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1. Y RNAs are conserved endogenous RIG-I ligands across RNA virus infection and are targeted by HIV-1

Author

Vabret, Nicolas, Najburg, Valérie, Solovyov, Alexander, Gopal, Ramya, McClain, Christopher, Šulc, Petr, Balan, Sreekumar, Rahou, Yannis, Beauclair, Guillaume, Chazal, Maxime, Varet, Hugo, Legendre, Rachel, Sismeiro, Odile, Sanchez David, Raul Y., Chauveau, Lise, Jouvenet, Nolwenn, Markowitz, Martin, van der Werf, Sylvie, Schwartz, Olivier, Tangy, Frédéric, Bhardwaj, Nina, Greenbaum, Benjamin D., and Komarova, Anastassia V.

Published
2022
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2. Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Antinori, Andrea, Apea, Vanessa, Asmuth, David, Avery, Ann, Benson, Paul, Bergin, Colm, Berhe, Mezgebe, Brar, Indira, Brinson, Cynthia, Brunetta, Jason, Burack, Jeffrey, Campbell, Thomas, Cespedes, Michelle, Clarke, Amanda, Coleman, Megan, Coll, Josep, Crespo Casal, Manuel, Creticos, Catherine, Crofoot, Gordon, Cruickshank, Frederick, Cua, Eric, Daar, Eric, de Wet, Joseph, DeJesus, Edwin, Del Romero Guerrero, Jorge, Dinges, William, Doblecki-Lewis, Susanne, Donovan, Taylor, Dosekun, Olamide, Flamm, Jason, Gallant, Joel, Gerstoft, Jan, Gilson, Richard, Gladstein, Jay, Grant, Robert, Grossberg, Robert, Haas, Bernhard, Halperin, Jason, Hardy, W. David, Hare, Charles, Hassler, Shawn, Hengel, Richard, Henry, William, Hodge, Theo, Jr., Hosek, Sybil, Hurt, Christopher, Iandiorio, Michelle, Jessen, Heiko, Kegg, Stephen, Knecht, Gabriele, Kronborg, Gitte, Krznaric, Ivanka, LaMarca, Anthony, Larsen, Carsten Schade, Larsen, Olav Ditlevsen, Lazzarin, Adriano, Leen, Clifford, Lucasti, Christopher, Mallon, Patrick, Mannheimer, Sharon, Markowitz, Martin, Martorell, Claudia, Mayer, Kenneth, Mills, Anthony, Molina, Jean-Michel, Morris, Sheldon, Mounzer, Karam, Nwokolo, Nneka, Ogbuagu, Onyema, Osiyemi, Olayemi, Petroll, Andrew, Philibert, Patrick, Phoenix, John, Pialoux, Gilles, Podzamczer, Daniel, Post, Frank, Prins, Maria, Ramgopal, Moti, Rashbaum, Bruce, Reeves, Iain, Richmond, Gary, Rieger, Armin, Ruane, Peter, Salazar, Laura, Scarsella, Anthony, Schembri, Gabriel, Scott, Mia, Shalit, Peter, Sinclair, Gary, Sobieszczyk, Magdalena, Spinner, Christoph, Stephens, Jeffrey, Szabo, Jason, Taylor, Stephen, Thompson, Melanie, Tremblay, Cecile, Trottier, Benoit, Voskuhl, Gene, Wade, Barbara, Wohl, David, Workowski, Kimberly, Yawetz, Sigal, Young, Benjamin, Ruane, Peter J, Salazar, Laura C, Henry, Keith, Asmuth, David M, Shao, Yongwu, Ebrahimi, Ramin, Cox, Stephanie, Kintu, Alexander, Carter, Christoph, Das, Moupali, Baeten, Jared M, Brainard, Diana M, Whitlock, Gary, Brunetta, Jason M, and Spinner, Christoph D

Published
2021
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3. Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic.

