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  • These conclusions complement the work by Nguyen and colleagu

    2018-11-07

    These conclusions complement the work by Nguyen and colleagues recently published in EBioMedicine, in which the authors described pathological examination conducted on 3 aborted fetuses with CRS acquired during the 2011–2012 rubella epidemic in Vietnam (). In this second observation, ocular lesions with congenital cataract and hepatic involvement associating necrotizing and inflammatory changes were predominant. RV antigens were detected in multiple cell types in multiple organs, particularly via infiltrating CD34 positive hematopoietic mononuclear cells, as well as in epithelial cells in ciliary body representing a possible cause of cataracts. The only common feature between these two studies was the neural cell infection in both cases. Contrasting results in RV antigen positive cells could be related to the difference between gestational age of the CRS cases studied including either aborted fetuses at 13, 22 and 23weeks, respectively, in Nguyen\'s work or term babies, or close to the term, in Lazar\'s report. This could reflect the wide range of cell types infected at the initial, acute and disseminated phase of the disease, distinct from the narrower spectrum of persistently infected cells in the organs where the virus is capable of causing chronic typical CRS lesions.
    Antibodies mediating antibody-dependent cellular cytotoxicity (ADCC) have been of increasing interest since their identification as a protective immune correlate in the RV144 clinical vaccine efficacy trial (). Earlier studies associated these non-neutralizing oxyntomodulin with protection against HIV infection and disease progression in both humans and non-human primates (for review see ). Therefore it is somewhat surprising to find them now linked to HIV pathogenesis. HIV disease progression is marked by a gradual loss of CD4 T cells during which a small proportion of HIV-infected CD4 T cells and a much larger proportion of uninfected “bystander” CD4 T cells are killed. While numerous mechanisms have been described for infected cell killing, the mechanism of bystander killing has remained controversial. In this issue, attribute bystander killing largely to antibodies mediating ADCC. They further suggest that a small CD4 mimetic developed by the Sodroski group might be used to alter this pathogenic mechanism for therapeutic benefit. How can the conflicting findings regarding ADCC antibodies be explained? And what caveats should be considered in using CD4 mimetics? As reported by Richard et al. in this issue of , the external envelope of HIV is labile and continually sheds the gp120 component which then binds the primary viral receptor, CD4, on bystander uninfected T cells. A subsequent conformational change opens the co-receptor binding site exposing an epitope recognized by cluster A antibodies, including the prototypic ADCC-mediating monoclonal antibody, A32. Killing of the bystander CD4 T cells follows. Concurrently, the virus subverts killing of infected cells by down-regulating CD4, inhibiting tetherin, and internalizing Env (as cited in ). Consequently, less Env is expressed on the infected-cell surface, less CD4 is available to complex with gp120, and less expression of Env in the open conformation occurs. Thus ADCC killing of the infected cell is diminished in favor of bystander killing. CD4 mimetics were previously shown to interact with the viral envelope, inducing conformational changes, exposing the co-receptor binding site, and rendering the virus susceptible to neutralization by CD4-induced antibodies (). The Finzi laboratory also previously reported that gp120/CD4 binding within the same infected cell led to exposure of ADCC epitopes () and that the CD4 mimetic sensitized infected cells to ADCC killing (). In the current paper they show that the mimetic decreases binding of shed gp120 to bystander CD4 cells, inferring that less ADCC-mediated killing of these uninfected cells will result. They also suggest that binding of the mimetic to envelope remaining on the infected cell surface should “redirect” ADCC-mediating antibodies to the infected cell away from bystanders, as stated above. Recent support of this hypothesis showed ADCC killing of primary HIV-infected T cells was enhanced by co-culturing with the CD4 mimetic ().