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.
Abstract
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.
HIV-specific cytolytic CD4 T cell responses during acute HIV
infection predict disease outcome.
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.
Abstract
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.
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