Abstract
Based on outcomes of informative HIV-1 vaccine prevention trials and the literature, it seems protection against HIV-1 acquisition more likely pertains to innate rather than adaptive immunity mechanisms. The proposed innate mechanism appears to be launched by alternatively activated macrophages in response to viral vectors and might be enhanced by natural female hormones. It was also suggested this novel immune mechanism was not likely amenable to discovery using standard or traditional approaches and is unlikely to be present in non-human models. A plausible, candidate innate mechanism with these characteristics pertains to the induction and production of human endogenous retrovirus–K102 (HERV-K102) particles by viruses which occurs in and generates foamy macrophages. HERV-K102 has salient features of non-pathogenic foamy retroviruses and its activation is part of the human-specific HERV-K HML-2 protective response described in HIV-1 patients. HERV-K102 particle production may be a novel and phylogenetically more recent form of innate immunity remarkably involving a viral anti-viral response. Accumulating clinical, biological and phylogenetic evidence supports a role of the HERV-K102 virus along with HML-2 responses, in the antagonism of HIV-1 replication and/or in the prevention of HIV-1 acquisition. Thus, it will be important to test the hypothesis that HERV-K HML-2 activation, HERV-K102 particle production and antibodies and T cell responses to select HERV-K102 or HML-2 antigens might comprise correlates of protection in HIV-1 vaccine prevention trials. Other proposed work would be to expand existing studies in HIV-1 highly exposed seronegative cohorts (HESN) and elite controllers to further evaluate a role of HERV-K102 and HML-2 in protection against HIV-1 replication and acquisition. The results of such inquiries may have important ramifications for the HIV-1 cure in addition to vaccines.
Highlights
It has been recently stated that immune correlates of protection for HIV-1 prevention vaccines must be complex and/or reliant on the right combination of multiple types of immune responses as a ‘true’ correlate of protection has not yet been characterized (Kuri-Cervantes et al, 2016; Tomaras & Plotkin, 2017)
In support of the notion of non-specific effects of the viral vectors employed, Huang et al (2014) found that while HIVspecific responses measured at 4 weeks after the second vaccination in the STEP trial were not associated with risk of HIV-1 infection, levels of IFN-gamma by ELISpot assay in the mock responses performed in the absence of HIV-1 antigens showed a hazard ratio (HR) of 1.62 which was strengthened among participants with pre-existing anti-Ad5 antibodies
That the risk enhancement/reduction was only temporary in either trial, generally lasting 6 to 12 months after the last immunization (Buchbinder et al, 2008; Rerks-Ngarm et al, 2009), was consistent with an innate rather than adaptive immunity mechanism. Since both risk enhancement (Buchbinder et al, 2008) and risk reduction (Rerks-Ngarm et al, 2009) were found with viral vectored vaccines, and not in the VAX003 and VAX004 HIV-1 vaccine trials, which instead involved proteins and adjuvants, this raises the likelihood that viruses in general may preferentially activate the macrophage-based defense mechanism and/or that adjuvants diminish it. These observations point to the existence of a novel, potent innate HIV-1 protection mechanism induced by viruses and enhanced with female hormones, which is launched by alternatively activated macrophages, and that this activation may be sensitive to inhibition by locally bound antibodies, for example as might be the case through tuftsin
Summary
The extensive revision discusses in depth why generally adaptive immune response mechanisms are unlikely to significantly affect HIV-1 acquisition rates, and why HIV-1 vaccine prevention trials have had poor outcomes. It expands the discussion of these outcomes with more citations, and why the proposed correlates of protection might be rejected. HERV-K102 particle production which generates foamy macrophages, along with HML-2 activation, appears to be a new dimension of human innate immunity inversely correlated with triggering adaptive immune mechanisms, which is hypothesized, partially based on clues and on some initial data, to prevent HIV-1 acquisition
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