Team ,acyclovir ,antiretroviral therapy ,herpes simplex virus ,human immunodeficiency virus ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundImmune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-infected persons beginning antiretroviral therapy (ART) has been incompletely characterized for herpes simplex virus type 2 (HSV-2).MethodsWe evaluated genital ulcer disease (GUD) and HSV-2-associated GUD at quarterly visits or when spontaneously reported at monthly visits in 3381 HIV/HSV-2-coinfected individuals in a placebo-controlled trial of suppressive acyclovir therapy to prevent HIV transmission, 349 of whom initiated ART during the study. Incidence was calculated for months before and after ART initiation, and incidence rate ratios (IRRs) were calculated.ResultsGUD incidence increased from 15.0 episodes per 100 person-years before ART to 26.9 episodes per 100 person-years in the first full quarter after ART initiation (IRR, 1.83;P= .03), and the incidence of HSV-2-associated GUD increased from 8.1 to 19.0 episodes per 100 person-years (IRR, 2.20;P= .02). Subsequently, the incidence of GUD was similar to that before ART, although the numbers were small. Persons receiving suppressive acyclovir had fewer GUD episodes, but the IRR after beginning ART was similar in the acyclovir and placebo groups.ConclusionsInitiation of ART in HIV/HSV-2-coinfected persons is associated with a transient increase in GUD and HSV-2 GUD. Acyclovir reduces the incidence of GUD but does not prevent an increase in GUD incidence during the first quarter following initiation of ART.
- Published
- 2016
22. Effect of Condom Use on Per-act HSV-2 Transmission Risk in HIV-1, HSV-2-discordant Couples
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Magaret, Amalia S, Mujugira, Andrew, Hughes, James P, Lingappa, Jairam, Bukusi, Elizabeth A, DeBruyn, Guy, Delany-Moretlwe, Sinead, Fife, Kenneth H, Gray, Glenda E, Kapiga, Saidi, Karita, Etienne, Mugo, Nelly R, Rees, Helen, Ronald, Allan, Vwalika, Bellington, Were, Edwin, Celum, Connie, Wald, Anna, Baeten, Jared M, Campbell, Mary, Corey, Lawrence, Coombs, Robert W, Magaret, Amalia, McElrath, M Juliana, Morrow, Rhoda, Mullins, James I, Coetzee, David, Fife, Kenneth, Essex, Max, Makhema, Joseph, Katabira, Elly, Allen, Susan, Kayitenkore, Kayitesi, Bukusi, Elizabeth, Cohen, Craig, Kanweka, William, Manongi, Rachel, Farquhar, Carey, John-Stewart, Grace, Kiarie, James, Inambao, Mubiana, de Bruyn, Guy, Gray, Glenda, McIntyre, James, and Mugo, Nelly Rwamba
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,HIV/AIDS ,Sexually Transmitted Infections ,Infectious Diseases ,Prevention ,Aetiology ,2.2 Factors relating to the physical environment ,Infection ,Reproductive health and childbirth ,Good Health and Well Being ,Condoms ,Disease Transmission ,Infectious ,Family Characteristics ,Female ,HIV Infections ,Herpes Genitalis ,Herpesvirus 2 ,Human ,Humans ,Infection Control ,Male ,Risk Assessment ,Partners in Prevention HSV/HIV Transmission Study Team ,HIV ,HSV-2 ,condom ,efficacy ,transmission ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Clinical sciences - Abstract
BackgroundThe efficacy of condoms for protection against transmission of herpes simplex virus type 2 (HSV-2) has been examined in a variety of populations with different effect measures. Often the efficacy has been assessed as change in hazard of transmission with consistent vs inconsistent use, independent of the number of acts. Condom efficacy has not previously measured on a per-act basis.MethodsWe examined the per-act HSV-2 transmission rates with and without condom use among 911 African HSV-2 and human immunodeficiency virus type 1 (HIV-1) serodiscordant couples followed for an average of 18 months in an HIV prevention study. Infectivity models were used to associate the log10 probability of HSV-2 transmission over monthly risk periods with reported numbers of protected and unprotected sex acts. Condom efficacy was computed as the proportionate reduction in transmission risk for protected relative to unprotected sex acts.ResultsTransmission of HSV-2 occurred in 68 couples, including 17 with susceptible women and 51 with susceptible men. The highest rate of transmission was from men to women: 28.5 transmissions per 1000 unprotected sex acts. We found that condoms were differentially protective against HSV-2 transmission by sex; condom use reduced per-act risk of transmission from men to women by 96% (P < .001) and marginally from women to men by 65% (P = .060).ConclusionsCondoms are recommended as an effective preventive method for heterosexual transmission of HSV-2.
