B cell immunopathology during HIV-1 infection: Lessons to learn for HIV-1 vaccine design
TL;DR: Novel data indicate that B cell activation may be at the basis of impaired immune responses and the molecular events leading to B cell damage must be further characterized with the aim of selecting vaccine components allowing preservation of B cell functions.
About: This article is published in Vaccine.The article was published on 2008-06-06. It has received 56 citations till now. The article focuses on the topics: B cell & Vaccination.
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TL;DR: This Review focuses on advances in understanding of the mechanisms of B-cell dysfunction in HIV-associated disease and discusses similarities with other diseases that are associated with B- cell dysfunction.
Abstract: In recent years, intense research efforts have been dedicated to elucidating the pathogenic mechanisms of HIV-associated disease progression. In addition to the progressive depletion and dysfunction of CD4(+) T cells, HIV infection also leads to extensive defects in the humoral arm of the immune system. The lack of immune control of the virus in almost all infected individuals is a great impediment to the treatment of HIV-associated disease and to the development of a successful HIV vaccine. This Review focuses on advances in our understanding of the mechanisms of B-cell dysfunction in HIV-associated disease and discusses similarities with other diseases that are associated with B-cell dysfunction.
638 citations
TL;DR: Investigation of B cells before and after reduction of HIV plasma viremia by antiretroviral therapy provides new insights on B cells in HIV infection and how early initiation of ART may prevent irreversible immune system damage.
235 citations
TL;DR: Timing of HAART initiation is the major factor predicting the longevity of B cell responses in vaccinated HIV-1-infected children, and both late-treated HIV- 1 controllers and noncontrollers loose protective antibody titers against common vaccination antigens.
Abstract: HIV-1 infection induces a progressive disruption of the B cell compartment impairing long-term immune responses to routine immunizations. Depletion of specific memory B cell pools occurs during the 1st stages of the infection and cannot be reestablished by antiretroviral treatment. We reasoned that an early control of viral replication through treatment could preserve the normal development of the memory B cell compartment and responses to routine childhood vaccines. Accordingly, we evaluated the effects of different highly-active antiretroviral therapy (HAART) schedules in 70 HIV-1 vertically-infected pediatric subjects by B cell phenotypic analyses, antigen-specific B cell enzyme-linked immunosorbent spot (ELISpot) and ELISA for common vaccination and HIV-1 antigens. Initiation of HAART within the 1st year of life permits the normal development and maintenance of the memory B cell compartment. On the contrary, memory B cells from patients treated later in time are remarkably reduced and their function is compromised regardless of viral control. A cause for concern is that both late-treated HIV-1 controllers and noncontrollers loose protective antibody titers against common vaccination antigens. Timing of HAART initiation is the major factor predicting the longevity of B cell responses in vaccinated HIV-1-infected children.
159 citations
TL;DR: The multiple roles of MZ B-cells in humans, non-human primates, and rodents are discussed and it is revealed that viruses and bacteria have developed strategies to deplete innate-like B- cells during the acute phase of infection and to impair the antibody response.
Abstract: To maintain the integrity of an organism constantly challenged by pathogens, the immune system is endowed with a variety of cell types. B lymphocytes were initially thought to only play a role in the adaptive branch of immunity. However, a number of converging observations revealed that two B-cell subsets, marginal zone (MZ) and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses. In addition to their capacity to mount a local antibody response against type-2 T-cell-independent (TI-2) antigens, MZ B-cells can participate to T-cell-dependent (TD) immune responses through the capture and import of blood-borne antigens to follicular areas of the spleen. Here, we discuss the multiple roles of MZ B-cells in humans, non-human primates, and rodents. We also summarize studies – performed in transgenic mice expressing fully human antibodies on their B-cells and in macaques whose infection with Simian immunodeficiency virus (SIV) represents a suitable model for HIV-1 infection in humans – showing that infectious agents have developed strategies to subvert MZ B-cell functions. In these two experimental models, we observed that two microbial superantigens for B-cells (protein A from Staphylococcus aureus and protein L from Peptostreptococcus magnus) as well as inactivated AT-2 virions of HIV-1 and infectious SIV preferentially deplete innate-like B-cells – MZ B-cells and/or B1 B-cells – with different consequences on TI and TD antibody responses. These data revealed that viruses and bacteria have developed strategies to deplete innate-like B-cells during the acute phase of infection and to impair the antibody response. Unraveling the intimate mechanisms responsible for targeting MZ B-cells in humans will be important for understanding disease pathogenesis and for designing novel vaccine strategies.
87 citations
Cites background from "B cell immunopathology during HIV-1..."
...Even efficient anti-retroviral therapy only partially normalizes expression of B-cell activation markers, proportions of memory B-cells, and terminal differentiation (Viau and Zouali, 2001; Cagigi et al., 2008)....
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...…changes in B-cell responses have been described, including hyper-gammaglobulinemia, increased expression of markers of activation and terminal differentiation, augmented secretion of Igs in vitro and in vivo, and increased susceptibility to apoptosis (Viau and Zouali, 2001; Cagigi et al., 2008)....
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TL;DR: It is shown that the acquisition of MBC is a dynamic process in which the vaccine-specific MBC pool rapidly expands and then contracts, and that CpG enhances the kinetics, magnitude, and longevity of this response.
