Obstacles to ideal anti-HIV antibody-dependent cellular cytotoxicity responses

A safe and effective vaccine against HIV is a global health priority. Large-scale phase III clinical vaccine trials based on neutralizing antibodies and cytotoxic T-lymphocytes have failed to provide protection, highlighting the lack of understanding of basic immune correlates of protection against HIV. The partial success of the RV144 vaccine trial, however, sparked an intense research effort to identify and describe the protective potential of non-neutralizing antibodies. Correlates of protection analyses have identified antibodies that induced antibody-dependent cellular cytotoxicity (ADCC) as potentially important. Despite the attractiveness of utilizing ADCC antibodies for HIV vaccine design, it is important to note that effective ADCC responses are contingent on many factors. As discussed in this review, these factors are important considerations for determining the feasibility of designing an optimal ADCC antibody-inducing vaccine construct. Important determinants of ADCC responses include characteristics of the antibody, such as isotype and subclass, antigen-specificity, titer, durability and glycosylation of the constant region. Second, ADCC immune responses are highly contingent on the natural killer (NK) cell effectors. This review will describe the current state of knowledge regarding the ontogeny of NK cells, highlighting the continuous “education” they undergo that determines their functional potential upon stimulation. Other important NK cell factors, such as constant region receptor polymorphisms, cellular exhaustion, and the effects of the cytokine milieu on cellular function, will also be covered. Finally, an exciting, but yet untested, role for NK cell-mediated ADCC lies in its potential ability to eliminate latently infected cells, which harbor the viral reservoir. The review will address the potential of a two-pronged attack, where latently infected cells are induced to express HIV antigens and then eliminated by NK cells via an ADCC mechanism, with the goal of inducing a cure.