Critical issues in mucosal immunity for HIV-1 vaccine development

doi:10.1016/j.jaci.2008.03.036

Journal of Allergy and Clinical Immunology

Volume 122, Issue 1, July 2008, Pages 3-9

https://doi.org/10.1016/j.jaci.2008.03.036 Get rights and content

Development of a safe and effective vaccine for HIV-1 infection is a critical global priority. However, the nature of host-virus interactions that lead to early immunosuppression and CD4 depletion, HIV-1 diversity, and the inability of the immune system to eliminate the latently infected CD4 pool of cells has to date thwarted successful vaccine development. Moreover, both the initial antibody-inducing vaccine (protein envelope gp120) and cell-mediated vaccine (recombinant adenovirus containing HIV-1 genes) strategies have failed in efficacy trials, and the latter cell-mediated vaccine appeared to have caused enhanced HIV-1 acquisition. Thus basic and translational research to understand why current vaccines have failed and elucidation of new mechanisms of virus control at mucosal surfaces is essential for eventual successful development of a preventive HIV-1 vaccine.

Section snippets

HIV-1 transmission

HIV-1 is remarkably diverse, with a reverse transcriptase enzyme that has a high error rate such that the average HIV-1 genome differs from its parent by at least 1 mutation and results in HIV-1 consisting of quasispecies or a “swarm” of related viruses.8, 9, 10 As a result, HIV-1 has evolved over time into a number of subtypes, or clades, with different clades in different locations worldwide.¹¹ Moreover, HIV-1 can diversify by recombining among virus strains when 2 or more virus strains

The neutralizing antibody problem

A number of rare human mAbs have been isolated from HIV-1–infected patients that indeed do broadly neutralize diverse HIV-1 strains, such as mAbs 2F5 and 4E10 against the gp41 membrane proximal region and mAb 1b12 reactive with the gp120 CD4-binding site.26, 27, 28 HIV-1 envelope constructs made in the laboratory express the binding sites of these antibodies (ie, they are antigenic), but when these HIV envelopes are injected into animals or human subjects, they do not induce broadly

HIV-1 and the latent pool of CD4⁺ T cells

Because many of the strategies used for successful vaccines have now been tried and failed in the quest for a preventive AIDS vaccine, the field has now turned to more basic and translational research areas to understand what is needed to make a vaccine against an integrating lentivirus and, indeed, to determine whether such a vaccine is possible. Because HIV-1 is an integrating retrovirus that forms a latent pool of infected cells that is sheltered from both antiretroviral therapy and from

The sequence of transmission events at the mucosal surface

Pope and Haase⁵⁶ have summarized their work and the work of others in defining what are thought to be the HIV-1 transmission events across mucosal surfaces (Fig 2). HIV-1 crosses the mucosal barrier in 2 to 6 hours and, during the first 3 to 6 days, disseminates locally and reaches draining lymph nodes. This might have been even faster if infected cells within an infectious ejaculate can gain entry through genital ulceration, appearing in draining lymph nodes within 24 hours and distal sites

The correlates of immunity to HIV-1 at mucosal surfaces

For induction of sterilizing immunity to HIV-1, most agree that a vaccine must induce anti-HIV-1 neutralizing antibody at mucosal surfaces at the time of transmission, induce cytolytic T lymphocytes (CTLs) in mucosal submucosal areas that can rapidly kill virus-infected cells, or a combination of both.⁶² Unfortunately, in the unvaccinated subject both anti-HIV-1 antibodies and anti-HIV-1 CTLs usually arise too late after transmission to be effective, arising between 20 and 25 days after

The mucosal targets and barriers for HIV-1

The linings of the gastrointestinal and genitourinary tracts are covered in mucus containing both IgA and IgG that forms a natural protective barrier against pathogen invasion, including HIV-1 virions.17, 71 Natural mucosal defenses to HIV-1 include the production of molecules including α and β defensins72, 73 and secretory leukocyte protease inhibitor.⁷⁴ Although the earliest events controlling viral transmission across intact mucosal surfaces remain controversial,⁵⁸ genital infections,

What does a successful HIV-1 vaccine need to do?