- Published
- 2016
23. The immunogenicity of an HIV-1 gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy
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Jacobson, Jeffrey M., primary, Felber, Barbara K., additional, Chen, Huichao, additional, Pavlakis, George N., additional, Mullins, James I., additional, de Rosa, Stephen C., additional, Kuritzkes, Daniel R., additional, Tomaras, Georgia D., additional, Kinslow, Jennifer, additional, Bao, Yajing, additional, Olefsky, Maxine, additional, Rosati, Margherita, additional, Bear, Jenifer, additional, Hannaman, Drew, additional, Laird, Gregory M., additional, Cyktor, Joshua C., additional, Heath, Sonya L., additional, Collier, Ann C., additional, Koletar, Susan L., additional, Taiwo, Babafemi O., additional, Tebas, Pablo, additional, Wohl, David A., additional, belanzauran-Zamudio, Pablo F., additional, Mcelrath, M. Juliana, additional, and Landay, Alan L., additional
- Published
- 2023
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- View/download PDF
24. In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia
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Cole, Basiel, Lambrechts, Laurens, Gantner, Pierre, Noppe, Ytse, Bonine, Noah, Witkowski, Wojciech, Chen, Lennie, Palmer, Sarah, Mullins, James I., Chomont, Nicolas, Pardons, Marion, and Vandekerckhove, Linos
- Published
- 2021
- Full Text
- View/download PDF
25. The Genetics of HIV-1
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ANDERSON, JON P., primary, RAIN, MATTHEW, additional, SHRINER, DANIEL, additional, RODRIGO, ALLEN G., additional, WANG, YANG, additional, NICKLE, DAVID, additional, LEARN, GERALD H., additional, NAUGLER, WILLSCOTT E., additional, and MULLINS, JAMES I., additional
- Published
- 2021
- Full Text
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26. Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial.
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Edlefsen, Paul T, Rolland, Morgane, Hertz, Tomer, Tovanabutra, Sodsai, Gartland, Andrew J, deCamp, Allan C, Magaret, Craig A, Ahmed, Hasan, Gottardo, Raphael, Juraska, Michal, McCoy, Connor, Larsen, Brendan B, Sanders-Buell, Eric, Carrico, Chris, Menis, Sergey, Kijak, Gustavo H, Bose, Meera, RV144 Sequencing Team, Arroyo, Miguel A, O'Connell, Robert J, Nitayaphan, Sorachai, Pitisuttithum, Punnee, Kaewkungwal, Jaranit, Rerks-Ngarm, Supachai, Robb, Merlin L, Kirys, Tatsiana, Georgiev, Ivelin S, Kwong, Peter D, Scheffler, Konrad, Pond, Sergei L Kosakovsky, Carlson, Jonathan M, Michael, Nelson L, Schief, William R, Mullins, James I, Kim, Jerome H, and Gilbert, Peter B
- Subjects
RV144 Sequencing Team ,Humans ,HIV-1 ,HIV Infections ,AIDS Vaccines ,Sequence Alignment ,Sequence Analysis ,Protein ,Binding Sites ,Genome ,Viral ,Models ,Molecular ,Molecular Sequence Data ,Human Immunodeficiency Virus Proteins ,Sequence Analysis ,Protein ,Genome ,Viral ,Models ,Molecular ,Mathematical Sciences ,Biological Sciences ,Information and Computing Sciences ,Bioinformatics - Abstract
The RV144 clinical trial showed the partial efficacy of a vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients). A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino acid sites that differed between the vaccine and placebo groups. Here we extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods based on individual sites, k-mers and genes/proteins. We identified 56 amino acid sites or "signatures" and 119 k-mers that differed between the vaccine and placebo groups. Of those, 19 sites and 38 k-mers were located in the regions comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites in Env-gp120 were significantly enriched for known antibody-associated sites (p = 0.0021). In particular, site 317 in the third variable loop (V3) overlapped with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4 binding site neutralization. The identified signature sites significantly covaried with other sites across the genome (mean = 32.1) more than did non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or structural relevance of the signature sites. Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the associations were insignificant following correction for multiple testing, we predict that few of the genetic differences are strongly linked to the RV144 vaccine-induced immune pressure. In addition to presenting results of the first complete-genome analysis of the breakthrough infections in the RV144 trial, this work describes a set of statistical methods and tools applicable to analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens.
