Modeling partially effective HIV vaccines in vitro.

Significant public health benefits could be realized with human immunodeficiency virus (HIV) vaccines that are incompletely effective. However, standard assays of experimental HIV vaccine immunogenicity may not correlate with antiviral effectiveness and cannot identify subtle effects. We developed an in vitro challenge assay (IVCA) that measures the net antiviral effect in whole peripheral blood mononuclear cells (PBMCs) to any titered HIV isolate. We then modeled partially effective postvaccination immune status 4 ways: use of PBMCs from highly exposed, uninfected individuals; depletion and partial reconstitution of autologous CD8+ cells from PBMCs from HIV-positive long-term nonprogressors; partial blocking of infection with chemokines; and variation in challenge virus dose. IVCA could detect as little as 3-fold differences in the challenge titer (30, 10, and 3 50% tissue-culture infective doses) or odds ratio of HIV infection. This robust and simple assay should be useful in determining which HIV vaccine candidates are suitable for field trials of efficacy.

Risk associated HIV-1 cross-clade resistance of whole peripheral blood mononuclear cells from exposed uninfected individuals with wild-type CCR5.

Highly HIV exposed, persistently uninfected individuals (EUs) may hold clues to the generation of effective vaccine induced acquired immunity against HIV, and considerable effort has been devoted to detecting and characterizing HIV specific immune responses in EU cohorts. When searching for such clues, it is important to exclude individuals with genetically determined absence of receptors, as this protective mechanism could not be induced by HIV specific vaccines. Homozygosity for the DeltaC32 mutation of CCR5 prevents R5 HIV infection, independent of any virus-specific immune responses that may be acquired by exposure, while heterozygosity influences susceptibility to low level exposure. Reports on the in vitro susceptibility of EU cells compared to controls have been conflicting. Therefore, we studied 14 EUs with homozygous wild type CCR5, using a newly developed in vitro challenge assay (IVCA) to measure the magnitude and breadth of resistance to infection among EUs. CD8+ cells were relatively increased compared to controls, and were largely responsible for resistance to challenge, which depended on dose of virus inoculum, and extended across clades. Consistent with some EU cohort studies, resistance waned among individuals who reduced their high-risk behavior.