IMMUNOLOGIC & VIROLOGIC FEATURES OF EARLY HIV INFECTION

Summary

Principal Investigator: J A Levy
Affiliation: University of California
Country: USA
Abstract: We propose to continue our HIV-1 acute infection and early disease research program (AIEDRP) that uses innovative approaches to recruit 60 or more subjects a year with acute/early HIV infection with high retention rates. Our overall objective is to understand the pathogenic steps in acute HIV infection and find therapeutic approaches to assure a favorable clinical course through enhancement of immune responses. Those subjects enrolled over the past 5 years and newly recruited subjects will constitute a cohort for longitudinal assessment of immunologic, virologic and clinical endpoints of HIV infection. Consenting subjects already on antiviral therapy will be participating in an ongoing STI trial. Other subjects will be randomized to receive combination antiviral treatment with or without IL-2 and with or without immunization with an HIV antigen. We will assess whether immune-based therapies enhance the ability of antiviral drug-treated individuals to maintain immunologic responses to HIV and keep the virus suppressed in blood and genital fluids after interruption of therapy. Subjects who have decided not to receive treatment will be followed and studied as observational controls. The findings should provide valuable information for the long-term control of HIV infection and transmission. Our Specific Objectives are the following: Determine the immunologic features that correlate with low viral load in blood and genital fluids, high CD4+ cell counts, and a healthy clinical state; Determine the optimal treatment approaches that will lead to a desirable immunologic and virologic set point for long-term control of HIV infection; Determine when a selected therapeutic strategy is stopped, which immunologic features prior to treatment interruption correlates with effective control of HIV infection. By investigating acute/early infection with the proposed in-depth virologic and immunologic studies, insights into the basic pathogenesis of HIV infection will be gained. The results should provide useful approaches for both industrialized and developing countries to improve the clinical outcome of infection and block HIV transmission.
Funding Period: 1997-07-01 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Longitudinal analysis of B cell repertoire and antibody gene rearrangements during early HIV infection
    M K Elkins
    Department of Neurology, University of California at San Francisco, CA 94143-0435, USA
    Genes Immun 6:66-9. 2005
  2. ncbi Loss of T cell responses following long-term cryopreservation
    Rachel E Owen
    Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, CA 94118, USA
    J Immunol Methods 326:93-115. 2007
  3. ncbi FOXP3 expressing CD127lo CD4+ T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 infection
    Lishomwa C Ndhlovu
    Division of Experimental Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA
    J Leukoc Biol 83:254-62. 2008
  4. ncbi Immune reconstitution of CD56(dim) NK cells in individuals with primary HIV-1 infection treated with interleukin-2
    Jakob Michaelsson
    Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
    J Infect Dis 197:117-25. 2008
  5. ncbi Conferral of enhanced natural killer cell function by KIR3DS1 in early human immunodeficiency virus type 1 infection
    Brian R Long
    Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, USA
    J Virol 82:4785-92. 2008
  6. ncbi Comparison of algorithms that interpret genotypic HIV-1 drug resistance to determine the prevalence of transmitted drug resistance
    Lin Liu
    University of California San Diego, La Jolla, California 92093 0679, USA
    AIDS 22:835-9. 2008
  7. ncbi The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1) proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis
    Jakob Michaelsson
    Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
    BMC Immunol 9:41. 2008
  8. ncbi Prevalence of oral disease among adults with primary HIV infection
    F J Owotade
    Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ile Ife, Nigeria
    Oral Dis 14:497-9. 2008
  9. ncbi Immunity to HIV-1 is influenced by continued natural exposure to exogenous virus
    Christian B Willberg
    Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA
    PLoS Pathog 4:e1000185. 2008
  10. ncbi CD8+ cell anti-HIV activity rapidly increases upon discontinuation of early antiretroviral therapy
    M Scott Killian
    Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
    J Clin Immunol 29:311-8. 2009

