Immunological tolerance as a barrier to protective HIV humoral immunity
Graphical abstract
Introduction
Of the more than 25 vaccines currently used in medicine, all largely depend on pathogen-specific antibodies as mediators of protection [1]. However, only two of these vaccines (HPV and Hepatitis B) were specifically designed to elicit protective antibodies against a particular viral protein presented by the vaccine. The remaining vaccines are instead administered as purified inactivated or attenuated viruses or bacteria or their products (e.g., toxoids, polysaccharide capsules) and were empirically determined to be remarkably effective. Thus, our ability to rationally design effective vaccines against clinically important pathogens has been rather limited to date, as the precise immunological cellular and molecular mechanisms by which successful vaccines provide prophylactic immunity remain ill defined. This has been especially highlighted by our unsuccessful attempts to eradicate the human immune deficiency virus (HIV-1) that continues to infect millions annually and remains a global health burden. In this review, we highlight the association that exists between autoimmunity and HIV-1 and specifically the evidence that immunological tolerance is one barrier which impedes HIV-1 protective humoral immunity both physiologically and prophylactically with a vaccine. We further argue that for pathogens such as HIV that are not easily controlled by the host adaptive immune system, either naturally or upon vaccination, the development of an effective vaccine will need to exploit our increasing understanding of B cell biology and the mechanisms that regulate whether and how these lymphocytes mount antibody responses. The recent success of checkpoint blockade immunotherapy in promoting tumor immunity documents that experimental findings in mouse models [2, 3, 4] are able to provide important scientific guiding principles for the clinic. As we discuss in this review, mouse models of antibody response can also be valuable in demonstrating proof-of-principle concepts important for HIV vaccine design.
HIV-1 was identified as the etiologic agent of acquired immune deficiency syndrome, or AIDS [5], over three decades ago and soon thereafter it was shown that CD4 was the high affinity HIV-1 receptor [6, 7] to which the HIV envelope gp120 protein (Env) bound to infect T cells. Despite this long-standing knowledge, an effective HIV-1 vaccine has remained elusive and presumably for the same reasons that also impede a protective host antibody response upon natural HIV-1 infection. Principal amongst these barriers is the propensity of the virus to rapidly mutate as a result of an error prone viral reverse transcriptase. Thus, although HIV-specific antibodies able to neutralize the infecting (autologous) founder virus eventually appear months after initial infection, by this time the high mutability of HIV-1 renders them ineffective [8•]. HIV-1 Env is also heavily glycosylated and, again as a consequence of its genetic variability, sites of gp120 glycosylation vary with time [9]. This not only provides a dynamic physical barrier to neutralizing epitopes, but also cloaks HIV-1 with N-linked glycans, which are indistinguishable by the immune system from ‘self’ carbohydrates [8•]. Further, and in contrast to most viral envelope proteins, HIV-1 virions also have a relatively low density of Env gp120/gp41 heterotrimeric spikes on the virus surface [10] with an average distance between viral proteins that exceeds the ability of a gp120-specific antibody to bind bivalently, for example, with both antigen-binding sites [11]. Consequently, HIV-1 virions with sparsely distributed Env proteins are not expected to be able to efficiently activate potentially protective naïve B cells expressing a weak affinity gp120-specific germline-encoded B cell antigen receptor (BCR) [12, 13, 14].
Section snippets
HIV-1 broadly neutralizing antibodies (bnAbs) display unusual features difficult to elicit by vaccination
Despite these HIV-1 barriers that discourage the activation and recognition of neutralizing epitopes by naïve B cells, HIV-specific antibodies capable of neutralizing a wide breadth of HIV-1 genetic subtypes exist in some infected individuals; this indicates protective humoral immunity against the virus can be elicited. In the first 25 years of HIV research a handful of HIV-specific antibodies were identified that could neutralize a relatively broad range of HIV-1 genetic subtypes [15].
HIV-1 and autoimmunity
An association between autoimmunity and HIV-1 has been appreciated in the literature for decades. Specifically, naïve uninfected autoimmune prone MRL/lpr mice were reported to harbor serum antibodies specific for HIV-1 Env [26, 27]. Similarly, individuals with the autoimmune disease systemic lupus erythematosus (SLE) have also repeatedly been found to display HIV-specific serum antibodies, again in the absence of viral infection [28, 29, 30, 31, 32]. Further, the incidence of HIV-1 infection in
Immunological tolerance as a barrier to protective HIV-1 humoral immunity
Immunological tolerance functions to reduce the potential for autoimmune disease by removing or functionally silencing autoreactive specificities from lymphocyte populations. Newly generated B cells in the bone marrow of healthy individuals display an enriched frequency of poly-/auto-reactive BCRs that are largely censored by central B cell tolerance mechanisms [37, 38, 39]. Although central B cell tolerance greatly culls the majority of autoreactive B cells, a small but significant population
How common are breaches in peripheral tolerance and is this a consideration to promote HIV-1 humoral immunity?
Under some settings (e.g., common infections) and under the influence of genetic and environmental factors, anergic B cells escape peripheral tolerance and likely contribute to autoimmunity via the production of autoantibodies [61, 62, 63•, 64•]. Given this potential risk, it remains unclear why the immune system has evolved to allow these potentially dangerous B cells to populate peripheral lymphoid compartments unless conditions exist in which they may prove useful. Accordingly, Goodnow and
Concluding remarks
Despite the significant progress made in the identification and characterization of HIV-1 bnAbs and design of promising Env immunogens, HIV-1 continues to be a major global health burden and a viable vaccine is not yet on the horizon. The induction of bnAbs that are capable of neutralizing HIV-1 strains across the genetically diverse genetic subtypes is crucial to the development of a protective vaccine. Evidence is accumulating that immunological tolerance prohibits the induction of a subset
Conflict of interest statement
The authors have no conflicts of interest.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Roberta Pelanda and Divij Mathew for critical reading of the manuscript. This work was supported in part by NIH grant AI052157 and T32 training grants AR007534 and NIH/NCATS Colorado CTSA TL1 TR001081.
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