There have been quite a few reports on the efficacy of antimalarials- namely chloroquine & hydroxychloroquine in COVID-19, mostly from China. Some countries, specifically the Indian council of Medical Research have now put out recommendations, suggesting doctors likely to be exposed to COVID19 use hydroxychloroquine for prophylaxis. The basis for such recommendations is unclear. There is very little to commend use of these medications in the treatment of COVID19 except anecdotal reports, let alone for prophylaxis.
Presumably, these recommendations are based on some studies that show in vitro efficacy of hydroxychloroquine against certain viruses. however, there are no RCTs that show in vivo efficacy.
It is instructive that hydroxychloroquine is used principally for the treatment of autoimmune diseases such as SLE, Rheumatoid, sarcoid, DLE, etc. The mechanism by which it works in these conditions is thought to be by raising the pH of endosomes, including lysosomes. The latter operates in a facultatively acidic pH. Two immune processes that occur in lysosomes would be of relevance here.
Firstly, antigen presenting cells (APC) such as dendritic cells digest antigens internalized by Fc gamma receptors present on the cell surface. The latter of course are designed to bind to the Fc portion of IgG, and thus gain access to the antigen which the Fab portion of IgG has bound in turn. These antigens are digested in the acid environment of lysosomes and taken up in the groove of HLA Class I & HLA Class II molecules, to be presented by the APC to CD8+, and CD4+ T cells respectively. The former have particular relevance to killing viruses directly by cytolytic action, while the latter stimulate B cells through CD40-CD40L interaction. Hydroxycholoroquine abrogates this action, which is advantageous in conditions such as Lupus, where the Fc gamma portion of IgG binds to many autoantigens that would have been cleared from circulation in otherwise normal subjects. The latter is one of the principal drivers of Lupus.
A similar acid pH is required for partial digestion and activation of Toll like receptors (TLR). The 3 main TLRs dealing with viruses are all intracellular- TLR3, which binds ssRNA, TLR7, which binds dsRNA, and TLR9, which binds DNA. These TLRs are produced in the ER, and then chaperoned to endosomes by a protein called Unc90 3b, there to be partially digested and activated, ready to receive their cognate RNA or DNA. Again, turning down this function is particularly useful for SLE.
There is no conceivable reason why this should be useful for viral infections though. Perhaps the most important APC relating to viral infections is the plasmacytoid dendritic cell, which produces copious amounts of type I & type III interferons on antigenic stimulation. These interferons are viricidal, and therefore, turning down these functions would not be beneficial for viral infections.
There is a suggestion however, of a differential effect. Apparently, hydroxychloroquine differentially inhibits the processing of weak antigens such as auto-antigens in lupus while sparing the response to strong antigens such as viruses. Even if this were the case, it would only provide reassurance that the drug would not increase the risk of viral infections while being used in SLE. It would not connote a viricidal effect per se.
Presumably, these recommendations are based on some studies that show in vitro efficacy of hydroxychloroquine against certain viruses. however, there are no RCTs that show in vivo efficacy.
It is instructive that hydroxychloroquine is used principally for the treatment of autoimmune diseases such as SLE, Rheumatoid, sarcoid, DLE, etc. The mechanism by which it works in these conditions is thought to be by raising the pH of endosomes, including lysosomes. The latter operates in a facultatively acidic pH. Two immune processes that occur in lysosomes would be of relevance here.
Firstly, antigen presenting cells (APC) such as dendritic cells digest antigens internalized by Fc gamma receptors present on the cell surface. The latter of course are designed to bind to the Fc portion of IgG, and thus gain access to the antigen which the Fab portion of IgG has bound in turn. These antigens are digested in the acid environment of lysosomes and taken up in the groove of HLA Class I & HLA Class II molecules, to be presented by the APC to CD8+, and CD4+ T cells respectively. The former have particular relevance to killing viruses directly by cytolytic action, while the latter stimulate B cells through CD40-CD40L interaction. Hydroxycholoroquine abrogates this action, which is advantageous in conditions such as Lupus, where the Fc gamma portion of IgG binds to many autoantigens that would have been cleared from circulation in otherwise normal subjects. The latter is one of the principal drivers of Lupus.
A similar acid pH is required for partial digestion and activation of Toll like receptors (TLR). The 3 main TLRs dealing with viruses are all intracellular- TLR3, which binds ssRNA, TLR7, which binds dsRNA, and TLR9, which binds DNA. These TLRs are produced in the ER, and then chaperoned to endosomes by a protein called Unc90 3b, there to be partially digested and activated, ready to receive their cognate RNA or DNA. Again, turning down this function is particularly useful for SLE.
There is no conceivable reason why this should be useful for viral infections though. Perhaps the most important APC relating to viral infections is the plasmacytoid dendritic cell, which produces copious amounts of type I & type III interferons on antigenic stimulation. These interferons are viricidal, and therefore, turning down these functions would not be beneficial for viral infections.
There is a suggestion however, of a differential effect. Apparently, hydroxychloroquine differentially inhibits the processing of weak antigens such as auto-antigens in lupus while sparing the response to strong antigens such as viruses. Even if this were the case, it would only provide reassurance that the drug would not increase the risk of viral infections while being used in SLE. It would not connote a viricidal effect per se.
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