Belyakov, I.M., Derby, M.A., Ahlers, J.D., Kelsall, B.L., Earl, P., Moss, B. et al. Mucosal immunization with HIV-1 peptide vaccine induces mucosal and systemic cytotoxic T lymphocytes and protective immunity in mice against intrarectal recombinant HIV-vaccinia challenge. Proc. Natl. Acad. Sci. USA 95, 1709-1714

Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/1998; 95(4). DOI: 10.1073/pnas.95.4.1709
Source: PubMed Central


Mucosal tissues are major sites of HIV entry and initial infection. Thus, the induction of a mucosal cytotoxic T lymphocyte (CTL) response is an important feature for an effective HIV vaccine. However, little is known about approaches to induce such a protective CTL response in the mucosa. Here for the first time we show that intrarectal immunization with a synthetic, multideterminant HIV peptide plus cholera toxin adjuvant induced long-lasting, antigen-specific CTL memory in both the inductive (Peyer’s patch) and effector (lamina propria) mucosal sites, as well as in systemic sites (spleen), whereas systemic immunization induced specific CTL only in the spleen. Cholera toxin adjuvant, while enhancing the response, was not essential. The CTL recognized target cells either pulsed with HIV peptide or expressing endogenous whole envelope glycoprotein of Mr 160,000 (gp160). Exploring the requirements for CTL induction, we show that mucosal CTL responses are both interleukin 12 and interferon-γ dependent by using antibody-treated and knock-out mice. Finally, to determine whether a mucosal response is actually protective against local mucosal challenge with virus, we show that intrarectal immunization with the synthetic HIV peptide vaccine protected mice against infection via mucosal challenge with a recombinant vaccinia virus expressing HIV-1IIIB gp160. These studies provide an approach to development of an HIV vaccine that induces CTL immunity in the mucosal and systemic immune systems and protects against mucosal infection with a virus expressing HIV-1 gp160.

