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Abstract
Prophylactic vaccination against HIV-1 sexual transmission will probably require antibody elicitation at genital mucosal surfaces. However, HIV-1 envelope glycoprotein (Env)-based antigens are weakly immunogenic, particularly when applied mucosally. The polyanion PRO 2000 is safe for human vaginal application, and thus may represent a potential formulating agent for vaginal delivery of experimental vaccine immunogens. Based upon its biochemical properties, we hypothesized that PRO 2000 might enhance mucosal immunogenicity of HIV-1 envelope glycoprotein (Env)-based antigens, promoting local and systemic immune responses. Vaginal immunization with Env-PRO 2000 resulted in significantly increased titres of Env-specific mucosal IgA and IgG in mice and rabbits, respectively, compared to Env alone, revealing modest but significant mucosal adjuvant activity for PRO 2000. In vitro, PRO 2000 associated with Env, protecting the glycoprotein from proteolytic degradation in human vaginal lavage. Unexpectedly, PRO 2000 antagonized TLR4 activation, suppressing local production of inflammatory cytokines. Since inflammation-mediated recruitment of viral target cells is a major risk factor in HIV-1 transmission, the immune modulatory and anti-inflammatory activities of PRO 2000 combined with its intravaginal safety profile suggests promise as an HIV-1 mucosal vaccine formulating agent.
Highlights
Despite increasing access to antiretroviral drugs in developing countries, prevention or reduction of HIV-1 sexual transmission is needed to contain the continuing growth of the pandemic [1]
Trimeric forms of HIV-1 envelope glycoprotein (Env) may be superior at inducing neutralizing antibody responses [26,27,28], and Clade C dominates the worldwide HIV-1 pandemic [29]
The small animal vaginal immunization models described here provide proof-of-principle for two important concepts: 1) that vaginally-applied PRO 2000, a gel that is well-tolerated in a human vaginal context, can act as a B cell adjuvant to increase and sustain both local and systemic specific antibody responses; 2) that PRO 2000 is a TLR4 antagonist that reduces mucosal proinflammatory responses and so drives a Th2 immune bias
Summary
Despite increasing access to antiretroviral drugs in developing countries, prevention or reduction of HIV-1 sexual transmission is needed to contain the continuing growth of the pandemic [1]. We do not know how to induce long-term mucosal immunity against HIV-1 by conventional immunization strategies, and obtaining high antibody titres at mucosal surfaces appears to be regulated by mechanisms distinct from the systemic immune system [6,7]. HIV-1 Env-based antigens generally lack robust intrinsic immunogenicity, and there are no licensed mucosal adjuvants currently available. Caution must be exercised when considering the use of adjuvants in a mucosal context, since mucosal application of an adjuvant-containing formulation may induce local inflammation, potentially increasing the HIV-1 transmission risk by recruitment of activated CD4+ T cells that are the primary targets for HIV-1 replication in vivo [9,10,11]. Adjuvants for mucosal HIV-1 immunization would ideally promote immune responses whilst maintaining a non-inflammatory environment
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