Scientific Experts

  • Jason David Barbour
  • Jakob Michaelsson
  • C Bradley Hare
  • Frederick M Hecht
  • Markus Moll
  • Philip J Norris
  • Rachel E Owen
  • Lishomwa C Ndhlovu
  • Christian B Willberg
  • M Scott Killian
  • Jay A Levy
  • Douglas F Nixon
  • Colleen F Kelley
  • Christopher P Loo
  • Steven G Deeks
  • Jeffrey N Martin
  • Brian R Long
  • Michael P Busch
  • David M Naeger
  • Peter W Hunt
  • Linda G Apuzzo
  • Susan J Little
  • Jean Pierre Routy
  • Joseph B Margolick
  • Ann C Collier
  • F J Owotade
  • Lin Liu
  • Benigno Rodriguez
  • Jorge R Oksenberg
  • Jennifer E Snyder Cappione
  • Uma Sriram
  • John W Northfield
  • Sharon Ng
  • Johan K Sandberg
  • Kimberly A Jordan
  • Jason M Brenchley
  • Evelyne T Lennette
  • Eberhard W Fiebig
  • M K Elkins
  • Elizabeth Sinclair
  • Joseph M McCune
  • Priscilla Hsue
  • David R Bangsberg
  • MARTIN H MARKOWITZ
  • Bruce D Walker
  • Christina M R Kitchen
  • Heide M Crane
  • Mari Kitahata
  • Michael Saag
  • Karin B Ernstrom
  • James Willig
  • Michael Mugavero
  • Brian Conway
  • Elizabeth Connick
  • Joel E Gallant
  • Jeremy Roop
  • Florin Vaida
  • J S Greenspan
  • Eric S Daar
  • C A Ramstead
  • Douglas D Richman
  • Jean-Pierre Routy
  • Martin Markowitz
  • Susanne May
  • L Poole
  • Davey M Smith
  • Lewis L Lanier
  • K Malvin
  • C H Shiboski
  • Christopher H Woelk
  • Stacy J Caillier
  • Jennifer E Snyder-Cappione
  • Fernando F Melo
  • Sergio E Baranzini
  • Duncan A Meiklejohn
  • Mary K Elkins
  • Paul Klenerman
  • Gerald Spotts
  • Priscilla R Costa
  • Michael Wong
  • Denise S Rodrigues
  • Esper G Kallas
  • Joan M Chapman
  • Ethan Bornstein
  • Timothy W Schacker
  • Alan Landay
  • Srinivas Rao
  • Louis J Picker
  • David A Price
  • Veronica D Gonzalez

