Following on from the recent post about the importance of virus-specific CD4 T cells in controlling SIV, another new paper adds to the evidence that they also play an important role in HIV infection. Conducted by the laboratory of Hendrik Streeck at the Ragon Institute in collaboration with David Heckerman at Microsoft, the study "represents the first comprehensive analysis conducted at the population level to identify HIV-specific CD4 T cell responses to individual HIV protein subunits and peptides and to elucidate the immunodominance profile of these responses in a large cohort of HIV-controllers and progressors." Given that there has long been an appreciation of the importance of CD4 T cells in immunity against many pathogens, it seems quite remarkable that it has taken until 2011 for such a study to be undertaken. The authors themselves note: "surprisingly little is known about the presence of these responses in the setting of HIV infection."
The main findings include:
- Individuals controlling HIV replication in the absence of treatment have HIV-specific CD4 T cell responses targeting a greater number of peptides on average compared to those with progressive infection (10.9 vs. 6.6).
- The breadth of the HIV-specific CD4 T cell response was inversely correlated with viral load, and this association was driven by CD4 T cells targeting the Gag protein.
- The magnitude of the CD4 T cell response to Gag showed a strong inverse correlation with viral load.
- Responses to Gag were associated with low viral load whereas responses to Env were linked to high viral load, and the ratio between Gag and Env responses was strongly correlated with viral load control: the lowest mean Env/Gag ratio was found in elite controllers (0.20) while the highest mean ratio was in progressors with high viral loads (2.63).
- CD4 T cell responses to three highly conserved Gag epitopes were identified as being strongly predictive of immunological control of HIV replication, independently of host HLA types.
The authors conclude: "Taken together, these data are consistent with our hypothesis that HIV-specific CD4 T cell responses are likely to be beneficial in the control of HIV during chronic infection."
In a separate paper just published online by the Journal of Immunology, Daniel McDermott and Steven Varga report new data on virus-specific CD4 T cells in the context of LCMV infection in mice. The researchers have developed a new method to assess the magnitude of the CD4 T cell response that uses cell surface markers (CD11a and CD49d) as opposed to previously used techniques that rely on measuring responses to specific antigens. By employing this approach, they are able to demonstrate that the CD4 T cell response to LCMV is much larger than prior studies suggested, comprising up to 50% of peripheral blood CD4 T cells in C57BL/6 mice at the peak (versus the 10% estimated previously in the same mouse strain). In the subsequent memory phase of the immune response, approximately 6.5% of CD4 T cells were LCMV-specific, also considerably higher than prior estimates. The researchers note, however, that the genetic background of the mice has a large influence; in the BALB/c mouse strain for example, the peak response was lower at around 15%.
The overall conclusion of the authors is that current methods have significantly underestimated the total magnitude of pathogen-specific CD4 T cell responses; they posit that, in contrast, their new approach can “accurately track the kinetics and magnitude of the entire endogenous CD4 T cell response from the expansion phase into memory.”
JVI Accepts, published online ahead of print on 26 October 2011
J. Virol. doi:10.1128/JVI.05577-11
Srinika Ranasinghe1, Michael Flanders1, Sam Cutler1, Damien Z. Soghoian1, Musie Ghebremichael1, Isaiah Davis1, Madelene Lindqvist1, Florencia Pereyra1, Bruce D. Walker1,2, David Heckerman3, and Hendrik Streeck1
1 Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
2 Howard Hughes Medical Institute, Chevy Chase, MD, USA
3 Microsoft Research, Redmond, Washington, US
A successful prophylactic vaccine is characterized by long-lived immunity, which is critically dependent on CD4 T cell-mediated helper signals. Indeed, most licensed vaccines induce antigen-specific CD4 T cell responses, in addition to high affinity antibodies. However, despite the important role of CD4 T cells in vaccine design and natural infection, few studies have characterized HIV-specific CD4 T cells due to their preferential susceptibility to HIV infection. To establish, on the population level, the impact of HIV-specific CD4 T cells on viral control and define the specificity of HIV-specific CD4 T cell peptide targeting, we conducted a comprehensive analysis of these responses to the entire HIV proteome in 93 subjects at different stages of HIV infection. We show that HIV-specific CD4 T cell responses were detectable in 92% of individuals, and the breadth of these responses showed a significant inverse correlation with viral load (p=0.009, R=-0.31). In particular, CD4 T cell responses targeting Gag were robustly associated with lower viremia (p=0.0002, R=-0.45). Importantly, differences in the immunodominance profile of HIV-specific CD4 T cell responses distinguished HIV controllers from progressors. Furthermore, Gag/Env ratios were a potent marker of viral control; with a high frequency and magnitude of Gag responses and low proportion of Env responses associated with effective immune control. At the epitope-level, targeting of three distinct Gag peptides was linked to spontaneous HIV control (Probability=0.60-0.85). Inclusion of these immunogenic proteins and peptides in future HIV vaccines may act as a critical cornerstone for enhancing protective T cell responses.
The Journal of Immunology
Published online before print October 31, 2011, doi: 10.4049/jimmunol.1102104
Daniel S. McDermott* and Steven M. Varga*,†‡
*Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242;
†Department of Pathology, University of Iowa, Iowa City, IA 52242; and
‡Department of Microbiology, University of Iowa, Iowa City, IA 52242
The number of virus-specific CD8 T cells increases substantially during an acute infection. Up to 90% of CD8 T cells are virus specific following lymphocytic choriomeningitis virus (LCMV) infection. In contrast, studies identifying virus-specific CD4 T cell epitopes have indicated that CD4 T cells often recognize a broader array of Ags than CD8 T cells, consequently making it difficult to accurately quantify the total magnitude of pathogen-specific CD4 T cell responses. In this study, we show that CD4 T cells become CD11ahiCD49d+ after LCMV infection and retain this expression pattern into memory. During the effector phase, all the LCMV-specific IFN-γ+ CD4 T cells display a CD11ahiCD49d+ cell surface expression phenotype. In addition, only memory CD11ahiCD49d+ CD4 T cells make IFN-γ after stimulation. Furthermore, upon secondary LCMV challenge, only CD11ahiCD49d+ memory CD4 T cells from LCMV-immune mice undergo proliferative expansion, demonstrating that CD11ahiCD49d+ CD4 T cells are truly Ag specific. Using the combination of CD11a and CD49d, we demonstrate that up to 50% of the CD4 T cells are virus specific during the peak of the LCMV response. Our results indicate that the magnitude of the virus-specific CD4 T cell response is much greater than previously recognized.