It has been known for decades that the development of a pathogen-specific immune response involves the activation (or “priming”) of naïve CD4 T cells. These cells subsequently divide extensively and, over a matter of weeks, generate memory CD4 T cells that coordinate ongoing surveillance against the pathogen (in many cases protecting against re-infection or, for some persistent infections such as CMV, keeping the pathogen in check for life). Based on this knowledge, it would be logical to surmise that many studies must have been conducted to investigate how this process plays out in HIV infection and the impact of the virus on HIV-specific memory CD4 T cell generation. Surprisingly, this is not the case. A new study in PLoS One represents the first published attempt to evaluate the effect of HIV on T cell priming in an in vitro model. This paper compliments the one detailed in vivo study conducted to date, which was published by Zohn Zaunders and colleagues in 2006.
The researchers, led by Rachel Lubon Sabado from NYU, established an in vitro system in which highly purified naïve CD4 T cells and antigen-presenting dendritic cells (both sampled from uninfected individuals) were exposed to live or inactivated HIV. The inactivated virus was created by chemical treatment with AT-2, a process developed by Larry Arthur and Jeff Lifson at NCI. After prolonged culture, both HIV-specific CD4 and, to a lesser extent, CD8 T cells could be generated. The magnitude of the response was lower when infectious virus was used, suggesting that viral replication impacts the memory T cell differentiation process. In terms of the HIV epitopes targeted, there was considerable overlap with the epitope-specific responses that have previously been described in vivo. The researchers identified some novel CD4 T cell responses against Env and Pol proteins, which led them to evaluate whether these responses might be seen in a cohort of acutely infected individuals. They found that almost all of the novel responses could be seen transiently during acute infection, but declined rapidly and became undetectable in chronic infection.
In discussing the findings, the study authors suggest that understanding why certain HIV-specific CD4 and CD8 T cell responses are rapidly lost in acute infection is an important goal for future research, particularly as long-term non-progressors tend to maintain responses better than individuals with progressive disease. They also note that AT-2-inactivated HIV may be a useful immunogen due to its ability to prime broad memory T cell responses from naïve cells.
One other statement in the discussion is worth highlighting. The researchers write: “The continuous presence of viral antigens gives rise to new memory T cells from the existing naïve population as long as the immune system remains functionally intact and/or the existing naïve T cells can respond to HIV-antigens, thus explaining the highly heterogeneous population of HIV-specific T cells that exist in HIV-infected individuals.” Although this phenomenon has been alluded to in prior studies, the implications for HIV pathogenesis may deserve more careful consideration. In particular, ongoing activation of HIV-specific naïve T cells could contribute to the elevated levels of immune activation that are observed in HIV infection (these activated cells express very high levels of CD38). This would be consistent with the correlation between immune activation and naïve T cell depletion that has been reported in HIV infection. A recent basic immunology study also suggests that depletion of naïve T cells could contribute to microbial translocation, which in turn can further exacerbate immune activation and naïve T cell depletion by broadening the array of antigens being presented to include those from gut bacteria.
PLoS ONE 4(1): e4256 doi:10.1371/journal.pone.0004256
Rachel Lubong Sabado1, Daniel G. Kavanagh2, Daniel E. Kaufmann2, Karlhans Fru4, Ethan Babcock1, Eric Rosenberg2, Bruce Walker2, Jeffrey Lifson3, Nina Bhardwaj1, Marie Larsson4*
1 New York University School of Medicine, New York, New York, United States of America, 2 Partners AIDS Research Center (PARC), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America, 3 SAIC Fredrick, Inc., National Cancer Institute, Fredrick, Frederick, Maryland, United States of America, 4 Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
The requirements for priming of HIV-specific T cell responses initially seen in infected individuals remain to be defined. Activation of T cell responses in lymph nodes requires cell-cell contact between T cells and DCs, which can give concurrent activation of T cells and HIV transmission.
The study aim was to establish whether DCs pulsed with HIV-1 could prime HIV-specific T cell responses and to characterize these responses. Both infectious and aldrithiol-2 inactivated noninfectious HIV-1 were compared to establish efficiencies in priming and the type of responses elicited.
Our findings show that both infectious and inactivated HIV-1 pulsed DCs can prime HIV-specific responses from naïve T cells. Responses included several CD4+ and CD8+ T cell epitopes shown to be recognized in vivo by acutely and chronically infected individuals and some CD4+ T cell epitopes not identified previously. Follow up studies of acute and recent HIV infected samples revealed that these latter epitopes are among the earliest recognized in vivo, but the responses are lost rapidly, presumably through activation-induced general CD4+ T cell depletion which renders the newly activated HIV-specific CD4+ T cells prime targets for elimination.
Our studies highlight the ability of DCs to efficiently prime naïve T cells and induce a broad repertoire of HIV-specific responses and also provide valuable insights to the pathogenesis of HIV-1 infection in vivo.