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New HIV Research Finds Early Disabled Immune Response
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Published 07 Jul 2009
Polyclonal B Cell Differentiation and Loss of Gastrointestinal Tract Germinal Centers in the Earliest Stages of HIV-1 Infection
Marc C. Levesque, M. Anthony Moody, Kwan-Ki Hwang, Dawn J. Marshall, John F. Whitesides, Joshua D. Amos, Thaddeus C. Gurley, Sallie Allgood, Benjamin B. Haynes, Nathan A. Vandergrift, Steven Plonk, Daniel C. Parker, Myron S. Cohen, Georgia D. Tomaras, Paul A. Goepfert, George M. Shaw, Jorn E. Schmitz, Joseph J. Eron, Nicholas J. Shaheen, Charles B. Hicks, Hua-Xin Liao, Martin Markowitz, Garnett Kelsoe, David M. Margolis, Barton F. Haynes
Polyclonal B Cell Differentiation and Loss of Gastrointestinal Tract Germinal Centers in the Earliest Stages of HIV-1 Infection
PLoS Medicine July 7 2009
"In this study we document, to our knowledge for the first time, polyclonal B cell activation in terminal ileum in early HIV-1 infection.....Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1."....."To help them design an effective HIV vaccine, scientists need to understand how the virus delays humoral responses to HIV infection (and how it later causes the production of HIV-specific antibodies to decline). Little is known, however, about the early effects of HIV infection on B lymphocytes."
"By as early as 17 d after transmission, HIV-1 infection induced B cell class switching manifested by acute reductions in numbers of naive B cells and striking elevations of memory B cells and plasmablasts/plasma cells in blood and terminal ileum. By 47 d after transmission, HIV-1 infection was associated with damage to GALT germinal centers, including follicular lysis due to B and T cell apoptosis as well as destruction of the FDC networks in terminal ileum Peyer's patches.".....The early loss of gut B cell germinal centers may impair effective humoral responses to HIV-1. CD4+ T cell help is required for induction of long-lived plasma cells and long-term production of high-affinity antiviral antibodies
"Conclusion: Early HIV-1 infection induces germinal center damage and loss as well as polyclonal activation of gut B cells. These data suggest that for an HIV-1 vaccine to be effective, it will need to induce significant levels of broadly neutralizing antibodies that are present before HIV-1 transmission. If transmission is not prevented by preexisting antibody, then an effective AIDS vaccine will also need to prime for rapid (hours to days) innate responses of anti-HIV-1 factors (such as defensins [75], alpha-1-antitrypsin [76], CCR5 binding chemokines [77], or anti-HIV-1 NK cell responses [78],[79]) that might protect against HIV-1-induced follicular germinal center B cell and CD4+ T cell loss until robust CD8+ T cell and secondary B cell responses are induced."
ABSTRACT
Background
The antibody response to HIV-1 does not appear in the plasma until approximately 2-5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1-specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4+ T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells.
Methods and Findings
In human participants, we analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. We found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT) B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI) included not only HIV-1-specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1-induced polyclonal B cell activation. Follicular damage or germinal center loss in terminal ileum Peyer's patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis.
Conclusions
Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1.
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981 and more than 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV infects and kills a type of immune system cell called CD4+ T lymphocytes. These cells are needed to maintain a vigorous immune response, so people infected with HIV eventually become susceptible to other infections and develop full-blown AIDS. However, early during HIV infection, other parts of the immune system attempt to fight off the virus. Soon after infection, immune system cells called B lymphocytes begin to produce HIV-specific antibodies (proteins that recognize viral molecules called antigens). The first antibodies to HIV usually appear two to seven weeks after infection; from about 12 weeks after infection, antibodies are made that can kill the specific HIV type responsible for the infection (neutralizing antibodies).
Introduction
Early HIV-1 infection is characterized by the death of both infected and uninfected CD4+ T cells, often resulting in extensive CD4+ T cell depletion in the gastrointestinal tract [1]-[6]. While HIV-1 induction of CD4+ T cell death in early infection is well documented, the effects of HIV-1 on blood and mucosal B cells and their inductive microenvironments in the earliest stages of infection have not been determined. In chronic infection, HIV-1 induces polyclonal B-cell activation, B cell exhaustion, hypergammaglobulinemia, reductions in the numbers of memory B cells in the blood, and increased numbers of circulating immature B cells [7]-[12]. People with early HIV-1 infection have elevated frequencies of blood antibody-secreting cells that may reflect Env-mediated polyclonal activation [10],[13],[14], but have been reported to have normal numbers of blood naive and memory B cells [15].
