Abstract
Improved understanding of the dynamics of host immune responses and viral evolution is critical for effective HIV-1 vaccine design. We comprehensively analyzed Cytotoxic T-lymphocyte (CTL)-viral epitope dynamics in an antiretroviral therapy-naïve subject over the first four years of HIV-1 infection. We found that CTL responses developed sequentially and required constant antigenic stimulation for maintenance. CTL responses exerting strong selective pressure emerged early and led to rapid escape, proliferated rapidly and were predominant during acute/early infection. Although CTL responses to a few persistent epitopes developed over the first two months of infection, they proliferated slowly. As CTL epitopes were replaced by mutational variants, the corresponding responses immediately declined, most rapidly in the cases of strongly selected epitopes. CTL recognition of epitope variants, via cross-reactivity and de novo responses, was common throughout the period of study. Our data demonstrate that HIV-specific CTL responses, especially in the critical acute/early stage, were focused on regions that are prone to escape. Failure of CTL responses to strongly target functional or structurally critical regions of the virus, as well as the sequential cascade of CTL responses, followed closely by viral escape and decline of the corresponding responses, likely contribute to a lack of sustainable viral suppression. Focusing early and rapidly proliferating CTL on persistent epitopes may be essential for durable viral control in HIV-1 infection.
Highlights
Cytotoxic T-lymphocyte (CTL) responses are associated with variable levels of HIV-1 infection control [1,2,3], yet these responses are unable to clear the virus
For epitopes against which CTL responses peaked at over 1000 spot forming cells (SFC)/ 106 peripheral blood mononuclear cells (PBMC), we found that stronger selection correlated with responses reaching this level earlier (p,0.0001, Spearman rank coefficient; Figure 5A) and faster (p,0.0001, Figure 5B)
We comprehensively analyzed the dynamics of CTL responses and viral evolution over the first four years of HIV-1 infection of an antiretroviral therapy-naıve subject
Summary
Cytotoxic T-lymphocyte (CTL) responses are associated with variable levels of HIV-1 infection control [1,2,3], yet these responses are unable to clear the virus. Viruses are able to evade CTL responses via mutations both within and flanking the epitopes [4,5,6,7], and selection for escape mutants is a major driving force of HIV-1 evolution [6,8,9,10]. Decay of corresponding CTL responses [11,12] and generation of responses directed towards mutants and epitopes at new locations have been observed [8,13,14,15,16,17]. Goonetilleke et al [11] comprehensively examined the dynamics of primary HIV-1-specific CTL responses in three acutely infected subjects and found that these responses rapidly selected escape mutations, rapidly waned afterwards, and were followed by responses to epitopes that escaped more slowly or were invariant. The dynamics of later CTL responses and CTL responses to epitope variants were not clear
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