title: HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome.
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.
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Damien Z
authors.initials: DZ
authors.lastname: Soghoian
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.forename: Michael
authors.initials: M
authors.lastname: Flanders
authors.forename: Kailan
authors.initials: K
authors.lastname: Sierra-Davidson
authors.forename: Sam
authors.initials: S
authors.lastname: Cutler
authors.forename: Thomas
authors.initials: T
authors.lastname: Pertel
authors.forename: Srinika
authors.initials: S
authors.lastname: Ranasinghe
authors.forename: Madelene
authors.initials: M
authors.lastname: Lindqvist
authors.forename: Isaiah
authors.initials: I
authors.lastname: Davis
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lane
authors.forename: Jenna
authors.initials: J
authors.lastname: Rychert
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Alicja
authors.initials: A
authors.lastname: Piechocka-Trocha
authors.forename: Abraham L
authors.initials: AL
authors.lastname: Brass
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Hendrik
authors.initials: H
authors.lastname: Streeck
mesh_terms: D015415:Biomarkers / Q000097:blood; D001900:Boston; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D005858:Germany; D053804:Granzymes / Q000378:metabolism; D015658:HIV Infections / Q000175:diagnosis / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000821:virology; D010641:Phenotype; D011379:Prognosis; D012367:RNA, Viral / Q000097:blood; D013997:Time Factors; D019562:Viral Load; D014779:Virus Replication
chemical_list: D015415:Biomarkers; D012367:RNA, Viral; D053804:Granzymes; C509212:GZMA protein, human