Author

Kinloch, Natalie N, MacMillan, Daniel R, Le, Anh Q, Cotton, Laura A, Bangsberg, David R, Buchbinder, Susan, Carrington, Mary, Fuchs, Jonathan, Harrigan, P Richard, Koblin, Beryl, Kushel, Margot, Markowitz, Martin, Mayer, Kenneth, Milloy, MJ, Schechter, Martin T, Wagner, Theresa, Walker, Bruce D, Carlson, Jonathan M, Poon, Art FY, and Brumme, Zabrina L

Subjects
Humans, HIV-1, HIV Infections, Histocompatibility Antigens Class I, Cohort Studies, Adaptation, Biological, Phylogeny, Genotype, North America, Male, pol Gene Products, Human Immunodeficiency Virus, Genetic Variation, Epidemics, Adaptation, Biological, pol Gene Products, Human Immunodeficiency Virus, Virology, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences
Abstract

UnlabelledHuman leukocyte antigen (HLA) class I-associated polymorphisms in HIV-1 that persist upon transmission to HLA-mismatched hosts may spread in the population as the epidemic progresses. Transmission of HIV-1 sequences containing such adaptations may undermine cellular immune responses to the incoming virus in future hosts. Building upon previous work, we investigated the extent of HLA-associated polymorphism accumulation in HIV-1 polymerase (Pol) through comparative analysis of linked HIV-1/HLA class I genotypes sampled during historic (1979 to 1989; n = 338) and modern (2001 to 2011; n = 278) eras from across North America (Vancouver, BC, Canada; Boston, MA; New York, NY; and San Francisco, CA). Phylogenies inferred from historic and modern HIV-1 Pol sequences were star-like in shape, with an inferred most recent common ancestor (epidemic founder virus) sequence nearly identical to the modern North American subtype B consensus sequence. Nevertheless, modern HIV-1 Pol sequences exhibited roughly 2-fold-higher patristic (tip-to-tip) genetic distances than historic sequences, with HLA pressures likely driving ongoing diversification. Moreover, the frequencies of published HLA-associated polymorphisms in individuals lacking the selecting HLA class I allele was on average ∼2.5-fold higher in the modern than in the historic era, supporting their spread in circulation, though some remained stable in frequency during this time. Notably, polymorphisms restricted by protective HLA alleles appear to be spreading to a greater relative extent than others, though these increases are generally of modest absolute magnitude. However, despite evidence of polymorphism spread, North American hosts generally remain at relatively low risk of acquiring an HIV-1 polymerase sequence substantially preadapted to their HLA profiles, even in the present era.ImportanceHLA class I-restricted cytotoxic T-lymphocyte (CTL) escape mutations in HIV-1 that persist upon transmission may accumulate in circulation over time, potentially undermining host antiviral immunity to the transmitted viral strain. We studied >600 experimentally collected HIV-1 polymerase sequences linked to host HLA information dating back to 1979, along with phylogenetically reconstructed HIV-1 sequences dating back to the virus' introduction into North America. Overall, our results support the gradual spread of many-though not all-HIV-1 polymerase immune escape mutations in circulation over time. This is consistent with recent observations from other global regions, though the extent of polymorphism accumulation in North America appears to be lower than in populations with high seroprevalence, older epidemics, and/or limited HLA diversity. Importantly, the risk of acquiring an HIV-1 polymerase sequence at transmission that is substantially preadapted to one's HLA profile remains relatively low in North America, even in the present era.

Published
2016

4. Impaired Nef Function Is Associated with Early Control of HIV-1 Viremia

Author

Kuang, Xiaomei T, Li, Xiaoguang, Anmole, Gursev, Mwimanzi, Philip, Shahid, Aniqa, Le, Anh Q, Chong, Louise, Qian, Hua, Miura, Toshiyuki, Markle, Tristan, Baraki, Bemuluyigza, Connick, Elizabeth, Daar, Eric S, Jessen, Heiko, Kelleher, Anthony D, Little, Susan, Markowitz, Martin, Pereyra, Florencia, Rosenberg, Eric S, Walker, Bruce D, Ueno, Takamasa, Brumme, Zabrina L, and Brockman, Mark A

