Clues to finding correlates of risk/protection for HIV-1 vaccines

Abstract

Almost a decade later, we still do not understand why in the STEP trial (2008), males with pre-existing antibodies to the Ad5 vector were associated with initial increased risk of HIV-1 acquisition. Similarly, we have little conclusive evidence of why in the RV144 trial (2009),  vaccination with the ALVAC-HIV/AIDSVAX B/E was associated initially with almost a 60% vaccine efficacy at year one, which waned over 42 months to 31.2%, and where females were more protected than males. Based on the literature and trial outcomes, it was deduced that the elusive correlate of risk/protection may pertain to a novel, potent, innate protector mechanism launched by alternatively activated macrophages, which is probably induced by viruses and female steroid hormones. It was also suggested this mechanism was not likely amenable to discovery using standard or traditional approaches.   A plausible, candidate mechanism was identified with these characteristics, namely the production of human endogenous retrovirus–K102 (HERV-K102) particles, which occurs in, and generates, foamy macrophages in vitro.  Accumulating clinical, biological and phylogenetic evidence supports its role in the antagonism of HIV-1 replication and/or in the prevention of HIV-1 acquisition.  Thus, it will be important to examine HERV-K102 particle production, increased integration and envelop antibody production as candidate correlates of protection in HIV-1 vaccine trials, as well as in HIV-1 highly exposed seronegative cohorts and elite controllers.  The results of such efforts may have important ramifications for the HIV-1 cure in addition to vaccines.