coping with viral diversity in hiv vaccine design艾滋病疫苗设计中应对病毒的多样性.pdfVIP

Coping with Viral Diversity in HIV Vaccine Design 1 1 1¤a 2 1 1¤b David C. Nickle , Morgane Rolland , Mark A. Jensen , Sergei L. Kosakovsky Pond , Wenjie Deng , Mark Seligman , 3 1* 3 David Heckerman , James I. Mullins , Nebojsa Jojic 1 Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America, 2 Department of Pathology, University of California San Diego, La Jolla, California, United States of America, 3 Microsoft Research, Redmond, Washington, United States of America The ability of human immunodeficiency virus type 1 (HIV-1) to develop high levels of genetic diversity, and thereby acquire mutations to escape immune pressures, contributes to the difficulties in producing a vaccine. Possibly no single HIV-1 sequence can induce sufficiently broad immunity to protect against a wide variety of infectious strains, or block mutational escape pathways available to the virus after infection. The authors describe the generation of HIV-1 immunogens that minimizes the phylogenetic distance of viral strains throughout the known viral population (the center of tree [COT]) and then extend the COT immunogen by addition of a composite sequence that includes high- frequency variable sites preserved in their native contexts. The resulting COTþ antigens compress the variation found in many independent HIV-1 isolates into lengths suitable for vaccine immunogens. It is possible to capture 62% of the variation found in the Nef protein and 82% of the variation in the Gag protein into immunogens of three gene lengths. The authors put forward immunogen designs that maximize representation of the diverse antigenic featu