Article

Evidence of Early B-Cell Dysregulation in Simian Immunodeficiency Virus Infection: Rapid Depletion of Naïve and Memory B-Cell Subsets with Delayed Reconstitution of the Naïve B-Cell Population

Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Journal of Virology (Impact Factor: 4.65). 03/2010; 84(5):2466-76. DOI: 10.1128/JVI.01966-09
Source: PubMed

ABSTRACT Despite eliciting a robust antibody response in humans, several studies in human immunodeficiency virus (HIV)-infected patients have demonstrated the presence of B-cell deficiencies during the chronic stage of infection. While several explanations for the HIV-induced B-cell deficit have been proposed, a clear mechanistic understanding of this loss of B-cell functionality is not known. This study utilizes simian immunodeficiency virus (SIV) infection of rhesus macaques to assess B-cell population dynamics beginning at the acute phase and continuing through the chronic phase of infection. Flow cytometric assessment demonstrated a significant early depletion of both naïve and memory B-cell subsets in the peripheral blood, with differential kinetics for recovery of these populations. Furthermore, the altered numbers of naïve and memory B-cell subsets in these animals corresponded with increased B-cell activation and altered proliferation profiles during the acute phase of infection. Finally, all animals produced high titers of antibody, demonstrating that the measurement of virus-specific antibody responses was not an accurate reflection of alterations in the B-cell compartment. These data indicate that dynamic B-cell population changes in SIV-infected macaques arise very early after infection at the precise time when an effective adaptive immune response is needed.

0 Followers
 · 
80 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The ability to elicit potent and long-lasting broadly neutralizing HIV Envelope (Env)-specific antibodies has become a key goal for HIV vaccine development. Consequently, the ability to rapidly and efficiently monitor development of memory B cells in pre-clinical and clinical vaccine trails is critical for continued progress in vaccine design. We have developed an improved flow cytometry-based method for the rapid and efficient identification of gp120-specific memory B cells in peripheral blood, bone marrow, and mucosal tissues which allows their direct staining without the need for prior cell sorting or enrichment. We demonstrate staining of both HIV and SIV Env-specific memory B cells in PBMC, bone marrow, and rectal tissue of vaccinated and infected rhesus macaques. Validation of the method is illustrated by statistically significant correlations with memory B cell levels quantified by ELISPOT assay and with serum binding antibody titers determined by ELISA. In addition to quantification, this method will bring the power of flow cytometry to the study of homing and trafficking of Env-specific memory B cells.
    Journal of Immunological Methods 06/2014; 412. DOI:10.1016/j.jim.2014.06.012 · 2.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: B cell functional defects are associated with delayed neutralizing antibody development in pathogenic lentivirus infections. However, the timeframe for alterations in the antibody repertoire and somatic hypermutation (SHM) remains unclear. Here, we utilized the SIV/rhesus macaque (RM) model to investigate the dynamics of immunoglobulin VH gene diversity and SHM following infection. Three RMs were infected with SIVmac239, and VH1, VH3, and VH4 genes were amplified from peripheral blood at 0, 2, 6, 24, and 36 weeks postinfection for next-generation sequencing. Analysis of over 3.8 million sequences against currently available RM germline VH genes revealed a highly biased VH gene repertoire in outbred RMs. SIV infection did not significantly perturb the predominant IgG1 response, but overall immunoglobulin SHM declined during the course of SIV infection. Moreover, SHM at the AID deamination hotspot, WRC, rapidly decreased and was suppressed throughout SIV infection. In contrast, a transient increase in mutations at the APOBEC3G deamination hotspot, CCC, coincided with a spike in APOBEC3G expression during acute SIV infection. The results outline a timetable for altered VH gene repertoire and IgG SHM in the SIV/RM model and suggest a burst of APOBEC3G-mediated antibody SHM during acute SIV infection.
    Immunogenetics 05/2015; DOI:10.1007/s00251-015-0844-3 · 2.49 Impact Factor
  • Source
    HIV and AIDS - Updates on Biology, Immunology, Epidemiology and Treatment Strategies, 10/2011; , ISBN: 978-953-307-665-2