Detail Information

Publications33

  1. ncbi Longitudinal analysis of B cell repertoire and antibody gene rearrangements during early HIV infection
    M K Elkins
    Department of Neurology, University of California at San Francisco, CA 94143-0435, USA
    Genes Immun 6:66-9. 2005
    ..A modest association between B cell repertoire integrity and viremia levels as well as treatment was detected...
  2. ncbi Loss of T cell responses following long-term cryopreservation
    Rachel E Owen
    Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, CA 94118, USA
    J Immunol Methods 326:93-115. 2007
    ..Long-term cryopreservation, however, may lead to the loss of CD4(+) T cell responses and mild skewing of T cell phenotypic marker expression...
  3. ncbi FOXP3 expressing CD127lo CD4+ T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 infection
    Lishomwa C Ndhlovu
    Division of Experimental Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA
    J Leukoc Biol 83:254-62. 2008
    ....
  4. ncbi Immune reconstitution of CD56(dim) NK cells in individuals with primary HIV-1 infection treated with interleukin-2
    Jakob Michaelsson
    Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
    J Infect Dis 197:117-25. 2008
    ..Importantly, NK cell receptor expression and IFN-gamma production were maintained over time. This reconstitution of NK cells may be useful in helping contain viremia if patients discontinue therapy or develop drug resistance...
  5. ncbi Conferral of enhanced natural killer cell function by KIR3DS1 in early human immunodeficiency virus type 1 infection
    Brian R Long
    Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, USA
    J Virol 82:4785-92. 2008
    ....
  6. ncbi Comparison of algorithms that interpret genotypic HIV-1 drug resistance to determine the prevalence of transmitted drug resistance
    Lin Liu
    University of California San Diego, La Jolla, California 92093 0679, USA
    AIDS 22:835-9. 2008
    ..We compared eight genotypic interpretation methods to determine whether the method used would affect the rates of reported transmitted drug resistance...
  7. ncbi The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1) proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis
    Jakob Michaelsson
    Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
    BMC Immunol 9:41. 2008
    ..The purpose of this study was to assess the frequency and phenotype of TReg cells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP) patients, and to correlate with measures of T cell activation...
  8. ncbi Prevalence of oral disease among adults with primary HIV infection
    F J Owotade
    Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ile Ife, Nigeria
    Oral Dis 14:497-9. 2008
    ..To explore the type and prevalence of oral mucosal lesions among adults with primary HIV infection (PHI) compared with HIV-negative adults at high risk for HIV disease, and in relation to HIV viral load...
  9. ncbi Immunity to HIV-1 is influenced by continued natural exposure to exogenous virus
    Christian B Willberg
    Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA
    PLoS Pathog 4:e1000185. 2008
    ..Continued sexual exposure to exogenous HIV-1 was associated with increased HIV-1-specific T cell responses, in the absence of systemic super-infection, and correlated with the level and type of exposure...
  10. ncbi CD8+ cell anti-HIV activity rapidly increases upon discontinuation of early antiretroviral therapy
    M Scott Killian
    Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
    J Clin Immunol 29:311-8. 2009
    ..CD8+ lymphocytes can suppress HIV replication without killing the infected cells. This CD8+ cell noncytotoxic anti-HIV response (CNAR) is associated with a beneficial clinical course...
  11. ncbi Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment
    Colleen F Kelley
    Emory University, Atlanta, Georgia, USA
    Clin Infect Dis 48:787-94. 2009
    ....
  12. ncbi Tolerability and efficacy of PI versus NNRTI-based regimens in subjects receiving HAART during acute or early HIV infection
    Linda G Apuzzo
    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
    J Acquir Immune Defic Syndr 50:267-75. 2009
    ..Little is known about modifications to highly active antiretroviral therapy (HAART) initiated during acute or early HIV infection...
  13. ncbi High CD8+ T cell activation marks a less differentiated HIV-1 specific CD8+ T cell response that is not altered by suppression of viral replication
    Jason D Barbour
    Department of Medicine, HIV AIDS Division, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 4:e4408. 2009
    ..We hypothesized that anti-retroviral suppression of T cell activation levels would lead to alterations in the T cell differentiation of total and HIV-1 specific CD8+ T cell responses among recently HIV-1 infected adults...
  14. ncbi HIV-1-specific T Cell-dependent natural killer (NK) cell activation: major contribution by NK cells to interferon-gamma production in response to HIV-1 antigens
    Christopher P Loo
    Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA
    AIDS Res Hum Retroviruses 25:603-5. 2009
    ..These results indicate that T cell-dependent NK cell IFN-gamma production can be important for immune control of HIV-1, and have implications for the interpretation of data from vaccine trials using ELISPOT and ELISA...
  15. ncbi Quantitative longitudinal analysis of T cell receptor repertoire expression in HIV-infected patients on antiretroviral and interleukin-2 therapy
    Uma Sriram
    Department of Neurology University of California at San Francisco, California 94143, USA
    AIDS Res Hum Retroviruses 23:741-7. 2007
    ..These results suggest that homeostasis in the T cell receptor repertoire is more robust in those patients who stay on HAART for a long time and confirm the polyclonal stimulating capacity of IL-2...
  16. ncbi The relation between symptoms, viral load, and viral load set point in primary HIV infection
    Colleen F Kelley