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Genetics, Infectious Diseases, Immunization, HIV/AIDS, Clinical Research, Aetiology, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Infection, CD4 Antigens, Down-Regulation, Genotype, HIV Infections, HIV-1, Histocompatibility Antigens Class I, Humans, Molecular Sequence Data, Plasma, Polymorphism, Genetic, RNA, Viral, Sequence Analysis, DNA, Viral Load, Viremia, nef Gene Products, Human Immunodeficiency Virus, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Virology, Agricultural, veterinary and food sciences, Biological sciences, Biomedical and clinical sciences
Abstract

UnlabelledHost and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P

Published
2014

5. Genotypic and functional impact of HIV-1 adaptation to its host population during the North American epidemic.

Author

Cotton, Laura A, Kuang, Xiaomei T, Le, Anh Q, Carlson, Jonathan M, Chan, Benjamin, Chopera, Denis R, Brumme, Chanson J, Markle, Tristan J, Martin, Eric, Shahid, Aniqa, Anmole, Gursev, Mwimanzi, Philip, Nassab, Pauline, Penney, Kali A, Rahman, Manal A, Milloy, M-J, Schechter, Martin T, Markowitz, Martin, Carrington, Mary, Walker, Bruce D, Wagner, Theresa, Buchbinder, Susan, Fuchs, Jonathan, Koblin, Beryl, Mayer, Kenneth H, Harrigan, P Richard, Brockman, Mark A, Poon, Art FY, and Brumme, Zabrina L

Subjects
Humans, HIV-1, HIV Infections, HLA Antigens, Adaptation, Physiological, Phylogeny, Amino Acid Sequence, Genotype, Polymorphism, Genetic, Molecular Sequence Data, North America, Male, Adaptation, Physiological, Polymorphism, Genetic, Developmental Biology, Genetics
Abstract

HLA-restricted immune escape mutations that persist following HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as the epidemic progresses. To assess the extent and phenotypic impact of this phenomenon in an immunogenetically diverse population, we genotypically and functionally compared linked HLA and HIV (Gag/Nef) sequences from 358 historic (1979-1989) and 382 modern (2000-2011) specimens from four key cities in the North American epidemic (New York, Boston, San Francisco, Vancouver). Inferred HIV phylogenies were star-like, with approximately two-fold greater mean pairwise distances in modern versus historic sequences. The reconstructed epidemic ancestral (founder) HIV sequence was essentially identical to the North American subtype B consensus. Consistent with gradual diversification of a "consensus-like" founder virus, the median "background" frequencies of individual HLA-associated polymorphisms in HIV (in individuals lacking the restricting HLA[s]) were ∼ 2-fold higher in modern versus historic HIV sequences, though these remained notably low overall (e.g. in Gag, medians were 3.7% in the 2000s versus 2.0% in the 1980s). HIV polymorphisms exhibiting the greatest relative spread were those restricted by protective HLAs. Despite these increases, when HIV sequences were analyzed as a whole, their total average burden of polymorphisms that were "pre-adapted" to the average host HLA profile was only ∼ 2% greater in modern versus historic eras. Furthermore, HLA-associated polymorphisms identified in historic HIV sequences were consistent with those detectable today, with none identified that could explain the few HIV codons where the inferred epidemic ancestor differed from the modern consensus. Results are therefore consistent with slow HIV adaptation to HLA, but at a rate unlikely to yield imminent negative implications for cellular immunity, at least in North America. Intriguingly, temporal changes in protein activity of patient-derived Nef (though not Gag) sequences were observed, suggesting functional implications of population-level HIV evolution on certain viral proteins.

