T-cell-mediated immune effector mechanisms play an important role in the containment of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication after infection. Both vaccination-and infection-induced T-cell responses

The recombinant canarypox vector, ALVAC-HIV, together with human immunodeficiency virus (HIV) gp120 envelope glycoprotein, has protected 31.2% of Thai individuals from HIV acquisition in the RV144 HIV vaccine trial. This outcome was unexpected, given the limited ability of the vaccine components to induce CD8 ؉ T-cell responses or broadly neutralizing antibodies. We vaccinated macaques with an immunization regimen intended to mimic the RV144 trial and exposed them intrarectally to a dose of the simian immunodeficiency virus SIV mac251 that transmits few virus variants, similar to HIV transmission to humans. Vaccination induced anti-envelope antibodies in all vaccinees and CD4؉ and CD8 ؉ T-cell responses. Three of the 11 macaques vaccinated with ALVAC-SIV/gp120 were protected from SIV mac251 acquisition, but the result was not significant. The remaining vaccinees were infected and progressed to disease. The magnitudes of vaccine-induced SIV mac251 -specific T-cell responses and binding antibodies were not significantly different between protected and infected animals. However, sera from protected animals had higher avidity antibodies to gp120, recognized the variable envelope regions V1/V2, and reduced SIV mac251 infectivity in cells that express high levels of ␣ 4 ␤ 7 integrins, suggesting a functional role of antibodies to V2. The current results emphasize the utility of determining the titer of repeated mucosal challenge in the preclinical evaluation of HIV vaccines.

Most HIV transmission in women occurs through the cervicovaginal mucosa, which is coated by a bacterial biofilm including Lactobacillus. This commensal bacterium plays a role in maintaining healthy mucosa and can be genetically engineered to produce anti-viral peptides. Here, we report a 63% reduction in transmission of a chimeric simian/human immunodeficiency virus (SHIVSF162P3) after repeated vaginal challenges of macaques treated with Lactobacillus jensenii expressing the HIV-1 entry inhibitor cyanovirin-N. Furthermore, peak viral loads in colonized macaques with breakthrough infection were reduced 6-fold. Colonization and prolonged anti-viral protein secretion by the genetically engineered lactobacilli did not cause any increase in proinflammatory markers. These findings lay the foundation for an accessible and durable approach to reduce heterosexual transmission of HIV in women that is coitally independent, inexpensive, and enhances the natural protective effects of the vaginal microflora.

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A guiding principle for HIV vaccine design has been that cellular and humoral immunity work together to provide the strongest degree of efficacy. However, three efficacy trials of Ad5-vectored HIV vaccines showed no protection. Transmission was increased in two of the trials, suggesting that this vaccine strategy elicited CD4+ T-cell responses that provide more targets for infection, attenuating protection or increasing transmission. The degree to which this problem extends to other HIV vaccine candidates is not known. Here, we show that a gp120-CD4 chimeric subunit protein vaccine (full-length single chain) elicits heterologous protection against simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) acquisition in three independent rhesus macaque repeated low-dose rectal challenge studies with SHIV162P3 or SIVmac251. Protection against acquisition was observed with multiple formulations and challenges. In each study, protection correlated with antibody-dependent cellular cytotoxicity specific for CD4-induced epitopes, provided that the concurrent antivaccine T-cell responses were minimal. Protection was lost in instances when T-cell responses were high or when the requisite antibody titers had declined. Our studies suggest that balance between a protective antibody response and antigen-specific T-cell activation is the critical element to vaccine-mediated protection against HIV. Achieving and sustaining such a balance, while enhancing antibody durability, is the major challenge for HIV vaccine development, regardless of the immunogen or vaccine formulation.

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of human immunodeficiency virus type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime–protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical trial. Robust cross-subtype HIV-1-specific T cell responses were detected in IFN-γ ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 Env antigens and also neutralized pseudotyped viruses that express the primary Env antigens from multiple HIV-1 subtypes. These findings demonstrate that the DNA prime–protein boost approach is an effective immunization method to elicit both humoral and cell-mediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds.

