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.
Highlights
It has been recently stated that immune correlates of risk/protection for HIV-1 vaccines must be complex and/or reliant on the right combination of multiple types of immune responses, as correlates of protection have eluded investigators (Tomaras & Plotkin, 2017)
Tuftsin may modulate HERV-K102 DNA production in vitro Relevant to the increased risk of HIV-1 acquisition related to Ad5 antibodies in the STEP trial (Buchbinder et al, 2008), at a high concentration (2 mg/ml), tuftsin inhibited the production of HERV-K102 DNA in cultured CB by 53%, while at a lower concentration (200 ng/ml), tuftsin enhanced the replication of HERV-K102 pol containing DNA over normal genomic levels by 237%
It has been reported that subsets of chimpanzees with chronic HIV-1 infection showed progression analogous to humans, including greater expression of CD38 in CD8+ HLA-DR+ T cells (O’Neil et al, 2000), this raises the notion that an HERV-K102 ancestor, as a potential antidote for HIV-1 infection may have been selected through evolution in chimpanzees before it was acquired by humans. It is possible over about a 2 to 3.5 million-year window or longer, the HERV-K102 ancestor may have adapted to an HIV-1 like ancestor lentiviruses in chimpanzees prior to its acquisition by humans. This inquiry has led to the notion that HERV-K102 particle production, which generates foamy macrophages, appears to fulfil the requirements of a deduced candidate correlate of protection against HIV-1 acquisition
Summary
Clues to finding correlates of risk/protection for HIV-1 vaccines [version 1; peer review: 1 not approved].
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