Person: Letvin, Norman Lee
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Letvin
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Norman Lee
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Letvin, Norman Lee
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Publication P01-01. The Blood Transcriptional Response to Early Acute HIV Infection is Transient and Responsive to Antiretroviral Therapy(BioMed Central, 2009) Skinner, JA; Baldwin, N; Lemoine, B; Blankenship, D; De Vol, EB; Mejias, A; Ramilo, O; Soderberg, K; Denny, TN; Shianna, K; McMichael, A; Banchereau, J; Chaussabel, D; Sharma, M; Cohen, M; Letvin, Norman Lee; Goldstein, D; Haynes, BBackground: Systemic events in acute HIV infection (AHI) are associated with disease severity and progression to AIDS. Timely identification of AHI patients has posed a significant challenge to identifying the underlying mechanisms driving these events. The aim of this study is to elucidate these pathways by characterizing the genome-wide transcriptional signature expressed by whole blood during early AHI. Methods: Longitudinal whole blood samples from ART treated and untreated patients from both the United States (n = 16) and Africa (n = 16) were collected at study enrollment and weeks 1, 2, 4, 12, and 24. AHI and non-infected controls were analyzed using Illumina HT-12 microarrays. Both gene and module level analysis were conducted to identify biologic pathways active in AHI. Results: Nineteen annotated and 24 undefined transcriptional modules constitute a robust transcriptional signature that collectively distinguished early AHI patients from noninfected controls. The activity of transcriptional modules related to interferon, cell cycle, cytotoxic, and mitochondrial responses were significantly increased in AHI patients. At study enrollment, the intensity of this signature was not correlated with viral load and exhibited heterogeneity between patients. Association between viral load and signature intensity was found over time. However, three patients exhibited little change in transcriptional activity despite high viral loads. When compared to acute RSV and Influenza infections, only interferon signatures were conserved across all three infections while cell cycle, cytotoxic, and mitochondrial responses were unique to AHI. The AHI signature of untreated patients regressed to non-infected control levels by 12–24 weeks post enrollment. The initiation of ART accelerated the dissipation of this signature, returning the core AHI signature to normal levels within 4 weeks. Conclusion: The whole blood AHI transcriptional signature is unique, transient, and capable of classifying individual responses to infection. This signature is responsive to ART and contains pathways with both defined and novel associations with HIV infection.Publication Local Replication of Simian Immunodeficiency Virus in the Breast Milk Compartment of Chronically-infected, Lactating Rhesus Monkeys(BioMed Central, 2010) Permar, Sallie Robey; Kang, Helen H; Wilks, Andrew B; Mach, Linh V; Carville, Angela A L; Mansfield, Keith G.; Learn, Gerald H; Hahn, Beatrice H; Letvin, Norman LeeBreast milk transmission remains a major mode of infant HIV acquisition, yet anatomic and immunologic forces shaping virus quasispecies in milk are not well characterized. In this study, phylogenic analysis of envelope sequences of milk SIV variants revealed groups of nearly identical viruses, indicating local virus production. However, comparison of the patterns and rates of CTL escape of blood and milk virus demonstrated only subtle differences between the compartments. These findings suggest that a substantial fraction of milk viruses are produced by locally-infected cells, but are shaped by cellular immune pressures similar to that in the blood.Publication Common Genetic Variation and the Control of HIV-1 in Humans(Public Library of Science, 2009) Fellay, Jacques; Ge, Dongliang; Shianna, Kevin V.; Colombo, Sara; Ledergerber, Bruno; Cirulli, Elizabeth T.; Urban, Thomas J.; Zhang, Kunlin; Gumbs, Curtis E.; Castagna, Antonella; Cozzi-Lepri, Alessandro; De Luca, Andrea; Easterbrook, Philippa; Günthard, Huldrych F.; Mallal, Simon; Mussini, Cristina; Dalmau, Judith; Martinez-Picado, Javier; Miro, José M.; Obel, Niels; Wolinsky, Steven M.; Martinson, Jeremy J.; Detels, Roger; Margolick, Joseph B.; Jacobson, Lisa P.; Descombes, Patrick; Antonarakis, Stylianos E.; Beckmann, Jacques S.; McMichael, Andrew J.; Haynes, Barton F.; Carrington, Mary; Telenti, Amalio; Goldstein, David B.; NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI); Smith, Jason P.; O'Brien, Stephen; Letvin, Norman Lee; Feng, ShengTo extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.Publication P19-57 LB. Gene-Based Vaccination Protects Against Mucosal Infection by a Heterologous Highly Pathogenic SIV Isolate in Rhesus Monkeys(BioMed Central, 2009) Mascola, J; Buzby, A; Roederer, M; Hudgens, M; Gilbert, P; Seder, R; Douek, D; Koup, R; Nabel, G; Letvin, Norman Lee; Rao, S; Graham, BPublication Contributions of Mamu-A*01 Status and TRIM5 Allele Expression, But Not CCL3L Copy Number Variation, to the Control of SIVmac251 Replication in Indian-Origin Rhesus Monkeys(Public Library of Science, 2010) Chan, Tiffany; O'Brien, Kara