Abstract: Despite the central role of memory B cells (MBC) in protective immune responses, little is understood about how they are acquired in naive individuals in response to Ag exposure, and how this process is influenced by concurrent activation of the innate immune system's TLR. In this longitudinal study of malaria-naive individuals, we examined the MBC response to two candidate malaria vaccines administered with or without CpG, a TLR9 ligand. We show that the acquisition of MBC is a dynamic process in which the vaccine-specific MBC pool rapidly expands and then contracts, and that CpG enhances the kinetics, magnitude, and longevity of this response. We observed that the percentage of vaccine-specific MBC present at the time of reimmunization predicts vaccine-specific Ab levels 14 days later; and that at steady-state, there is a positive correlation between vaccine-specific MBC and Ab levels. An examination of the total circulating MBC and plasma cell pools also suggests that MBC differentiate into plasma cells through polyclonal activation, independent of Ag specificity. These results provide important insights into the human MBC response, which can inform the development of vaccines against malaria and other pathogens that disrupt immunological memory.
80 citations
References
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TL;DR: It is shown that human TLR9 expression in human immune cells correlates with responsiveness to bacterial deoxycytidylate-phosphate-deoxyguanylate (CpG)-DNA, and data suggest that hTLR9 conveys CpG-DNA responsiveness to human cells by directly engaging immunostimulating Cpg-DNA.
Abstract: The Toll-like receptor (TLR) family consists of phylogenetically conserved transmembrane proteins, which function as mediators of innate immunity for recognition of pathogen-derived ligands and subsequent cell activation via the Toll/IL-1R signal pathway. Here, we show that human TLR9 (hTLR9) expression in human immune cells correlates with responsiveness to bacterial deoxycytidylate-phosphate-deoxyguanylate (CpG)-DNA. Notably “gain of function” to immunostimulatory CpG-DNA is achieved by expressing TLR9 in human nonresponder cells. Transfection of either human or murine TLR9 conferred responsiveness in a CD14- and MD2-independent manner, yet required species-specific CpG-DNA motifs for initiation of the Toll/IL-1R signal pathway via MyD88. The optimal CpG motif for hTLR9 was GTCGTT, whereas the optimal murine sequence was GACGTT. Overall, these data suggest that hTLR9 conveys CpG-DNA responsiveness to human cells by directly engaging immunostimulating CpG-DNA.
1,545 citations
TL;DR: It is shown that human memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander T cell help and CpG DNA, which offers a means to maintain serological memory for a human lifetime.
Abstract: Production of antibodies can last for a lifetime, through mechanisms that remain poorly understood. Here, we show that human memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies to recall antigens are produced in vivo at levels proportional to the frequency of specific memory B cells, even several years after antigenic stimulation. Although antigen boosting leads to a transient increase in specific antibody levels, ongoing polyclonal activation of memory B cells offers a means to maintain serological memory for a human lifetime.
1,312 citations
TL;DR: A substantial fraction of plasma cells can survive and continue to secrete antibody for extended periods of time in the absence of any detectable memory B cells, demonstrating a new mechanism by which humoral immunity is maintained.
1,186 citations
TL;DR: It is concluded that epitopes recognized by the three monoclonal antibodies are important determinants for achieving substantial protection, thus providing a rational basis for AIDS vaccine development.
Abstract: Although maternal human immunodeficiency virus type 1 (HIV-1) transmission occurs during gestation, intrapartum and postpartum (by breast-feeding), 50-70% of all infected children seem to acquire HIV-1 shortly before or during delivery. Epidemiological evidence indicates that mucosal exposure is an important aspect of intrapartum HIV transmission. A simian immunodeficiency virus (SIV) macaque model has been developed that mimics the mucosal exposure that can occur during intrapartum HIV-1 transmission. To develop immunoprophylaxis against intrapartum HIV-1 transmission, we used SHIV-vpu+ (refs. 5,6), a chimeric simian-human virus that encodes the env gene of HIV-IIIB. Several combinations of human monoclonal antibodies against HIV-1 have been identified that neutralize SHIV-vpu+ completely in vitro through synergistic interaction. Here, we treated four pregnant macaques with a triple combination of the human IgG1 monoclonal antibodies F105, 2G12 and 2F5. All four macaques were protected against intravenous SHIV-vpu+ challenge after delivery. The infants received monoclonal antibodies after birth and were challenged orally with SHIV-vpu+ shortly thereafter. We found no evidence of infection in any infant during 6 months of follow-up. This demonstrates that IgG1 monoclonal antibodies protect against mucosal lentivirus challenge in neonates. We conclude that epitopes recognized by the three monoclonal antibodies are important determinants for achieving substantial protection, thus providing a rational basis for AIDS vaccine development.
913 citations
TL;DR: There is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody.
Abstract: Many effective vaccines act by inducing neutralizing antibodies, and this approach is a top priority in work on HIV vaccines. But a new study suggests that anti-HIV antibodies are most effective when they act in two ways: through neutralization — killing the virus outright and blocking its entry into T cells — and by killing infected cells. The use of engineered versions of a neutralizing human antibody that protects against HIV in a monkey model shows that protection is dependent not only the antibody's neutralizing activity, but also on its interaction with Fc receptors on effector cells, which may act to reduce virus yield from infected cells. This work suggests that the best results might be achieved with vaccines that recruit both neutralizing antibodies and cell-mediated immunity via agents such as macrophages and cytokinins, rather than antibodies. Passively administered neutralizing antibodies have been shown to protect macaques against challenge by the HIV/SIV chimeric SHIV. The antiviral effects of the monoclonal antibody b12 are crucially dependent on antibody effector mechanisms. Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine1,2. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge3,4. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.
882 citations