Mucosal Immunity and HIV-1 Infection: Applications for Mucosal AIDS Vaccine Development

Midwest Research Institute, 110 Thomas Johnson Drive, Suite 170 Frederick, MD 21702, USA.
Current topics in microbiology and immunology (Impact Factor: 4.1). 11/2011; 354(1):157-79. DOI: 10.1007/82_2010_119
Source: PubMed


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.

Download full-text


Available from: Igor M Belyakov,
  • Source
    • "One strategy for HIV vaccine development is to generate a local immune barrier at the site of infection [1]. Evidence demonstrating that in the majority of heterosexual transmission cases, infection is caused by a single founder virion [2] suggests that this strategy could be effective. "
    [Show abstract] [Hide abstract]
    ABSTRACT: One potential strategy for the prevention of HIV infection is to induce virus specific mucosal antibody that can act as an immune barrier to prevent transmission. The mucosal application of chemokines after immunisation, termed "prime-pull", has been shown to recruit T cells to mucosal sites. We wished to determine whether this strategy could be used to increase B cells and antibody in the vaginal mucosa following immunisation with an HIV antigen. BALB/c mice were immunised intranasally with trimeric gp140 prior to vaginal application of the chemokine CCL28 or the synthetic TLR4 ligand MPLA, without antigen six days later. There was no increase in vaginal IgA, IgG or B cells following the application of CCL28, however vaginal application of MPLA led to a significant boost in antigen specific vaginal IgA. Follow up studies to investigate the effect of the timing of the "pull" stimulation demonstrated that when given 14 days after the initial immunisation MPLA significantly increased systemic antibody responses. We speculate that this may be due to residual inflammation prior to re-immunisation. Overall we conclude that in contrast to the previously observed effect on T cells, the use of "prime-pull" has only a modest effect on B cells and antibody.
    PLoS ONE 11/2013; 8(11):e80559. DOI:10.1371/journal.pone.0080559 · 3.23 Impact Factor
  • Source
    • "In addition to cell-mediated immunity, the HIV vaccine should evoke early and robust broadly virus-neutralizing antibodies [18] similar to those identified in a subset of HIV-1 infected subjects [19]. It is also considered important that, in order to prevent the infection or reduce the infectious inoculum, the HIV vaccine should induce immune responses at mucosal surfaces, which represent sites of HIV entry [20], [21]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tuberculosis (TB) has emerged as the most prominent bacterial disease found in human immunodeficiency virus (HIV)-positive individuals worldwide. Due to high prevalence of asymptomatic Mycobacterium tuberculosis (Mtb) infections, the future HIV vaccine in areas highly endemic for TB will often be administrated to individuals with an ongoing Mtb infection. The impact of concurrent Mtb infection on the immunogenicity of a HIV vaccine candidate, MultiHIV DNA/protein, was investigated in mice. We found that, depending on the vaccination route, mice infected with Mtb before the administration of the HIV vaccine showed impairment in both the magnitude and the quality of antibody and T cell responses to the vaccine components p24Gag and gp160Env. Mice infected with Mtb prior to intranasal HIV vaccination exhibited reduced p24Gag-specific serum IgG and IgA, and suppressed gp160Env-specific serum IgG as compared to respective titers in uninfected HIV-vaccinated controls. Importantly, in Mtb-infected mice that were HIV-vaccinated by the intramuscular route the virus neutralizing activity in serum was significantly decreased, relative to uninfected counterparts. In addition mice concurrently infected with Mtb had fewer p24Gag-specific IFN-γ-expressing T cells and multifunctional T cells in their spleens. These results suggest that Mtb infection might interfere with the outcome of prospective HIV vaccination in humans.
    PLoS ONE 07/2012; 7(7):e41205. DOI:10.1371/journal.pone.0041205 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of a safe, effective and globally affordable HIV vaccine offers the best hope for the future control of the HIV-1 pandemic. Since 1987, scores of candidate HIV-1 vaccines have been developed which elicited varying degrees of protective responses in nonhuman primate models, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines and various prime-boost combinations. Four of these candidate vaccines have been tested for efficacy in human volunteers, but, to the exception of the recent RV144 Phase III trial in Thailand, which elicited a modest but statistically significant level of protection against infection, none has shown efficacy in preventing HIV-1 infection or in controlling virus replication and delaying progression of disease in humans. Protection against infection was observed in the RV144 trial, but intensive research is needed to try to understand the protective immune mechanisms at stake. Building-up on the results of the RV144 trial and deciphering what possibly are the immune correlates of protection are the top research priorities of the moment, which will certainly accelerate the development of an highly effective vaccine that could be used in conjunction with other HIV prevention and treatment strategies. This article reviews the state of the art of HIV vaccine development and discusses the formidable scientific challenges met in this endeavor, in the context of a better understanding of the immunopathogenesis of the disease.
    Vaccine 06/2011; 29(37):6191-218. DOI:10.1016/j.vaccine.2011.06.085 · 3.62 Impact Factor
Show more