Published
2014

10. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial

Author

Markowitz, Martin, Frank, Ian, Grant, Robert M, Mayer, Kenneth H, Elion, Richard, Goldstein, Deborah, Fisher, Chester, Sobieszczyk, Magdalena E, Gallant, Joel E, Van Tieu, Hong, Weinberg, Winkler, Margolis, David A, Hudson, Krischan J, Stancil, Britt S, Ford, Susan L, Patel, Parul, Gould, Elizabeth, Rinehart, Alex R, Smith, Kimberly Y, and Spreen, William R

Published
2017
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11. HIV Virology

Author

Livingston, Schuyler, primary, Markowitz, Martin, additional, Wright, William, additional, Young, Benjamin, additional, Mathur, Poonam, additional, and Gilliam, Bruce L., additional

Published
2019
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15. Increased Turnover of T Lymphocytes in HIV-1 Infection and Its Reduction by Antiretroviral Therapy

Author

Mohri, Hiroshi, Perelson, Alan S, Tung, Keith, Ribeiro, Ruy M, Ramratnam, Bharat, Markowitz, Martin, Kost, Rhonda, Hurley, Weinberger, Leor, Cesar, Denise, Hellerstein, Marc K, and Ho, David D

Subjects
Clinical Research, Infectious Diseases, HIV/AIDS, Infection, Adult, Apoptosis, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Division, Female, Gene Expression, HIV Infections, HIV-1, Health Status, Humans, In Situ Nick-End Labeling, Ki-67 Antigen, Kinetics, Longitudinal Studies, Male, Middle Aged, Monocytes, Time Factors, Viral Load, Medical and Health Sciences, Immunology
Abstract

The mechanism of CD4(+) T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1-infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death. In CD4(+) T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls. In CD8(+) T cells, the mean proliferation rate was 7.7-fold higher in HIV-1 infection, but the mean death rate was not significantly increased. Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy. The lymphocyte proliferation and death rates in both CD4(+) and CD8(+) cell populations were substantially reduced by 5-11 weeks and nearly normal by one year. Taken together, these new findings strongly indicate that CD4(+) lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.

Published
2001

17. Measuring Recent Thymic Emigrants in Blood of Normal and HIV-1–Infected Individuals before and after Effective Therapy

Author

Zhang, Linqi, Lewin, Sharon R, Markowitz, Martin, Lin, Hsi-Hsun, Skulsky, Eva, Karanicolas, Rose, He, Yuxian, Jin, Xia, Tuttleton, Sarah, Vesanen, Mika, Spiegel, Hans, Kost, Rhonda, van Lunzen, Jan, Stellbrink, Hans-Juergen, Wolinsky, Steven, Borkowsky, William, Palumbo, Paul, Kostrikis, Leondios G, and Ho, David D

Subjects
Infectious Diseases, HIV/AIDS, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Infection, Adolescent, Adult, Aging, Anti-HIV Agents, Base Sequence, Case-Control Studies, Cell Movement, Child, DNA Primers, DNA, Circular, Gene Rearrangement, T-Lymphocyte, HIV Infections, HIV-1, Humans, Polymerase Chain Reaction, T-Lymphocytes, Medical and Health Sciences, Immunology
Abstract

The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed alpha1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.

Published
1999

20. HIV Virology

Author

Livingston, Schuyler, primary, Young, Benjamin, additional, Markowitz, Martin, additional, Mathur, Poonam, additional, and Gilliam, Bruce L., additional

Published
2017
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22. Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials

Author

Eron, Joseph J, Cooper, David A, Steigbigel, Roy T, Clotet, Bonaventura, Gatell, Jose M, Kumar, Princy N, Rockstroh, Jurgen K, Schechter, Mauro, Markowitz, Martin, Yeni, Patrick, Loutfy, Mona R, Lazzarin, Adriano, Lennox, Jeffrey L, Strohmaier, Kim M, Wan, Hong, Barnard, Richard JO, Nguyen, Bach-Yen T, and Teppler, Hedy

Published
2013
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28. Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials

Author

Steigbige, Roy T., Cooper, David A., Teppler, Hedy, Eron, Joseph J., Gatell, Jose M., Kumar, Princy N., Rockstroh, Jurgen K., Schechter, Mauro, Katlama, Christine, Markowitz, Martin, Yeni, Patrick, Loutfy, Mona R., Lazzarin, Adriano, Lennox, Jeffrey L., Clotet, Bonaventura, Zhao, Jing, Wan, Hong, Rhodes, Rand R., Strohmaier, Kim M., Barnard, Richard J., Isaacs, Robin D., and Nguyen, Bach-Yen T.