Epitopes located in and around the coreceptor binding site of HIV-1 envelope glycoprotein (gp120) exhibit enhanced exposure after attachment to the CD4 receptor and comprise some of the most conserved and functionally important residues on the viral envelope. Therefore, antibody responses to these epitopes [designated as CD4-induced (CD4i)] should be highly cross-reactive and potentially useful for HIV vaccine development. To address this question, rhesus macaques were vaccinated with subunit immunogens designed to raise humoral responses against CD4i epitopes and challenged rectally with SHIV 162P3, which encodes a heterologous envelope versus the immunogen. We found that animals vaccinated with a rhesus full-length single-chain (rhFLSC) complex exhibited significantly accelerated clearance of plasma viremia and an absence of long-term tissue viremia compared with unvaccinated control animals. Such control of infection correlated with stronger responses to CD4i epitopes in the rhFLSC-vaccinated animals, compared with macaques immunized with gp120, crosslinked gp120 -CD4 complexes, or soluble CD4 alone. These responses were strongly boosted in the rhFLSC-vaccinated animals by SHIV 162P3 infection. The control of infection was not associated with anti-CD4 responses, overall anti-gp120-binding titers, or neutralizing activity measured in conventional assays. Vaccine-naive animals also developed anti-CD4i epitope responses after simian/ human immunodeficiency virus (SHIV) challenge, which appeared later than the overall anti-gp120 responses and in concert with the decline of viremia to a low set point. Collectively, these data suggest that antibodies to CD4i epitopes may play a role in controlling SHIV infection and provide insights for HIV vaccine development.vaccine ͉ infection ͉ immunity

Natural HIV transmission occurs through mucosa, but it is debated whether mucosal cytotoxic T lymphocytes (CTLs) can prevent or reduce dissemination from the initial mucosal site to the systemic circulation. Also, the role of CTL avidity in mucosal AIDS viral transmission is unknown. To address these questions, we used delay in acute-phase peak viremia after intrarectal challenge as an indicator of systemic dissemination. We found that a peptide-prime/poxviral boost vaccine inducing high levels of high-avidity mucosal CTLs can have an impact on dissemination of intrarectally administered pathogenic SHIV-ku2 in macaques and that IntroductionThe gastrointestinal and vaginal mucosae are the primary sites of natural HIV transmission and the former is also a major reservoir for HIV replication. [1][2][3][4] This mucosa-centric nature of HIV infection provides a strong rationale for development of mucosal HIV vaccines to induce sufficient mucosal response to clear virus from mucosal tissues. [5][6][7] Indeed, we previously demonstrated that intrarectal immunization of macaques with a peptide vaccine was superior to subcutaneous immunization both in the induction of mucosal CD8 ϩ cytotoxic T lymphocyte (CTL) responses and in limiting viral titers in the blood and intestine. 8,9 In addition, control of viremia in SIV/SHIV/HIV infection correlates with and is dependent on CD8 ϩ CTLs in macaques and chimpanzees. [10][11][12] However, it has been debated whether CTLs in the mucosa can eliminate the first round of virally infected cells fast enough to prevent or reduce dissemination of virus to the systemic circulation. Data from several laboratories show that virus remains in the mucosa from 2 to 7 days before spreading to other sites, 2,13 suggesting that if CTLs are present at the local site of infection early enough, it may be possible to eradicate the initial nidus of infection before it spreads. However, no data have been available to test this hypothesis, which is important to understand the role of mucosal CTLs in protection and thus in the design of mucosal AIDS vaccines. Here, we use the delay in acute-phase appearance of virus in the systemic circulation after intrarectal inoculation as an indicator of such dissemination from the mucosa to test this hypothesis in rhesus macaques immunized intrarectally with an experimental vaccine.In murine studies, high-avidity CD8 ϩ CTLs are more effective than low-avidity CD8 ϩ CTLs in clearance of viral infections. [14][15][16][17] However, only limited indirect information has been available in primates, 18 and the role of CTL avidity has not been studied explicitly in the mucosa. Here, while comparing mucosal vaccine regimens in macaques for protection against mucosal transmission of an AIDS virus, we made the unexpected observation that peptide priming increased mucosal CTL avidity, and further found a correlation between levels of high-avidity mucosal CTLs and delayed appearance of circulating plasma viral particles, which we interpret to reflect dissemination of virus f...