- Published
- 2015
27. p21(WAF1/CIP1) RNA expression in highly HIV-1 exposed, uninfected individuals.
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Herbeck, Joshua, Ghorai, Suvankar, Chen, Lennie, Rinaldo, Charles R, Margolick, Joseph B, Detels, Roger, Jacobson, Lisa, Wolinsky, Steven, and Mullins, James I
- Subjects
Humans ,HIV-1 ,HIV Infections ,RNA ,Risk Factors ,HIV Seronegativity ,Unsafe Sex ,Sexual Partners ,Cyclin-Dependent Kinase Inhibitor p21 ,General Science & Technology - Abstract
Some individuals remain HIV-1 antibody and PCR negative after repeated exposures to the virus, and are referred to as HIV-exposed seronegatives (HESN). However, the causes of resistance to HIV-1 infection in cases other than those with a homozygous CCR5Δ32 deletion are unclear. We hypothesized that human p21WAF1/CIP1 (a cyclin-dependent kinase inhibitor) could play a role in resistance to HIV-1 infection in HESN, as p21 expression has been associated with suppression of HIV-1 in elite controllers and reported to block HIV-1 integration in cell culture. We measured p21 RNA expression in PBMC from 40 HESN and 40 low exposure HIV-1 seroconverters (LESC) prior to their infection using a real-time PCR assay. Comparing the 20 HESN with the highest exposure risk (median = 111 partners/2.5 years prior to the 20 LESC with the lowest exposure risk (median = 1 partner/2.5 years prior), p21 expression trended higher in HESN in only one of two experiments (P = 0.11 vs. P = 0.80). Additionally, comparison of p21 expression in the top 40 HESN (median = 73 partners/year) and lowest 40 LESC (median = 2 partners/year) showed no difference between the groups (P = 0.84). There was a weak linear trend between risk of infection after exposure and increasing p21 gene expression (R2 = 0.02, P = 0.12), but again only in one experiment. Hence, if p21 expression contributes to the resistance to viral infection in HESN, it likely plays a minor role evident only in those with extremely high levels of exposure to HIV-1.
- Published
- 2015
28. Phylobook: a tool for display, clade annotation and extraction of sequences from molecular phylogenies
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Furlong, Jeffrey C, Darley, Peter D, Deng, Wenjie, Mullins, James I, and Bumgarner, Roger E
- Abstract
As the volume of sequence data from variable pathogens increases, means of analyzing, annotating and extracting specific taxa for study becomes more difficult. To meet these challenges for datasets with hundreds to thousands of taxa, ‘Phylobook’ was developed. Starting with a sequence alignment file, Phylobook generates and displays phylogenetic trees adjacent to highlighter plots showing the position of mutations, and allows the user to identify lineages and recombinants, annotate and export selected subsets of sequences for downstream analysis. Accurate lineage assignment, which is difficult to automate, is aided using annotations created by different clustering methods. Phylobook provides web-based display combined with automated clustering and manual editing to allow for expert assessment and correction of lineage assignments and extraction for downstream analysis.
