In asymptomatic human immunodeficiency virus (HIV) infection in humans, disturbed T cell functions such as anergy and programmed cell death, thought to result from inappropriate signaling by antigen-presenting cells due to HIV infection, precede increase in virus load, decline in CD4+ T cell numbers, and subsequent disease progression. Here, in 3 long-term HIV-1-infected asymptomatic chimpanzees, antigen-presenting cell function was intact and T cells had normal proliferative capacity with no evidence of HIV-1-associated programmed cell death. Polymerase chain reaction analysis demonstrated low frequencies of cells harboring proviral DNA. Primary virus isolation from the infected animals demonstrated the absence of monocytotropic HIV-1 variants, in concordance with complete insusceptibility of chimpanzee monocytes for HIV-1 infection. Possibly, because of the incapacity of HIV-1 to infect monocytes, systemic immune dysfunction will not occur, contributing to controlled viral replication and maintenance of the asymptomatic state in HIV-infected chimpanzees.

Immune correlates of vaccine protection from HIV-1 infection would provide important milestones to guide HIV-1 vaccine development. In a proof of concept study using mucosal priming and systemic boosting, the titer of neutralizing antibodies in sera were found to correlate with protection of mucosally exposed rhesus macaques from SHIV infection. Mucosal priming consisted of two sequential immunizations at 12-week intervals with replicating host range mutants of adenovirus type 5 (Ad5hr) expressing the HIV-189.6p env gene. Following boosting with either heterologous recombinant protein or alphavirus replicons at 12-week intervals animals were intrarectally exposed to infectious doses of the CCR5 tropic SHIVSF162p4. Heterologous mucosal prime systemic boost immunization elicited neutralizing antibodies (Nabs), antibody dependent cytotoxicity (ADCC), and specific patterns of antibody binding to envelope peptides. Vaccine induced protection did not correlate with the type of boost nor T-cell responses, but rather with the Nab titer prior to exposure.

Each year, approximately five million people die worldwide from putatively vaccine-preventable mucosally transmitted diseases. With respect to mass vaccination campaigns, one strategy to cope with this formidable challenge is aerosol vaccine delivery, which offers potential safety, logistical, and cost-saving advantages over traditional vaccination routes. Additionally, aerosol vaccination may elicit pivotal mucosal immune responses that could contain or eliminate mucosally transmitted pathogens in a preventative or therapeutic vaccine context. In this current preclinical non-human primate investigation, we demonstrate the feasibility of aerosol vaccination with the recombinant poxvirus-based vaccine vectors NYVAC and MVA. Real-time in vivo scintigraphy experiments with radiolabeled, aerosol-administered NYVAC-C (Clade C, HIV-1 vaccine) and MVA-HPV vaccines revealed consistent mucosal delivery to the respiratory tract. Furthermore, aerosol delivery of the vaccines was safe, inducing no vaccine-associated pathology, in particular in the brain and lungs, and was immunogenic. Administration of a DNA-C/NYVAC-C prime/boost regime resulted in both systemic and anal-genital HIV-specific immune responses that were still detectable 5 months after immunization. Thus, aerosol vaccination with NYVAC and MVA vectored vaccines constitutes a tool for large-scale vaccine efforts against mucosally transmitted pathogens.MVA HPV ͉ non-human primate ͉ NYVAC HIV ͉ preclinical study ͉ aerosol vaccine assessment

HIV-1 infection in humans results in an early and progressive NK cell dysfunction and an accumulation of an ''anergic'' CD56 À CD16 1 NK subset, which is characterised by low natural cytotoxicity receptor expression and low cytokine producing capacity. In contrast to humans, chimpanzee NK cells do not display a distinguishable CD56 bright and CD56 dim subset but, as shown here, could be subdivided into functionally different CD8 1 and CD8 À subsets. The CD8 1 NK cells expressed significantly higher levels of triggering receptors including NKp46 and, upon in vitro activation, produced more IFN-c, TNF-a and CD107 than their CD8 À counterparts. In addition, chimpanzee CD8 À NK cells had relatively high levels of HLA-DR expression, suggestive of an activated state. Killing inhibitory receptors were expressed only at low levels; however, upon in vitro stimulation, they were upregulated in CD8 1 but not in CD8 À NK cells and were functionally capable of inhibiting NKp30-triggered killing. In contrast to HIV-1-infected humans, infected chimpanzees maintained their dominant CD8 1 NK cell population, with high expression of natural cytotoxicity receptors.

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