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Available from: Igor M Belyakov
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    • "Studies in HIV transmission have shown that mucosal tissues are the primary sites for HIV entry and infection (Belyakov et al., 1998). Once HIV enters the body, it will target specific cells that contain the cell receptor CD4+ such as helper T-cells, and some macrophages and dendritic cells (Hutchinson, 2001; McDonald et al., 2003). "
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    DESCRIPTION: Human immunodeficiency virus (HIV) has one of the highest incidence and mortality rates of any infectious disease, with more than 33 million people infected worldwide. Specifically, HIV causes the destruction of helper T cells, ultimately resulting in the suppression of the immune system and leaving its human host susceptible to countless of other pathogenic agents. The development of an effective HIV vaccine has continued for more than 20 years. But the use of preventative vaccines using traditional vaccine technologies, which have proven successful for other diseases, has thus far failed with HIV. One vaccine, AIDSVAX, was the first HIV vaccine to reach a phase III efficacy trial, but has not yet been shown to eradicate HIV. Hope now lies in the development of therapeutic vaccines using novel technologies. One such vaccine is ALVAC-HIV, which when used in conjunction with other vaccines (AIDSVAX or Lipo-6T with IL-2 injections) has shown a great deal of promise in clinical trials suppressing viral replication and improving the immune system. Other therapeutic vaccines, such as Ad5, however, have been unsuccessful. While many believed that developing an effective HIV vaccine is impossible, efforts continue into researching its structure, transmission, immune system suppression, genetic variability, and immune system evasion. As long as research continues, hope remains that someday an effective vaccine will be developed.
    Full-text · Research · May 2015
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    • "They were Ad-HVR1-lgs-His6-V3, Ad-HVR1-V3, Ad-HVR1-long-V3 and Ad-HVR1-lgs-V3-His6-lgs (Figure  1A). All vectors contain the same short V3 sequence (rgpgrafvti, HIV-1 strain IIIB, located in aa 318–327, also named I10 peptide [35]), two of which also contain spacers prior to or after the I10 peptide (Figure  1A). Physical titers and infectious titers were determined, leading to the calculation of VP/IP ratios. "
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    ABSTRACT: Background Due to potential advantages, human adenoviral vectors have been evaluated pre-clinically as recombinant vaccine vectors against several cancers and infectious diseases, including human immunodeficiency virus (HIV) infection. The V3 loop of HIV-1 glycoprotein 120 (gp120) contains important neutralizing epitopes and plays key roles in HIV entry and infectivity. Methods In order to investigate the humoral immune response development against portions of the V3 loop, we sought to generate four versions of adenovirus (Ad)-based V3 vectors by incorporating four different antigen inserts into the hypervariable region 1 (HVR1) of human adenovirus type 5 (hAd5) hexon. The strategy whereby antigens are incorporated within the adenovirus capsid is known as the “Antigen Capsid-Incorporation” strategy. Results Of the four recombinant vectors, Ad-HVR1-lgs-His6-V3 and Ad-HVR1-long-V3 had the capability to present heterologous antigens on capsid surface, while maintaining low viral particle to infectious particle (VP/IP) ratios. The VP/IP ratios indicated both high viability and stability of these two vectors, as well as the possibility that V3 epitopes on these two vectors could be presented to immune system. Furthermore, both Ad-HVR1-lgs-His6-V3 and Ad-HVR1-long-V3 could, to some extent escape the neutralization by anti-adenovirus polyclonal antibody (PAb), but rather not the immunity by anti-gp120 (902) monoclonal antibody (MAb). The neutralization assay together with the whole virus enzyme-linked immunosorbent assay (ELISA) suggested that these two vectors could present V3 epitopes similar to the natural V3 presence in native HIV virions. However, subsequent mice immunizations clearly showed that only Ad-HVR1-lgs-His6-V3 elicited strong humoral immune response against V3. Isotype ELISAs identified IgG2a and IgG2b as the dominant IgG isotypes, while IgG1 comprised the minority. Conclusions Our findings demonstrated that human adenovirus (hAd) vectors which present HIV antigen via the “Antigen Capsid-Incorporation” strategy could successfully elicit antigen-specific humoral immune responses, which could potentially open an avenue for the development of Ad-based HIV V3 vaccines.
    Full-text · Article · Jun 2014 · Virology Journal
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    • "The CTL responses in spleen after I.R. immunization were similar to those induced by subcutaneous (S.C.) immunization (Belyakov et al. 1998b). In contrast, S.C. immunization with PCLUS3-18IIIB induced systemic CD8 + CTL responses with little evidence of mucosal CD8 + T cell responses (Belyakov et al. 1998b). Strong long-lasting mucosal CD8 + CTL responses can also be generated by mucosal immunization with recombinant vaccinia virus vectors (Belyakov et al. 1998d, 1999; Wyatt et al. 2008). "
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    ABSTRACT: Natural transmission of human immunodeficiency virus type 1 (HIV-1) occurs through gastrointestinal and vaginal mucosa. These mucosal tissues are major reservoirs for initial HIV replication and amplification, and the sites of rapid CD4(+) T cell depletion. In both HIV-infected humans and SIV-infected macaques, massive loss of CD4(+) CCR5(+) memory T cells occurs in the gut and vaginal mucosa within the first 10-14 days of infection. Induction of local HIV-specific immune responses by vaccines may facilitate effective control of HIV or SIV replication at these sites. Vaccines that induce mucosal responses, in particular CD8(+) cytotoxic T lymphocytes (CTL), have controlled viral replication at mucosal sites and curtailed systemic dissemination. Thus, there is strong justification for development of next generation vaccines that induce mucosal immune effectors against HIV-1 including CD8(+) CTL, CD4(+) T helper cells and secretory IgA. In addition, further understanding of local innate mechanisms that impact early viral replication will greatly inform future vaccine development. In this review, we examine the current knowledge concerning mucosal AIDS vaccine development. Moreover, we propose immunization strategies that may be able to elicit an effective immune response that can protect against AIDS as well as other mucosal infections.
    Full-text · Article · Nov 2011 · Current topics in microbiology and immunology
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