A successful, sterilizing, preventive AIDS vaccine must induce protective antibodies that are present at the time of transmission at sufficient concentrations to prevent virion movement from the epithelial surface to dendritic cells and induce anti–HIV-1 CD4⁺ and CD8⁺ T cells in the submucosa. Whether the latent pool of CD4⁺ T cells is established sufficiently late after transmission to allow time for a memory B-cell response to be effective is not known. That postexposure prophylaxis is not

Summary

A number of difficult obstacles continue to stand in the way of making a successful preventive HIV-1 vaccine, including HIV-1 diversity, the early formation of a latently infected CD4⁺ T-cell pool, the resulting narrow window of time for a vaccine to induce immune responses that might extinguish the transmitted virus, the inability of current envelope proteins to induce broadly neutralizing anti-HIV-1 antibodies, and HIV-1 infection of CD4⁺ T cells and induction of massive CD4 cell death. The

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The major routes of human immunodeficiency virus (HIV) or simian immunodeficiency virus transmission, except for blood-borne infection, are all through mucosal surfaces, genital, gastrointestinal, or oral. The gastrointestinal mucosa also serves as a major reservoir for virus replication, seeding the bloodstream, and is one of the first sites to experience depletion of CD4⁺ T cell loss of integrity of associated lymphoid tissues. These mucosal tissues have multiple barriers to infection, including physical barriers, such as mucus; innate antiviral molecules and cells; and adaptive immune cells, T and B cells, and antibodies. Together, these greatly reduce the risk of transmission and create a bottleneck in which often only one founder virus is transmitted, if any. However, the barriers vary among the different types of mucosa. Understanding these natural mechanisms of protection is key to designing effective vaccines and microbicides to prevent mucosal HIV transmission.
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An HIV vaccine capable of inducing high and durable levels of broadly neutralizing antibodies has thus far proven elusive. A promising antigen is the membrane-proximal external region (MPER) from gp41, a segment of the viral envelope recognized by a number of broadly neutralizing antibodies. Though an attractive vaccine target due to the linear nature of the epitope and its highly conserved sequence, MPER peptides are poorly immunogenic and may require display on membranes to achieve a physiological conformation matching the native virus. Here we systematically explored how the structure and composition of liposomes displaying MPER peptides impacts the strength and durability of humoral responses to this antigen as well as helper T-cell responses in mice. Administration of MPER peptides anchored to the surface of liposomes induced MPER-specific antibodies whereas MPER administered in oil-based emulsion adjuvants or alum did not, even when combined with Toll-like receptor agonists. High-titer IgG responses to liposomal MPER required the inclusion of molecular adjuvants such as monophosphoryl lipid A. Anti-MPER humoral responses were further enhanced by incorporating high-T_m lipids in the vesicle bilayer and optimizing the MPER density to a mean distance of ∼10–15 nm between peptides on the liposomes' surfaces. Encapsulation of helper epitopes within the vesicles allowed efficient “intrastructural” T-cell help, which promoted IgG responses to MPER while minimizing competing B-cell responses against the helper sequence. These results define several key properties of liposome formulations that promote durable, high-titer antibody responses against MPER peptides, which will be a prerequisite for a successful MPER-targeting vaccine.
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Human immunodeficiency virus (HIV) prevention tools that women can use and control are urgently needed. Microbicides are chemical products applied to the vagina or rectum to prevent the sexual transmission of HIV. Four classes of candidate microbicides have been tested to date: those that (1) enhance the natural defences in the vagina to inactivate HIV; (2) inactivate HIV in the vagina; (3) prevent HIV from attaching to, and fusing with, the host cells; and (4) prevent HIV from replicating in genital tract host cells. Despite numerous disappointing efficacy trial results over the past 20 years, substantial progress is now being made in microbicide development after the release of the CAPRISA 004 trial, which provided proof-of-concept that topical antiretroviral microbicides can prevent sexual transmission of HIV and herpes simplex type-2 infection. Microbicides, which fill an important gap for women-controlled prevention methods, have the potential to alter the course of the HIV pandemic.
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Citation Excerpt :
The HIV epidemic remains a major global health challenge, with heterosexual transmission accounting for the majority of new infections [1–5]. After transmission, the virus disseminates to the local draining lymph nodes followed by systemic spread within 6–25 days [6,7]. Development of a strong vaginal immunological response is considered an essential component of a female-targeted prophylactic vaccine.
A robust vaginal immune response is considered essential for an effective prophylactic vaccine that prevents transmission of HIV and other sexually acquired diseases. Considerable attention has recently focused on the potential of vaginally administered vaccines as a means to induce such local immunity. However, the potential for vaccination at this site remains in doubt as the vaginal mucosa is generally considered to have low immune inductive potential. In the current study, we explored for the first time the use of a quick release, freeze-dried, solid dosage system for practical vaginal administration of a protein antigen. These solid dosage forms overcome the common problem associated with leakage and poor retention of vaginally administered antigen solutions. Mice were immunized vaginally with H4A, an HIV gp41 envelope based recombinant protein, using quick release, freeze-dried solid rods, and the immune responses compared to a control group immunized via subcutaneous H4A injection. Vaginally immunized mice failed to elicit robust immune responses. Our detailed investigations, involving cytokine analysis, the stability of H4A in mouse cervicovaginal lavage, and elucidation of the state of H4A protein in the immediate-release dosage form, revealed that antigen instability in vaginal fluid, the state of the antigen in the dosage form, and the cytokine profile induced are all likely to have contributed to the observed lack of immunogenicity. These are important factors affecting vaginal immunization and provide a rational basis for explaining the typically poor and variable elicitation of immunity at this site, despite the presence of immune responsive cells within the vaginal mucosae. In future mucosal vaccine studies, a more explicit focus on antigen stability in the dosage form and the immune potential of available antigen-responsive cells is recommended.
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Induction of mucosal antibodies to prevent HIV infection is an important strategy for the HIV-1 prophylaxis. Here we report an epitope-vaccine based antigen that was able to elicit mucosal antibodies capable of blocking HIV-1 transcytosis. Because the ELDKWA epitope of neutralizing antibody 2F5 plays a crucial role in transcytosis, a series of immunogens that contain tandem copies of ELDKWA were prepared. Mice were immunized with these immunogens intranasally, and received intraperitoneal + intranasal boosters. The immunogens that contained more ELDKWA epitopes elicited higher level of mucosal ELDKWA-epitope specific IgAs and systemic IgGs. Although the antisera from the immunized mice exhibited mild neutralizing potency to HIV-1 isolates HXB2 and JRFL, the affinity purified mucosal ELDKWA-epitope specific antibodies could block the transcytosis of cell-free CNE3 (a primary isolate of subtype CRF01_AE) in human tight epithelial models.