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- 2024
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29. The replication-competent HIV reservoir is a genetically restricted, younger subset of the overall pool of HIV proviruses persisting during therapy, which is highly genetically stable over time
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Shahid, Aniqa, primary, MacLennan, Signe, additional, Jones, Bradley R., additional, Sudderuddin, Hanwei, additional, Dang, Zhong, additional, Cobarrubias, Kyle, additional, Duncan, Maggie C., additional, Kinloch, Natalie N., additional, Dapp, Michael J., additional, Archin, Nancie M, additional, Fischl, Margaret A., additional, Ofotokun, Igho, additional, Adimora, Adaora, additional, Gange, Stephen, additional, Aouizerat, Bradley, additional, Kuniholm, Mark H., additional, Kassaye, Seble, additional, Mullins, James I., additional, Goldstein, Harris, additional, Joy, Jeffrey B., additional, Anastos, Kathryn, additional, and Brumme, Zabrina L., additional
- Published
- 2023
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30. HIV population-level adaptation can rapidly diminish the impact of a partially effective vaccine
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Herbeck, Joshua T., Peebles, Kathryn, Edlefsen, Paul T., Rolland, Morgane, Murphy, James T., Gottlieb, Geoffrey S., Abernethy, Neil, Mullins, James I., Mittler, John E., and Goodreau, Steven M.
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- 2018
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31. HIV Type 1 Superinfection with a Dual-Tropic Virus and Rapid Progression to AIDS: A Case Report
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Gottlieb, Geoffrey S., Nickle, David C., Jensen, Mark A., Kaslow, Richard A., Margolick, Joseph B., and Mullins, James I.
- Published
- 2007
32. Evolution of Intrahost HIV-1 Genetic Diversity during Chronic Infection
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Shriner, Daniel, Liu, Yi, Nickle, David C., and Mullins, James I.
- Published
- 2006
33. Definition of the viral targets of protective HIV-1-specific T cell responses
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Mothe, Beatriz, Llano, Anuska, Ibarrondo, Javier, Daniels, Marcus, Miranda, Cristina, Zamarreño, Jennifer, Bach, Vanessa, Zuniga, Rosario, Pérez-Álvarez, Susana, Berger, Christoph T, Puertas, Maria C, Martinez-Picado, Javier, Rolland, Morgane, Farfan, Marilu, Szinger, James J, Hildebrand, William H, Yang, Otto O, Sanchez-Merino, Victor, Brumme, Chanson J, Brumme, Zabrina L, Heckerman, David, Allen, Todd M, Mullins, James I, Gómez, Guadalupe, Goulder, Philip J, Walker, Bruce D, Gatell, Jose M, Clotet, Bonaventura, Korber, Bette T, Sanchez, Jorge, and Brander, Christian
- Abstract
Abstract Background The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity. Methods Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders. Results For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes. Conclusions The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.
- Published
- 2011
34. Viral linkage in HIV-1 seroconverters and their partners in an HIV-1 prevention clinical trial.
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Campbell, Mary S, Mullins, James I, Hughes, James P, Celum, Connie, Wong, Kim G, Raugi, Dana N, Sorensen, Stefanie, Stoddard, Julia N, Zhao, Hong, Deng, Wenjie, Kahle, Erin, Panteleeff, Dana, Baeten, Jared M, McCutchan, Francine E, Albert, Jan, Leitner, Thomas, Wald, Anna, Corey, Lawrence, Lingappa, Jairam R, and Partners in Prevention HSV/HIV Transmission Study Team
- Subjects
Partners in Prevention HSV/HIV Transmission Study Team ,Humans ,HIV-1 ,HIV Seropositivity ,Bayes Theorem ,Sequence Analysis ,DNA ,Demography ,Phylogeny ,Adult ,Sexual Partners ,Female ,Male ,env Gene Products ,Human Immunodeficiency Virus ,gag Gene Products ,Human Immunodeficiency Virus ,Genetic Linkage ,Sequence Analysis ,DNA ,env Gene Products ,Human Immunodeficiency Virus ,gag Gene Products ,General Science & Technology - Abstract
