Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection1,2,3. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development.
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We thank the Advanced Computing Laboratory at the Los Alamos National Lab for providing time on the Nirvana supercomputer for the maximum likelihood phylogenetic analysis, and Tanmoy Bhattacharya for his advice. This study was supported by the Doris Duke Charitable Foundation (M.A., E.S.R.,B.D.W.), the NIH (M.A., E.S.R., B.D.W.), the Foundation for AIDS & Immune Research (M.A.), and the Partners/Fenway/Shattuck Center for AIDS Research (T.A., X.G.Y.). B.D.W. is the recipient of a Doris Duke Distinguished Clinical Scientist Award; B.T.K. and P.J.R.G. are recipients of the Elizabeth Glaser Scientist Award.
The authors declare that they have no competing financial interests.
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New England Journal of Medicine (2019)
HIV controllers suppress viral replication and evolution and prevent disease progression following intersubtype HIV-1 superinfection
PLOS Pathogens (2018)
Journal of Virology (2018)
Frontiers in Microbiology (2018)