In the course of HIV infection, the virus first binds to attachment factors, for example, mannose binding C-type lectin receptor and intracellular adhesion molecule (ICAM-3) on the surface of host CD4 + T cells. The glycoprotein 120 (gp120) subunit of the virus envelope binds to immunoglobulin G of CD4 + and undergoes conformational changes, allowing the virus to interact with its coreceptors, CXCR4 or CCR5. These interactions favour downstream conversions of gp41 envelope subunit to a competent fusion conformation. Initial studies showed that membrane-impermeable PDI inhibitors and monoclonal antibodies against PDI prevent HIV-1 infection [65] . It was then revealed that the domain D2 of the CD4 has redox-active disulfide bonds and is regulated by thioredoxin [66] . Using membrane-impermeable reducing agents (especially arsenical-derived compounds) and labelling thiol reagents, it was demonstrated that CD4 + reactive thiols critically drive HIV entry into cells [66] . Work from another group also revealed that PDI, on the surface of HIV-1 target cells, reduces disulfide bonds of the recombinant envelope glycoprotein gp120 (reaction 1, Figure 1 ), a reaction prevented by the usual PDI inhibitors [67] . Intriguingly, PDI silencing in U373 and HeLa cells had little impact on HIV infection itself as compared to the effect mediated by general thiol inhibitors [68] . The reasons for this discrepancy remain to be elucidated and raise the question whether the reductive effect of PDI is coupled to other redox proteins (e.g., thioredoxin or Nox's) that could amplify virus-CD4 redox association in some cells. It is noteworthy that in these later studies, PDI knockdown on the cell surface was not evident as compared to massive loss of most PDIs within the ER; an observation that supports the idea that PDI in the ER has little impact in HIV-mediated infection [68] . Thiol inhibitors also affect viral fusion as that mediated by the fusion (F) protein from the Paramyxovirus Newcastle disease virus [69] . The overexpression of PDI family members PFDI and ERdj5 has also been shown to significantly catalyze the reduction of thiols in F protein, facilitating membrane fusion [70] . There is evidence suggesting a possible association between PDI and infection mediated by some members of the of Herpesviridae viruses family [71] .