BackgroundCharacterization of viruses in HIV-1 transmission pairs will help identify biological determinants of infectiousness and evaluate candidate interventions to reduce transmission. Although HIV-1 sequencing is frequently used to substantiate linkage between newly HIV-1 infected individuals and their sexual partners in epidemiologic and forensic studies, viral sequencing is seldom applied in HIV-1 prevention trials. The Partners in Prevention HSV/HIV Transmission Study (ClinicalTrials.gov #NCT00194519) was a prospective randomized placebo-controlled trial that enrolled serodiscordant heterosexual couples to determine the efficacy of genital herpes suppression in reducing HIV-1 transmission; as part of the study analysis, HIV-1 sequences were examined for genetic linkage between seroconverters and their enrolled partners.Methodology/principal findingsWe obtained partial consensus HIV-1 env and gag sequences from blood plasma for 151 transmission pairs and performed deep sequencing of env in some cases. We analyzed sequences with phylogenetic techniques and developed a Bayesian algorithm to evaluate the probability of linkage. For linkage, we required monophyletic clustering between enrolled partners' sequences and a Bayesian posterior probability of ≥ 50%. Adjudicators classified each seroconversion, finding 108 (71.5%) linked, 40 (26.5%) unlinked, and 3 (2.0%) indeterminate transmissions, with linkage determined by consensus env sequencing in 91 (84%). Male seroconverters had a higher frequency of unlinked transmissions than female seroconverters. The likelihood of transmission from the enrolled partner was related to time on study, with increasing numbers of unlinked transmissions occurring after longer observation periods. Finally, baseline viral load was found to be significantly higher among linked transmitters.Conclusions/significanceIn this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner, illustrating the relevance of these methods in the design of future HIV-1 prevention trials in serodiscordant couples. A hierarchy of sequencing techniques, analysis methods, and expert adjudication contributed to the linkage determination process.
- Published
- 2011
35. Clonal Expansion of Human Immunodeficiency Virus—Infected Cells and Human Immunodeficiency Virus Persistence During Antiretroviral Therapy
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Mullins, James I. and Frenkel, Lisa M.
- Published
- 2017
36. Neutralization profiles of HIV-1 viruses from the VRC01 Antibody Mediated Prevention (AMP) trials
- Author
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Mkhize, Nonhlanhla N., primary, Yssel, Anna E. J., additional, Kaldine, Haajira, additional, van Dorsten, Rebecca T., additional, Woodward Davis, Amanda S., additional, Beaume, Nicolas, additional, Matten, David, additional, Lambson, Bronwen, additional, Modise, Tandile, additional, Kgagudi, Prudence, additional, York, Talita, additional, Westfall, Dylan H., additional, Giorgi, Elena E., additional, Korber, Bette, additional, Anthony, Colin, additional, Mapengo, Rutendo E., additional, Bekker, Valerie, additional, Domin, Elizabeth, additional, Eaton, Amanda, additional, Deng, Wenjie, additional, DeCamp, Allan, additional, Huang, Yunda, additional, Gilbert, Peter B., additional, Gwashu-Nyangiwe, Asanda, additional, Thebus, Ruwayhida, additional, Ndabambi, Nonkululeko, additional, Mielke, Dieter, additional, Mgodi, Nyaradzo, additional, Karuna, Shelly, additional, Edupuganti, Srilatha, additional, Seaman, Michael S., additional, Corey, Lawrence, additional, Cohen, Myron S., additional, Hural, John, additional, McElrath, M. Juliana, additional, Mullins, James I., additional, Montefiori, David, additional, Moore, Penny L., additional, Williamson, Carolyn, additional, and Morris, Lynn, additional
- Published
- 2023
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37. Variation Within Major Internal Repeats of KSHV In Vivo
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Santiago, Jan Clement, primary, Westfall, Dylan H, additional, Adams, Scott V, additional, Okuku, Fred, additional, Phipps, Warren, additional, and Mullins, James I, additional
- Published
- 2023
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38. Efficient ex vivo expansion of conserved element vaccine-specific CD8+ T-cells from SHIV-infected, ART-suppressed nonhuman primates
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Dross, Sandra, primary, Venkataraman, Rasika, additional, Patel, Shabnum, additional, Huang, Meei-Li, additional, Bollard, Catherine M., additional, Rosati, Margherita, additional, Pavlakis, George N., additional, Felber, Barbara K., additional, Bar, Katharine J., additional, Shaw, George M., additional, Jerome, Keith R., additional, Mullins, James I., additional, Kiem, Hans-Peter, additional, Fuller, Deborah Heydenburg, additional, and Peterson, Christopher W., additional
- Published
- 2023
- Full Text
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39. Consensus and Ancestral State HIV Vaccines
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Nickle, David C., Jensen, Mark A., Gottlieb, Geoffrey S., Shriner, Daniel, Learn, Gerald H., Rodrigo, Allen G., Mullins, James I., Gao, F., Bhattacharya, T., Gaschen, B., Taylor, J., Moore, J. P., Novitsky, V., Yusim, K., Lang, D., Foley, B., Beddows, S., Alam, M., Haynes, B., Hahn, B. H., and Korber, B.
