Research Article: Antibody-Dependent Cellular Cytotoxicity and NK Cell-Driven Immune Escape in HIV Infection: Implications for HIV Vaccine Development

Date Published: April 29, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Gamze Isitman, Ivan Stratov, Stephen J. Kent.


The HIV-1 genome is malleable and a difficult target tot vaccinate against. It has long been recognised that cytotoxic T lymphocytes and neutralising antibodies readily select for immune escape HIV variants. It is now also clear that NK cells can also select for immune escape. NK cells force immune escape through both direct Killer-immunoglobulin-like receptor (KIR)-mediated killing as well as through facilitating antibody-dependent cellular cytotoxicity (ADCC). These newer finding suggest NK cells and ADCC responses apply significant pressure to the virus. There is an opportunity to harness these immune responses in the design of more effective HIV vaccines.

Partial Text

The human immunodeficiency virus (HIV-1) pandemic is causing substantial morbidity and mortality across the globe, particularly in developing countries. Antiretroviral drug therapy for HIV is highly effective in controlling disease; however, eradication of HIV-1 is currently not feasible so treatment is life long and is both expensive and leads to considerable toxicity and drug resistance. A vaccine is widely viewed as being essential to controlling the epidemic. Several advanced efforts to develop an effective vaccine have failed or shown only marginal efficacy to date [1–4]. One of the greatest challenges in developing a vaccine against HIV is to overcome its ability to constantly mutate and escape anti-HIV immune responses. This high mutation rate is a direct result of the presence of the virus’ low fidelity RNA polymerase enzyme as well as the high levels of recombination it undergoes [5, 6].

Immune escape from HIV was first demonstrated for CTL-based immunity in 1991 [8]. Considerable work since then has shown CTL escape is typically regulated by the effect of the escape mutation on comparative viral fitness, a complex parameter illustrating the overall contribution of all mutation-related advantages and losses (Table 1). Even though the evasion of immune responses presented by escape mutations presents a definite fitness benefit to the virus, the HIV-1 proteome is not infinitely malleable hence the same mutations can result in fitness costs. Some CTL immune escape variants have reduced replicative capacity of the virus (reduced “fitness”) that slows the progression of disease [10, 11]. Studies have demonstrated that certain viruses composed of immune escape mutations are associated with lower viral loads within subjects [12, 13]. It has also been suggested that the rate of viral escape likely reflects the strength of the immune pressure and the fitness cost of the mutant virus [14]. Fitness costs are most dramatically illustrated in vivo by the reversion of transmitted escape mutations during acute and early HIV-1 infection [15–19].

Considerable data exist illustrating the effect of neutralizing antibodies in protecting against HIV-1 infection in vitro [37, 38] and in vivo using animal models [39–46]. Although antibodies are made to all HIV proteins within a few weeks, only those to the envelope glycoproteins can prevent or neutralize HIV infection. These neutralizing antibodies (Nab) take considerably longer to develop than binding antibodies, generally months to years [47]. HIV-infected subjects almost always develop Nab to their own virus (autologous neutralization), although Nabs typically respond to earlier viral isolates, with the subject’s contemporaneous virus having escaped. Some subjects eventually develop Nabs able to cross-neutralize additional viruses (heterologous neutralization), but their concurrent virus is still usually escaped from their autologous Nab. This highlights many of the difficulties involved in controlling HIV replication by Nab and the ability of HIV to escape antibody pressure through a process of genetic change [38]. The envelope gene presents the highest ratio of genetic diversity, most likely as a direct result of Nab pressure. However, for the virus to remain infective, portions of the envelope gene that encode regions essential for functional activity, such as CD4 and coreceptor binding, need to be conserved, and hence escape from Env Nabs probably results in little fitness cost. Individuals who do develop outstanding Nab responses generally have antibodies directed towards such crucial functional regions [48]. Long-term nonprogressors who have remained symptom-free for many years without antiretroviral therapy in general have broader and more potent responses compared to persons who show progressive disease [49–53].

Sequencing single HIV genomes from subjects with acute HIV-1 infection reveals that multiple mutations are acquired during the first months of infection and most align with sites of CTL or Nab escape mutations [61, 62]. However, some mutations do not clearly map to known sites of CTL or Nab escape, suggesting there may be other immune responses, such as ADCC responses, sufficiently potent to select immune escape strains. ADCC antibodies bind to viral antigens on the surface of infected cells and engage Fc receptors on innate immune cells such as NK cells, macrophages, and neutrophils, which in turn lyse the HIV-infected cell (Figure 1(c)).

CTL and Nab immune responses are pivotal drivers in immune escape and viral variability. It is now clear that the role of NK cells in viral selection, both through direct killing and ADCC mechanisms, is likely to have been previously underestimated. Other effector cells of the innate immune system, including macrophages and neutrophils, may also be important in driving HIV evolution. Evidence of the pressure applied by ADCC antibodies now provides challenges to inducing the most effective ADCC antibodies by vaccination. A better understanding of the immune responses to HIV is required to fully harness the potential of a vaccine to both prevent viral entry and ongoing infection.