Priming immunizations of healthy humans with nonpathogenic non-HIV-1 viruses elicit detectable neutralizing antibody within a few days of priming, with peak neutralization titers observed on day 14 [16],[17]. In contrast, the earliest B cell responses to HIV-1 are not detected until ~19 d after transmission in the form of antibody-virion immune complexes, and ~2-5 wk after transmission in the form of HIV-1 antibodies in plasma [18]. Most importantly, functionally relevant neutralizing antibodies against autologous virus do not generally appear in plasma until ³12 wk after HIV-1 infection [19]-[21]. Moreover, antiretroviral therapy in chronic HIV-1 infection is associated with an increased rate of decline of plasma antibodies resulting in an apparent half-life of anti-HIV-1 gp120 antibody of 7-21 wk, and for anti-p24 antibody of 9-15 wk [14]. The mechanisms of delay in the appearance of anti-HIV-1 antibodies after HIV-1 transmission and of the rapid decline of induced anti-HIV-1 antibodies are not known.
Given the potential capacity of neutralizing serum antibody to prevent HIV-1 infection, as demonstrated by passive transfer of protective antibody to rhesus macaques challenged with simian human immunodeficiency virus [22],[23], it is critical to define the early effects of HIV-1 infection on B cells and on their inductive and effector mucosal microenvironments. Detailed examination of how HIV-1 subverts initial humoral responses will determine how quickly vaccine-primed neutralizing antibodies must appear in order to be effective. In this study, we investigated the effects of acute and early HIV-1 infection on naive B cells, memory B cells, and plasma cells in blood, Peyer's patches, and lamina propria.
Why Was This Study Done?
Unfortunately, by this time, it is too late for the antibody ("humoral") immune response to clear HIV from the body. Indeed, the humoral immune response to HIV is very slow; for most viruses, neutralizing antibodies appear within days of infection. To help them design an effective HIV vaccine, scientists need to understand how the virus delays humoral responses to HIV infection (and how it later causes the production of HIV-specific antibodies to decline). Little is known, however, about the early effects of HIV infection on B lymphocytes. These cells are born and mature in the bone marrow. "Naive" B lymphocytes, each of which carries an antigen-specific receptor (a protein that binds to a specific antigen), then enter the blood and circulate around the body, passing through the "peripheral lymphoid organs". Exposure to antigens in these organs, which include lymph nodes and gut-associated lymphoid tissues, activates the subset of B lymphocytes that recognize the specific antigens that are present. Finally, with the help of activated T lymphocytes, the activated B lymphocytes proliferate and change (differentiate) into antibody-secreting cells and memory B lymphocytes (which respond more quickly to antigen than naive B lymphocytes). In this study, the researchers investigate the effects of early HIV-1 infection on B lymphocytes in blood and in gut-associated lymphoid tissues.
What Did the Researchers Do and Find?
The researchers collected blood from patients as early as 17 days after HIV-1 infection and tissue samples from the lower portion of the small intestine (a region rich in gut-associated lymphoid structures called Peyer's patches) from 47 days after infection onward. When they analyzed the B lymphocytes in these samples (which were collected during two trials organized by the US Center for HIV/AIDS Vaccine Immunology [CHAVI]), they found that HIV-1 infection rapidly induced the activation of many different B cells that recognized a variety of antigens (polyclonal activation), as well as the appearance of differentiated B cells in blood and in gut-associated lymphoid tissue. The B lymphocytes that were activated in the gut made HIV-specific antibodies but also antibodies against unrelated antigens (such as flu virus proteins). Finally, the structure of Peyer's patches was altered early in HIV-1 infection. More specifically, most of the lymphoid follicles (organized collections of lymphocytes and antigen-presenting cells) in the Peyer's patches showed signs of damage and T- and B-lymphocyte death and the number of germinal centers (regions in lymphoid follicles in which B lymphocytes proliferate) was reduced.
What Do These Findings Mean?
Although the depletion of gut-associated CD4+ T lymphocytes in early HIV-1 infection is well known, these new results demonstrate the effects of early HIV-1 infection on gut-associated and circulating B lymphocytes. The results of this study are limited by the methods used to analyze the antibodies induced by HIV infection and by only taking tissue samples from one region of the gut. Nevertheless, the findings of polyclonal B-cell activation and damage to gut-associated lymphoid follicles soon after HIV-1 infection may have implications for HIV-1 vaccine design. Specifically, these findings suggest that an effective HIV-1 vaccine will need to ensure that significant levels of neutralizing antibodies are present in people before HIV-1 infection and that other protective immune defenses are fully primed so that, in the event of HIV-1 infection, the virus can be dealt with effectively before it disables any part of the immune system.
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