- Published
- 2003
40. Coping with Viral Diversity in HIV Vaccine Design
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Nickle, David C, Rolland, Morgane, Jensen, Mark A, Pond, Sergei L Kosakovsky, Deng, Wenjie, Seligman, Mark, Heckerman, David, Mullins, James I, and Jojic, Nebojsa
- Subjects
Immunization ,Biotechnology ,Vaccine Related ,Vaccine Related (AIDS) ,HIV/AIDS ,Infectious Diseases ,Prevention ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Good Health and Well Being ,AIDS Vaccines ,Antigenic Variation ,Drug Design ,Epitope Mapping ,Gene Products ,nef ,Genetic Variation ,nef Gene Products ,Human Immunodeficiency Virus ,Mathematical Sciences ,Biological Sciences ,Information and Computing Sciences ,Bioinformatics - Abstract
The ability of human immunodeficiency virus type 1 (HIV-1) to develop high levels of genetic diversity, and thereby acquire mutations to escape immune pressures, contributes to the difficulties in producing a vaccine. Possibly no single HIV-1 sequence can induce sufficiently broad immunity to protect against a wide variety of infectious strains, or block mutational escape pathways available to the virus after infection. The authors describe the generation of HIV-1 immunogens that minimizes the phylogenetic distance of viral strains throughout the known viral population (the center of tree [COT]) and then extend the COT immunogen by addition of a composite sequence that includes high-frequency variable sites preserved in their native contexts. The resulting COT(+) antigens compress the variation found in many independent HIV-1 isolates into lengths suitable for vaccine immunogens. It is possible to capture 62% of the variation found in the Nef protein and 82% of the variation in the Gag protein into immunogens of three gene lengths. The authors put forward immunogen designs that maximize representation of the diverse antigenic features present in a spectrum of HIV-1 strains. These immunogens should elicit immune responses against high-frequency viral strains as well as against most mutant forms of the virus.
- Published
- 2007
41. Coalescent Estimates of HIV-1 Generation Time in vivo
- Author
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Rodrigo, Allen G., Shpaer, Eugene G., Delwart, Eric L., Gallo, Michael V., Brojatsch, Jurgen, Hirsch, Martin S., Walker, Bruce D., and Mullins, James I.
- Published
- 1999
42. Lethal Mutagenesis of HIV with Mutagenic Nucleoside Analogs
- Author
-
Loeb, Lawrence A., Essigmann, John M., Kazazi, Farhad, Zhang, Jue, Rose, Karl D., and Mullins, James I.
- Published
- 1999
43. Genetic Evaluation of Suspected Cases of Transient HIV-1 Infection of Infants
- Author
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Frenkel, Lisa M., Mullins, James I., Learn, Gerald H., Manns-Arcuino, Laura, Herring, Belinda L., Kalish, Marcia L., Steketee, Richard W., Thea, Donald M., Nichols, Joan E., Liu, Shan-Lu, Harmache, Abdallah, He, Xi, Muthui, David, Madan, Anup, Hood, Leroy, Haase, Ashley T., Zupancic, Mary, Staskus, Katherine, Wolinsky, Steven, Krogstad, Paul, Zhao, JiaQi, Chen, Irvin, Koup, Richard, Ho, David, Korber, Bette, Apple, Raymond J., Coombs, Robert W., Pahwa, Savita, and Roberts,, Norbert J.
