It is also well established that there is a direct relationship between high viral loads and transmission

probability.[67] Despite this relationship, as indicated above, 75% of infections are by a single variant.[68] Hence, the challenge for blocking of acquisition immunologically becomes one of inhibiting productive infection of a small number of cells by a small number of virions at local mucosal sites within the first 3 days following exposure. Passive immunization studies in NHPs have established unequivocally that neutralization is a key mechanism of protection against infection with model AIDS viruses such as SHIV162p3.[16, 69] By contrast, the role of Fc-mediated effector function in blocking acquisition is indirect and more controversial.[70, 71] Two seminal passive immunization studies in NHPs employing the neutralizing monoclonal antibody (mAb), b12, point toward see more a role of Fc-mediated effector function in protection against both high-dose[70] and low-dose[71] vaginal challenges with SHIV162p3. Groups received either wild-type b12 capable of both neutralization and Fc-mediated effector function

or b12-LALA, in which Fc-mediated effector function, but not neutralization, was abrogated by L to A mutations at residues 234 and 235 in the CH2 domain of IgG1 (b12-LALA). In both models, protection against SHIV162p3 decreased by approximately 50% for b12-LALA. These are SRT1720 research buy the only passive immunization studies to date unambiguously indicating a role of Fc-mediated effector function in blocking acquisition. The contributing effector function is not known because b12-LALA is incapable of ADCC, ADCVI and phagocytosis. Further, b12 variants with improved Fc receptor binding and biological function did not increase protection in this model, although vaginal mAb levels

might not have been optimal to reveal enhanced protection at the times of challenge.[72] Hence the precise role of Fc-mediated effector function in blocking acquisition medroxyprogesterone in this model is unknown. There is no evidence that passive immunization with non-neutralizing mAbs can block acquisition by Fc-mediated effector function. By contrast, a recent study suggested that passive immunization using non-neutralizing antibodies with potent Fc-mediated effector function can increase post-infection control of viraemia.[17] That study reported statistically significant post-infection control against a vaginal challenge with SHIV162p3 using a mixture of two non-neutralizing anti-gp41 mAbs specific for its principal immunodominant domain.[17] These mAbs were vetted by an algorithm assigning weights based on their abilities to neutralize, mediate ADCC, block infection of monocyte-derived macrophages, bind Fc receptors on cell surfaces and capture free virions.