IMMUNOLOGIC & VIROLOGIC FEATURES OF EARLY HIV INFECTION
Principal Investigator: J A Levy
Affiliation: University of California
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
- Longitudinal analysis of B cell repertoire and antibody gene rearrangements during early HIV infectionM 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...
- Loss of T cell responses following long-term cryopreservationRachel 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...
- FOXP3 expressing CD127lo CD4+ T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 infectionLishomwa 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....
- Immune reconstitution of CD56(dim) NK cells in individuals with primary HIV-1 infection treated with interleukin-2Jakob 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...
- Conferral of enhanced natural killer cell function by KIR3DS1 in early human immunodeficiency virus type 1 infectionBrian 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....
- Comparison of algorithms that interpret genotypic HIV-1 drug resistance to determine the prevalence of transmitted drug resistanceLin 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...
- 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 paraparesisJakob 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...
- Prevalence of oral disease among adults with primary HIV infectionF 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...
- Immunity to HIV-1 is influenced by continued natural exposure to exogenous virusChristian 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...
- CD8+ cell anti-HIV activity rapidly increases upon discontinuation of early antiretroviral therapyM 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...
- Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatmentColleen F Kelley
Emory University, Atlanta, Georgia, USA
Clin Infect Dis 48:787-94. 2009....
- Tolerability and efficacy of PI versus NNRTI-based regimens in subjects receiving HAART during acute or early HIV infectionLinda 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...
- High CD8+ T cell activation marks a less differentiated HIV-1 specific CD8+ T cell response that is not altered by suppression of viral replicationJason 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...
- 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 antigensChristopher 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...
- Quantitative longitudinal analysis of T cell receptor repertoire expression in HIV-infected patients on antiretroviral and interleukin-2 therapyUma 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...
- The relation between symptoms, viral load, and viral load set point in primary HIV infectionColleen 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)...
- Synergy or independence? Deciphering the interaction of HLA Class I and NK cell KIR alleles in early HIV-1 disease progressionJason 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
- Intermittent low-level viremia in very early primary HIV-1 infectionEberhard 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...
- A screening assay for detecting CD8+ cell non-cytotoxic anti-HIV responsesM 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...
- Potential herpesvirus interaction during HIV type 1 primary infectionEvelyne 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)...
- Expansion of CD1d-restricted NKT cells in patients with primary HIV-1 infection treated with interleukin-2Markus 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...
- CD8 T cell effector maturation in HIV-1-infected childrenKimberly 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...
- Seroreversion in subjects receiving antiretroviral therapy during acute/early HIV infectionC Bradley Hare
Positive Health Program, University of California, San Francisco, San Francisco, CA, USA
Clin Infect Dis 42:700-8. 2006....
- Similar changes in plasmacytoid dendritic cell and CD4 T-cell counts during primary HIV-1 infection and treatmentM 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...
- The effects of early antiretroviral therapy and its discontinuation on the HIV-specific antibody responseM 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...
- Elevations in IL-10, TNF-alpha, and IFN-gamma from the earliest point of HIV Type 1 infectionPhilip 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...
- A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infectionFrederick M Hecht
University of California San Francisco, San Francisco, CA 94110, USA
J Infect Dis 194:725-33. 2006....
- Greater CD4 T-cell gains after one year of antiretroviral therapy are associated with lower HIV-1 pol replication capacityJason 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...
- Microbial translocation is a cause of systemic immune activation in chronic HIV infectionJason 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...
- 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 pointJohn 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....
- Individuals with pulmonary tuberculosis have lower levels of circulating CD1d-restricted NKT cellsJennifer 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...
- Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV diseaseDavid 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...