- Published
- 1998
44. Optimized SMRT-UMI protocol produces highly accurate sequence datasets from diverse populations – application to HIV-1 quasispecies
- Author
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Westfall, Dylan H., primary, Deng, Wenjie, additional, Pankow, Alec, additional, Murrell, Hugh, additional, Chen, Lennie, additional, Zhao, Hong, additional, Williamson, Carolyn, additional, Rolland, Morgane, additional, Murrell, Ben, additional, and Mullins, James I., additional
- Published
- 2023
- Full Text
- View/download PDF
45. Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection
- Author
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Altfeld, Marcus, Rosenberg, Eric S, Shankarappa, Raj, Mukherjee, Joia S, Hecht, Frederick M, Eldridge, Robert L, Addo, Marylyn M, Poon, Samuel H, Phillips, Mary N, Robbins, Gregory K, Sax, Paul E, Boswell, Steve, Kahn, James O, Brander, Christian, Goulder, Philip JR, Levy, Jay A, Mullins, James I, and Walker, Bruce D
- Subjects
Vaccine Related ,Prevention ,HIV/AIDS ,Infectious Diseases ,Immunization ,Infection ,Inflammatory and immune system ,Good Health and Well Being ,Acute Disease ,Amino Acid Sequence ,Antiretroviral Therapy ,Highly Active ,Base Sequence ,Cohort Studies ,DNA Primers ,Epitopes ,Female ,Genetic Variation ,HIV Infections ,HIV Seropositivity ,HIV-1 ,Humans ,Immunity ,Cellular ,Longitudinal Studies ,Male ,Molecular Sequence Data ,RNA ,Viral ,T-Lymphocytes ,Cytotoxic ,T-Lymphocytes ,Helper-Inducer ,Time Factors ,cytotoxic T lymphocytes ,T helper cell responses ,viral evolution ,cytotoxic T lymphocyte epitopes ,human leukocyte antigen ,Medical and Health Sciences ,Immunology - Abstract
Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.
- Published
- 2001
46. Human Immunodeficiency Virus Type 1 Infection despite Prior Immunization with a Recombinant Envelope Vaccine Regimen
- Author
-
McElrath, M. Juliana, Corey, Lawrence, Greenberg, Philip D., Matthews, Thomas J., Montefiori, David C., Rowen, Lee, Hood, Leroy, and Mullins, James I.
- Published
- 1996
47. Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load
- Author
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McLaren, Paul J., Coulonges, Cedric, Bartha, István, Lenz, Tobias L., Deutsch, Aaron J., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary N., Cossarizza, Andrea, Dalmau, Judith, De Luca, Andrea, Goedert, James J., Gurdasani, Deepti, Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kirk, Gregory D., Lambotte, Olivier, Luo, Ma, Mallal, Simon, van Manen, Daniëlle, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Mullins, James I., Obel, Niels, Poli, Guido, Sandhu, Manjinder S., Schuitemaker, Hanneke, Shea, Patrick R., Theodorou, Ioannis, Walker, Bruce D., Weintrob, Amy C., Winkler, Cheryl A., Wolinsky, Steven M., Raychaudhuri, Soumya, Goldstein, David B., Telenti, Amalio, de Bakker, Paul I. W., Zagury, Jean-François, and Fellay, Jacques
- Published
- 2015
48. Genomic changes in Kaposi Sarcoma-associated Herpesvirus and their clinical correlates
- Author
-
Santiago, Jan Clement, primary, Adams, Scott V., additional, Towlerton, Andrea, additional, Okuku, Fred, additional, Phipps, Warren, additional, and Mullins, James I., additional
- Published
- 2022
- Full Text
- View/download PDF
49. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection
- Author
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Wagner, Thor A., McLaughlin, Sherry, Garg, Kavita, Cheung, Charles Y. K., Larsen, Brendan B., Styrchak, Sheila, Huang, Hannah C., Edlefsen, Paul T., Mullins, James I., and Frenkel, Lisa M.
- Published
- 2014
50. Toll-like Receptor Polymorphism Associations With HIV-1 Outcomes Among Sub-Saharan Africans
- Author
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Mackelprang, Romel D., Bigham, Abigail W., Celum, Connie, de Bruyn, Guy, Beima-Sofie, Kristin, John-Stewart, Grace, Ronald, Allan, Mugo, Nelly R., Buckingham, Kati J., Bamshad, Michael J., Mullins, James I., McElrath, M. Juliana, and Lingappa, Jairam R.
- Published
- 2014
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