    Department of Medicine, San Francisco General Hospital, University of California at San Francisco, 995 Potrero Avenue, San Francisco, CA 94110, USA
    J Acquir Immune Defic Syndr 45:445-8. 2007
    ..To examine the relation between symptoms, initial viral load, and viral load set point in primary HIV infection (PHI)...
  17. ncbi Synergy or independence? Deciphering the interaction of HLA Class I and NK cell KIR alleles in early HIV-1 disease progression
    Jason D Barbour
    HIV AIDS Division, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America
    PLoS Pathog 3:e43. 2007
  18. ncbi Intermittent low-level viremia in very early primary HIV-1 infection
    Eberhard W Fiebig
    Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA
    J Acquir Immune Defic Syndr 39:133-7. 2005
    ..It is not known if blood is infectious during this period; however, given the low viral concentrations and transient nature of the observed viremic "blips," the risk of infectivity can be assumed to be small...
  19. ncbi A screening assay for detecting CD8+ cell non-cytotoxic anti-HIV responses
    M Scott Killian
    AIDS Research Institute and Department of Medicine, University of California San Francisco, San Francisco, CA 94143, United States
    J Immunol Methods 304:137-50. 2005
    ..Use of the CNAR screening assay should facilitate the evaluation of this important immune parameter in studies of HIV pathogenesis, resistance to infection, and vaccine development...
  20. ncbi Potential herpesvirus interaction during HIV type 1 primary infection
    Evelyne T Lennette
    Nectandra Institute, San Ramon, Costa Rica
    AIDS Res Hum Retroviruses 21:869-75. 2005
    ..uninfected individuals. Notably, lower HIV-1 viremia (7,313 vs. 55,548 geometric mean RNA copies/ml) at baseline was significantly associated with HHV-8 seropositivity (p < 0.004)...
  21. ncbi Expansion of CD1d-restricted NKT cells in patients with primary HIV-1 infection treated with interleukin-2
    Markus Moll
    CIM, Department of Medicine, F59, Karolinska Institute, Karolinska University Hospital, Huddinge, 14186 Stockholm, Sweden
    Blood 107:3081-3. 2006
    ..These data indicate that IL-2 treatment in combination with effective ART is beneficial for the restoration of innate NKT cell immunity in patients with primary HIV-1 infection...
  22. ncbi CD8 T cell effector maturation in HIV-1-infected children
    Kimberly A Jordan
    Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA
    Virology 347:117-26. 2006
    ..The data also suggest, however, that the perforin-deficient state of HIV-specific CD8 T cells in children may be reversible...
  23. ncbi Seroreversion in subjects receiving antiretroviral therapy during acute/early HIV infection
    C Bradley Hare
    Positive Health Program, University of California, San Francisco, San Francisco, CA, USA
    Clin Infect Dis 42:700-8. 2006
    ....
  24. ncbi Similar changes in plasmacytoid dendritic cell and CD4 T-cell counts during primary HIV-1 infection and treatment
    M Scott Killian
    Department of Medicine, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
    AIDS 20:1247-52. 2006
    ..Early ART appears to have similar restorative effects on pDC and CD4 T-cell counts...
  25. ncbi The effects of early antiretroviral therapy and its discontinuation on the HIV-specific antibody response
    M Scott Killian
    Department of Medicine, University of California San Francisco, 94143, USA
    AIDS Res Hum Retroviruses 22:640-7. 2006
    ..These results demonstrate that early ART prevents the typical evolution of the HIV-1-specific antibody response and can alter the expected kinetics of this response in subjects discontinuing therapy...
  26. ncbi Elevations in IL-10, TNF-alpha, and IFN-gamma from the earliest point of HIV Type 1 infection
    Philip J Norris
    Blood Systems Research Institute, San Francisco, California 94118, USA
    AIDS Res Hum Retroviruses 22:757-62. 2006
    ..Cytokine alterations occurred within 7 days of detectable HIV-1 viremia, emphasizing the need to study the earliest events of infection...
  27. ncbi A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection
    Frederick M Hecht
    University of California San Francisco, San Francisco, CA 94110, USA
    J Infect Dis 194:725-33. 2006
    ....
  28. ncbi Greater CD4 T-cell gains after one year of antiretroviral therapy are associated with lower HIV-1 pol replication capacity
    Jason D Barbour
    Positive Health Program, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, USA
    AIDS 20:2123-5. 2006
    ..Viral polRC was measured before starting ART in all subjects. We examined 243 individuals for a median 260 days after initiating ART. Low baseline polRC was associated with greater CD4 T-cell gains independent of virological responses...
  29. ncbi Microbial translocation is a cause of systemic immune activation in chronic HIV infection
    Jason M Brenchley
    Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    Nat Med 12:1365-71. 2006
    ..These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection...
  30. ncbi Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T(EMRA) cells in early infection are linked to control of HIV-1 viremia and predict the subsequent viral load set point
    John W Northfield
    Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom
    J Virol 81:5759-65. 2007
    ....
  31. ncbi Individuals with pulmonary tuberculosis have lower levels of circulating CD1d-restricted NKT cells
    Jennifer E Snyder Cappione
    Division of Experimental Medicine, University of California, San Francisco, CA 94143, USA
    J Infect Dis 195:1361-4. 2007
    ..This apparent loss of NKT cells from the peripheral blood is sustained during the 6 months after the initiation of MTB treatment. These findings indicate that NKT cells may be an important component of antituberculosis immunity...
  32. ncbi Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease
    David M Naeger
    Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 5:e8886. 2010
    ..The impact of untreated and treated HIV infection on the frequency of these cells remains undefined...