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: Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

: Supported by National Institutes of Health grant AI-0678501, the Center For HIV/AIDS Vaccine Immunology (B.H. and R.S.), and Collaboration for AIDS Vaccine Discovery (B.H.) and Grand Challenge (R.S.) grants from the Bill and Melinda Gates Foundation and Europrise (R.S.) network of excellence on vaccines and microbicides funded by the European Commission.

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Reviews and feature articleCritical issues in mucosal immunity for HIV-1 vaccine development

Section snippets

HIV-1 transmission

The neutralizing antibody problem

HIV-1 and the latent pool of CD4+ T cells

The sequence of transmission events at the mucosal surface

The correlates of immunity to HIV-1 at mucosal surfaces

The mucosal targets and barriers for HIV-1

What does a successful HIV-1 vaccine need to do?

Summary

Virology

Immunity

J Mol Biol

Virology

Microbes Infect

Vaccine

Blood

Trends Pharmacol Sci

Nature

Clin Immunol

Curr Opin Immunol

Medicine. The need for a global HIV vaccine enterprise

Science

The Global HIV/AIDS Vaccine Enterprise: scientific strategic plan. Coordinating Committee of the Global HIV/AIDS Vaccine Enterprise. The Global HIV/AIDS Vaccine Enterprise: Scientific Strategic Plan

PLoS Med

Antibody-based HIV-1 vaccines: recent developments and future directions

PLoS Med

Improving defences at the portal of entry: Mucosal and innate immunity (Summary Report from a Global HIV Vaccine Enterprise Working Group)

PLoS Med

The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development?

J Exp Med

The 15th annual meeting had its share of sobering news from clinical trials, but researchers also reported many exciting advances

IAVI Rep

Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity

Nature

Heterogeneity of HIV-1 and HIV-2

AIDS

Genetic diversity of HIV in Africa: impact on diagnosis, treatment, vaccine development and trials

AIDS

Identification of the transmitted HIV-1 envelope

Proc Natl Acad Sci U S A

The clades of HIV: their origins and clinical significance

AIDS Rev

Recombination in HIV-1

Nature

Search for the origin of HIV and AIDS

Science

Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes

Nature

Brief but efficient: acute HIV infection and the sexual transmission of HIV

J Infect Dis

Acute HIV revisited: new opportunities for treatment and prevention

J Clin Invest

Inhibiting sexual transmission of HIV-1 infection

Nat Rev Microbiol

Genotypic and phenotypic characterization of HIV-1 patients with primary infection

Science

Selective transmission of CCR5-utilizing HIV-1: the “gatekeeper” problem resolved?

Nat Rev Microbiol

Diversity considerations in HIV-1 vaccine selection

Science

Centralized immunogens as a vaccine strategy to overcome HIV-1 diversity

Expert Rev Vaccines

Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants

Nat Med

Coping with viral diversity in HIV vaccine design

PLoS Comput Biol

Centralized HIV-1 envelope immunogens and neutralizing antibodies

Curr HIV Res

Antibody vs. HIV in a clash of evolutionary titans

Proc Natl Acad Sci U S A

Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

Nature

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Expert Rev Vaccines

Atomic structure of the ectodomain from HIV-1 gp41

Nature

Antibody neutralization and escape by HIV-1

Nature

HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites

Reviews and feature article
Critical issues in mucosal immunity for HIV-1 vaccine development

HIV-1 and the latent pool of CD4⁺ T cells