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: 4.44). 03/2010; 84(5):2466-76. DOI: 10.1128/JVI.01966-09
Source: PubMed


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.

    • "Compared to the partial reversal of CD4 þ T-cell loss in the periphery and gut mucosa by ART therapy, B-cell dysregulation is not fully reversed (D'Orsogna et al., 2007; Moir and Fauci, 2009; Regidor et al., 2011), although early ART may help prevent it (Moir et al., 2010). B-cell dysregulation occurs early after HIV and SIV infection, usually before CD4 þ T-cells decline, and strikingly manifests itself by skewing memory populations (Chagnon-Choquet et al., 2014; Kuhrt et al., 2010; Titanji et al., 2010, 2014). Additional broader effects of HIV infection on B-cells have been recently reviewed (Moir and Fauci, 2009). "
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    ABSTRACT: Marginal zone (MZ) B cells generate T-independent antibody responses to pathogens before T-dependent antibodies arise in germinal centers. They have been identified in cynomolgus monkeys and monitored during acute SIV infection, yet have not been well-studied in rhesus macaques. Here we characterized rhesus macaque MZ B cells, present in secondary lymphoid tissue but not peripheral blood, as CD19(+), CD20(+), CD21(hi), IgM(+), CD22(+), CD38(+), BTLA(+), CD40(+), CCR6(+) and BCL-2(+). Compared to healthy macaques, SHIVSF162P4-infected animals showed decreased total B cells and MZ B cells and increased MZ B cell Ki-67 expression early in chronic infection. These changes persisted in late chronic infection, despite viremia reductions to low or undetectable levels. Expression levels of additional phenotypic markers and RNA PCR array analyses were in concert with continued low-level activation and diminished function of MZ B cells. We conclude that MZ B-cell dysregulation and dysfunction associated with SIV/HIV infection are not readily reversible. Published by Elsevier Inc.
    No preview · Article · Oct 2015 · Virology
    • "HIV and SIV infection in both humans and monkeys leads to early and severe B-cell dysregulation, concomitant with loss of CD4 T-cells [101] [102]. Thus, B-cell-targeted prophylactic vaccines that do not elicit sterilizing immunity able to prevent infection may exhibit less protective efficacy than expected due to an impaired humoral immune response. "
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    ABSTRACT: The RV144 clinical trial in Thailand associated vaccine-induced antibodies with protective efficacy, leading to a focus in HIV vaccine research on protective antibody induction. This has necessitated greater understanding of B cell biology in humans as well as non-human primates (NHP), the principle animal model for pre-clinical HIV/SIV vaccine research. This review covers development and maturation of NHP B cells within the framework of current knowledge of human and murine B cells. Identification of many NHP B cell subpopulations is now possible, although consensus is lacking in some cases, and better distinction of some populations is still needed. Elucidation of mechanisms that control germinal center maintenance, selection of B cells into the memory cell pool, and differentiation of B cells into long-term plasma cells remains critical for improving vaccine design. B cell dysfunction occurs during both HIV and SIV infection. Whether the processes leading to this impairment are identical in humans and NHP is not known. Uncovering the mechanisms involved could lead to improved treatment regimens. The SIV/NHP model effectively mimics HIV infection of people, but key differences between NHP and humans in antibody characteristics such as glycosylation and structure may lead to unexpected outcomes in pre-clinical studies. Important new areas for investigation include the role of B cell cytokines in the immune system and the impact of the microbiome on B cell development and maturation. Enhanced knowledge of B cells in NHP as well as humans should enable improved vaccine design, leading to induction of potent, long-lasting protective antibodies.
    No preview · Article · Jul 2015 · Current HIV research
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    • "In contrast, the timing, route, and dose of infection can be controlled, and samples at defined stages of the disease can be obtained in SIV-infected rhesus macaques (RMs). Importantly, the SIV/RM model recapitulates many aspects of both T and B cell dysfunction documented in HIV-1 disease (Das et al. 2011; Kuhrt et al. 2010; Titanji et al. 2010; Zhang et al. 2007). However, to date, it remains unknown how B cell dysfunction during the course of SIV infection of RMs influenced Ab repertoire diversity and SHM. "
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    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.
    Full-text · Article · May 2015 · Immunogenetics
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