Among the many tasks of the immune system, the responsibility for recognizing and killing virus-infected cells falls largely to the subset of CD8 T cells designated cytotoxic T-lymphocytes (CTL). Whether CD4 T cells (traditionally called just “helper” cells) can exert cytotoxic functions has historically been controversial, but over the past decade studies have convincingly documented the existence of cytotoxic CD4 T-cell responses in a variety of different settings, including HIV and SIV infection (as previously covered on this blog). A new paper in the open-access journal Retrovirology from Jonah Sacha’s research group at Oregon Health and Science University now reports that not only are cytotoxic CD4 T-cell responses detectable in macaques controlling a pathogenic SIV isolate, but they can drive the selection of immune escape mutations. As the authors note, this represents compelling evidence that CD4 T cells can directly suppress viral replication.
Although I neglected to highlight it on the blog at the time of publication, a human study from the laboratory of Hendrick Streeck also argues for a key role of cytotoxic CD4 T-cell responses in controlling HIV. Published in Science Translational Medicine back in February of this year, the study showed that HIV-specific cytotoxic CD4 T-cell activity predicted superior control of viral load and slower disease progression (as assessed by time to CD4 T-cell count <350, time to ART initiation, or time to viral load >100,000 copies/mm3) in a cohort of acutely HIV-infected individuals.
Taken together, these results further underscore the importance of considering virus-specific CD4 T-cell responses, both in studies of natural control of HIV replication and in attempts to design effective immune-based therapies.
Retrovirology. 2012 Nov 6;9:91. doi: 10.1186/1742-4690-9-91.
Burwitz BJ, Giraldo-Vela JP, Reed J, Newman LP, Bean AT, Nimityongskul FA, Castrovinci PA, Maness NJ, Leon EJ, Rudersdorf R, Sacha JB.
Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 NW 185th, Beaverton, OR, 97006, USA.
BACKGROUND: Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells. RESULTS: Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo. CONCLUSIONS: Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.
Sci Transl Med. 2012 Feb 29;4(123):123ra25. doi: 10.1126/scitranslmed.3003165.
Soghoian DZ, Jessen H, Flanders M, Sierra-Davidson K, Cutler S, Pertel T, Ranasinghe S, Lindqvist M, Davis I, Lane K, Rychert J, Rosenberg ES, Piechocka-Trocha A, Brass AL, Brenchley JM, Walker BD, Streeck H.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard Medical School, Charlestown, MA 02129, USA.
Early immunological events during acute HIV infection are thought to fundamentally influence long-term disease outcome. Whereas the contribution of HIV-specific CD8 T cell responses to early viral control is well established, the role of HIV-specific CD4 T cell responses in the control of viral replication after acute infection is unknown. A growing body of evidence suggests that CD4 T cells-besides their helper function-have the capacity to directly recognize and kill virally infected cells. In a longitudinal study of a cohort of individuals acutely infected with HIV, we observed that subjects able to spontaneously control HIV replication in the absence of antiretroviral therapy showed a significant expansion of HIV-specific CD4 T cell responses-but not CD8 T cell responses-compared to subjects who progressed to a high viral set point (P = 0.038). Markedly, this expansion occurred before differences in viral load or CD4 T cell count and was characterized by robust cytolytic activity and expression of a distinct profile of perforin and granzymes at the earliest time point. Kaplan-Meier analysis revealed that the emergence of granzyme A(+) HIV-specific CD4 T cell responses at baseline was highly predictive of slower disease progression and clinical outcome (average days to CD4 T cell count <350/μl was 575 versus 306, P = 0.001). These data demonstrate that HIV-specific CD4 T cell responses can be used during the earliest phase of HIV infection as an immunological predictor of subsequent viral set point and disease outcome. Moreover, these data suggest that expansion of granzyme A(+) HIV-specific cytolytic CD4 T cell responses early during acute HIV infection contributes substantially to the control of viral replication.