Published
2010

34. Evidence of dysregulation of dendritic cells in primary HIV infection

Author

Sabado, Rachel Lubong, O'Brien, Meagan, Subedi, Abhignya, Qin, Li, Hu, Nan, Taylor, Elizabeth, Dibben, Oliver, Stacey, Andrea, Fellay, Jacques, Shianna, Kevin V., Siegal, Frederick, Shodell, Michael, Shah, Kokila, Larsson, Marie, Lifson, Jeffrey, Nadas, Arthur, Marmor, Michael, Hutt, Richard, Margolis, David, Garmon, Donald, Markowitz, Martin, Valentine, Fred, Borrow, Persephone, and Bhardwaj, Nina

Published
2010
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45. Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Ogbuagu, Onyema, primary, Ruane, Peter J, additional, Podzamczer, Daniel, additional, Salazar, Laura C, additional, Henry, Keith, additional, Asmuth, David M, additional, Wohl, David, additional, Gilson, Richard, additional, Shao, Yongwu, additional, Ebrahimi, Ramin, additional, Cox, Stephanie, additional, Kintu, Alexander, additional, Carter, Christoph, additional, Das, Moupali, additional, Baeten, Jared M, additional, Brainard, Diana M, additional, Whitlock, Gary, additional, Brunetta, Jason M, additional, Kronborg, Gitte, additional, Spinner, Christoph D, additional, Antinori, Andrea, additional, Apea, Vanessa, additional, Asmuth, David, additional, Avery, Ann, additional, Benson, Paul, additional, Bergin, Colm, additional, Berhe, Mezgebe, additional, Brar, Indira, additional, Brinson, Cynthia, additional, Brunetta, Jason, additional, Burack, Jeffrey, additional, Campbell, Thomas, additional, Cespedes, Michelle, additional, Clarke, Amanda, additional, Coleman, Megan, additional, Coll, Josep, additional, Crespo Casal, Manuel, additional, Creticos, Catherine, additional, Crofoot, Gordon, additional, Cruickshank, Frederick, additional, Cua, Eric, additional, Daar, Eric, additional, de Wet, Joseph, additional, DeJesus, Edwin, additional, Del Romero Guerrero, Jorge, additional, Dinges, William, additional, Doblecki-Lewis, Susanne, additional, Donovan, Taylor, additional, Dosekun, Olamide, additional, Flamm, Jason, additional, Gallant, Joel, additional, Gerstoft, Jan, additional, Gladstein, Jay, additional, Grant, Robert, additional, Grossberg, Robert, additional, Haas, Bernhard, additional, Halperin, Jason, additional, Hardy, W. David, additional, Hare, Charles, additional, Hassler, Shawn, additional, Hengel, Richard, additional, Henry, William, additional, Hodge, Theo, additional, Hosek, Sybil, additional, Hurt, Christopher, additional, Iandiorio, Michelle, additional, Jessen, Heiko, additional, Kegg, Stephen, additional, Knecht, Gabriele, additional, Krznaric, Ivanka, additional, LaMarca, Anthony, additional, Larsen, Carsten Schade, additional, Larsen, Olav Ditlevsen, additional, Lazzarin, Adriano, additional, Leen, Clifford, additional, Lucasti, Christopher, additional, Mallon, Patrick, additional, Mannheimer, Sharon, additional, Markowitz, Martin, additional, Martorell, Claudia, additional, Mayer, Kenneth, additional, Mills, Anthony, additional, Molina, Jean-Michel, additional, Morris, Sheldon, additional, Mounzer, Karam, additional, Nwokolo, Nneka, additional, Ogbuagu, Onyema, additional, Osiyemi, Olayemi, additional, Petroll, Andrew, additional, Philibert, Patrick, additional, Phoenix, John, additional, Pialoux, Gilles, additional, Post, Frank, additional, Prins, Maria, additional, Ramgopal, Moti, additional, Rashbaum, Bruce, additional, Reeves, Iain, additional, Richmond, Gary, additional, Rieger, Armin, additional, Ruane, Peter, additional, Salazar, Laura, additional, Scarsella, Anthony, additional, Schembri, Gabriel, additional, Scott, Mia, additional, Shalit, Peter, additional, Sinclair, Gary, additional, Sobieszczyk, Magdalena, additional, Spinner, Christoph, additional, Stephens, Jeffrey, additional, Szabo, Jason, additional, Taylor, Stephen, additional, Thompson, Melanie, additional, Tremblay, Cecile, additional, Trottier, Benoit, additional, Voskuhl, Gene, additional, Wade, Barbara, additional, Workowski, Kimberly, additional, Yawetz, Sigal, additional, and Young, Benjamin, additional

