Understanding the T cell immune response in SARS coronavirus infection

Janice Oh, Hsueh-Ling; Ken-En Gan, Samuel; Bertoletti, Antonio; Tan, Yee-Joo

The association of certain HLA genotypes with increased resistance or the ability to clear viral infections have been reported in hepatitis C virus (HCV) and human papillomavirus studies. [47] [48] [49] [50] Although earlier studies done on SARS patients from Taiwan and Hong Kong suggested that the HLA-B, HLA-Cw and HLA-DR alleles were highly associated with SARS infection and disease development, [51] [52] [53] further investigation is required. Of these literature, SARS individuals from Hong Kong showed that HLA-B*07:03 and HLA-DR*03:01 conferred factors for susceptibility and resistance to SARS infection, respec-tively. 53 In agreement with this, a study on a Taiwanese cohort of SARS patients found that both HLA-Cw*15:02 and HLA-DR*03:01 were associated with resistance to SARS infection. 54 These observations suggested the important role of HLA-DR*03:01 in viral disease progression through enhancing the function of CD4 1 T helper cells. Similarly, we observed that the CD8 1 T cell responses against both the N and 3a proteins were all restricted by HLA-B subtype (unpublished data), thus pointing to the possible role of HLA-B subtypes in viral immunity. Among the HLA class I genes, HLA-B is known to be the most polymorphic, 55 and was associated in protective roles against the HIV, 56-58 HCV 59 and acute influenza infections. 60 CONCLUSION Currently, no antiviral therapy has yet been proven useful for SARS. Attempts to test potential anti-SARS agents using antiviral antibodies, entry inhibitors, proteinase inhibitors, calpain inhibitors, ribavirin (nucleoside analogues), interferons, and short interfering RNAs were riddled with contradictory reports from different laboratories. The lack of clinical trials also prevented the reaching of a conclusive agreement for effective anti-SARS strategies (reviewed by Weiss et al. 61 ). Nevertheless, human convalescent-phase plasma seemed to shorten hospitalization without adverse effects if it is administered as an immunotherapy to SARS patients early in the course of infection. 62 With the finding that recovered SARS patients have higher and more sustainable levels of neutralizing antibodies when compared to those who had succumbed to the disease, 63 monoclonal antibodies for passive immunization were also obtained using phage-display antibody libraries and immortalization of B cells from convalescent SARS patients. 64, 65 Although it is still not known whether naturally acquired immune responses can confer protection from re-infection of SARS-CoV, vaccines are likely to be the most effective way to provide protection against a future re-emergence of SARS-CoV. Several strategies for vaccine development included DNA vaccines, inactivated whole virus vaccines, 66, 67 virus-like particles, 68,69 recombinant virus vector vaccines, 70 and recombinant protein vaccine. 71 Most SARS-CoV vaccines that elicited neutralizing antibodies are believed to be protective, but as described, T cells may also play an important role in viral clearance in a primary SARS-CoV infection. 72, 73 Zhao et al. suggested that inefficient immune activation and a poor virus-specific T cell response underlay severe disease in SARS-CoV infected mice. 74 In their recent report, they showed that virus-specific T cells were necessary and sufficient for virus clearance and protection from clinical disease in mouse-adapted SARS-CoV (MA15) virus-infected mice. 73 In addition, CD4 1 T cells in a senescent mouse model were found to play