L.; Goldstein, David B.; Haynes, Barton F.; Malik, Harmit S.; Lim, So-Yon; Gelman, Rebecca; Whitney, James; Barouch, Dan; Letvin, Norman LeeCCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS in these monkeys. With 66 monkeys in the study, there was adequate power for these tests if the correlation of CCL3L and either peak or set-point plasma SIV RNA levels was 0.34 or 0.36, respectively. These findings call into question the premise that CCL3L CNV is important in HIV/SIV pathogenesis.Publication P03-07. Autologous Neutralizing Antibodies That Select Viral Escape Variants Emerge Late After SIV Infection of Rhesus Monkeys(BioMed Central, 2009) Rahman, I; Hraber, P; Giri, A; Nevidomskyte, D; Coffey, RT; Miljkovic, S; Keele, BF; Shaw, GM; Korber, BT; Yeh, Wendy Wen-Li; Asmal, Mohammed; Whitney, James; Seaman, Michael; Letvin, Norman LeePublication A Critical Role for CD8 T Cells in a Nonhuman Primate Model of Tuberculosis(Public Library of Science, 2009) Chen, Crystal Y.; Shen, Ling; Zeng, Gucheng; Yao, Shuyun; Shen, Yun; Halliday, Lisa; Fortman, Jeff; McAllister, Milton; Estep, Jim; Vasconcelos, Daphne; Du, George; Porcelli, Steven A.; Larsen, Michelle H.; Jacobs, William R.; Haynes, Barton F.; Letvin, Norman Lee; Huang, Dan; Wang, Richard; Hunt, Robert; Chen, Zheng-YiThe role of CD8 T cells in anti-tuberculosis immunity in humans remains unknown, and studies of CD8 T cell–mediated protection against tuberculosis in mice have yielded controversial results. Unlike mice, humans and nonhuman primates share a number of important features of the immune system that relate directly to the specificity and functions of CD8 T cells, such as the expression of group 1 CD1 proteins that are capable of presenting Mycobacterium tuberculosis lipids antigens and the cytotoxic/bactericidal protein granulysin. Employing a more relevant nonhuman primate model of human tuberculosis, we examined the contribution of BCG- or M. tuberculosis-elicited CD8 T cells to vaccine-induced immunity against tuberculosis. CD8 depletion compromised BCG vaccine-induced immune control of M. tuberculosis replication in the vaccinated rhesus macaques. Depletion of CD8 T cells in BCG-vaccinated rhesus macaques led to a significant decrease in the vaccine-induced immunity against tuberculosis. Consistently, depletion of CD8 T cells in rhesus macaques that had been previously infected with M. tuberculosis and cured by antibiotic therapy also resulted in a loss of anti-tuberculosis immunity upon M. tuberculosis re-infection. The current study demonstrates a major role for CD8 T cells in anti-tuberculosis immunity, and supports the view that CD8 T cells should be included in strategies for development of new tuberculosis vaccines and immunotherapeutics.Publication Low-Dose Rectal Inoculation of Rhesus Macaques by SIVsmE660 or SIVmac251 Recapitulates Human Mucosal Infection by HIV-1(Rockefeller University Press, 2009) Keele, Brandon F.; Learn, Gerald H.; Hraber, Peter; Giorgi, Elena E.; Grayson, Truman; Sun, Chuanxi; Chen, Yalu; Mascola, John R.; Nabel, Gary J.; Haynes, Barton F.; Bhattacharya, Tanmoy; Perelson, Alan S.; Korber, Bette T.; Hahn, Beatrice H.; Shaw, George M.; Li, Hui; Yeh, Wendy Wen-Li; Letvin, Norman LeeWe recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1–5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1–5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was >2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV–macaque mucosal infection model for HIV-1 vaccine and microbicide research.Publication P04-41. Kinetics of Antibody Neutralization and Viral Evolution Following Envelope Vaccination in SIV-infected Rhesus Monkeys(BioMed Central, 2009) Basavapathruni, A; Coffey, R; Hraber, P; Giri, A; Mascola, J; Nabel, G; Korber, B; Yeh, Wendy Wen-Li; Whitney, James; Rao, Sowmya R.; Seaman, Michael; Letvin, Norman LeePoster presentation. Conclusion: Our results indicate that env vaccination is associated with an accelerated development of autologous neutralizing antibodies. These antibodies were focused at least in part on the V1 region of Env, since there was selective pressure in this region of the envelope for the evolution of mutational changes.Publication Genital Tract Sequestration of SIV following Acute Infection(Public Library of Science, 2011) Whitney, James; Hraber, Peter T.; Luedemann, Corinne; Giorgi, Elena E.; Daniels, Marcus G.; Bhattacharya, Tanmoy; Rao, Srinivas S.; Mascola, John R.; Nabel, Gary J.; Korber, Bette T.; Letvin, Norman LeeWe characterized the evolution of simian immunodeficiency virus (SIV) in the male genital tract by examining blood- and semen-associated virus from experimentally and sham vaccinated rhesus monkeys during primary infection. At the time of peak virus replication, SIV sequences were intermixed between the blood and semen supporting a scenario of high-level virus "spillover" into the male genital tract. However, at the time of virus set point, compartmentalization was apparent in 4 of 7 evaluated monkeys, likely as a consequence of restricted virus gene flow between anatomic compartments after the resolution of primary viremia. These findings suggest that SIV replication in the male genital tract evolves to compartmentalization after peak viremia resolves.