Published
2021
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48. Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-α-producing and partially matured phenotype

Author

O'Brien, Meagan, Manches, Olivier, Sabado, Rachel Lubong, Baranda, Sonia Jimenez, Wang, Yaming, Marie, Isabelle, Rolnitzky, Linda, Markowitz, Martin, Margolis, David M., Levy, David, and Bhardwaj, Nina

Subjects
HIV (Viruses) -- Genetic aspects -- Health aspects -- Research, Interferon alpha -- Physiological aspects -- Research, Dendritic cells -- Physiological aspects -- Research, Health care industry
Abstract

Plasmacytoid DCs (pDCs) are innate immune cells that are specialized to produce IFN-α and to activate adaptive immune responses. Although IFN-α inhibits HIV-1 replication in vitro, the production of IFN-α by HIV activated pDCs in vivo may contribute more to HIV pathogenesis than to protection. We have now shown that HIV-stimulated human pDCs allow for persistent IFN-α production upon repeated stimulation, express low levels of maturation molecules, and stimulate weak T cell responses. Persistent IFN-α production by HIV-stimulated pDCs correlated with increased levels of IRF7 and was dependent upon the autocrine IFN-α/β receptor feedback loop. Because it has been shown that early endosomal trafficking of TLR9 agonists causes strong activation of the IFN-α pathway but weak activation of the NF-κB pathway, we sought to investigate whether early endosomal trafficking of HIV, a TLR7 agonist, leads to the IFN-α-producing phenotype we observed. We demonstrated that HIV preferentially traffics to the early endosome in human pDCs and therefore skews pDCs toward a partially matured, persistently IFN-α-secreting phenotype., Introduction Plasmacytoid DCs (pDCs) are innate immune cells that circulate in the blood and lymphoid tissues and are specialized to produce copious amounts of type I IFNs (IFN-α/β) in response [...]

Published
2011
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49. Long-term efficacy and safety of raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase III trials

Author

Steigbigel, Roy T., Cooper, David A., Teppler, Hedy, Eron, Joseph J., Gatell, Jose M., Kumar, Princy N., Rockstroh, Jurgen K., Schechter, Mauro, Katlama, Christine, Markowitz, Martin, Yeni, Patrick, Loutfy, Mona R., Lazzarin, Adriano, Lennox, Jeffrey L., Clotet, Bonaventura, Zhao, Jing, Wan, Hong, Rhodes, Rand R., Strohmaier, Kim M., Barnard, Richard J., Isaacs, Robin D., and Nguyen, Bach-Yen T.

Subjects
Raltegravir -- Dosage and administration, Raltegravir -- Research, HIV infection -- Drug therapy, HIV infection -- Research, Drug resistance -- Research, Clinical trials -- Research, Creatine kinase -- Physiological aspects, Creatine kinase -- Research, Health, Health care industry
Published
2010

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