The Breadth of Expandable Memory CD8+ T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers.
Previous studies have shown that elite controllers with minimal effector T cell responses harbor a low-frequency, readily expandable, highly functional, and broadly directed memory population. Here, we interrogated the in vivo relevance of this cell population by investigating whether the breadth of expandable memory responses is associated with the magnitude of residual viremia in individuals achieving durable suppression of HIV infection. HIV-specific memory CD8(+) T cells were expanded by using autologous epitopic and variant peptides. Viral load was measured by an ultrasensitive single-copy PCR assay. Following expansion, controllers showed a greater increase in the overall breadth of Gag responses than did untreated progressors (P = 0.01) as well as treated progressors (P = 0.0003). Nef- and Env-specific memory cells expanded poorly for all groups, and their expanded breadths were indistinguishable among groups (P = 0.9 for Nef as determined by a Kruskal-Wallis test; P = 0.6 for Env as determined by a Kruskal-Wallis test). More importantly, we show that the breadth of expandable, previously undetectable Gag-specific responses was inversely correlated with residual viral load (r = -0.6; P = 0.009). Together, these data reveal a direct link between the abundance of Gag-specific expandable memory responses and prolonged maintenance of low-level viremia. Our studies highlight a CD8(+) T cell feature that would be desirable in a vaccine-induced T cell response.


OBJECTIVE
Many studies have shown that the rare ability of some individuals to control HIV infection in the absence of antiretroviral therapy appears to be heavily dependent upon special HIV-specific killer T lymphocytes that are able to inhibit viral replication. The identification of key features of these immune cells has the potential to inform rational HIV vaccine design. This study shows that a special subset of killer lymphocytes, known as central memory CD8(+) T lymphocytes, is at least partially involved in the durable control of HIV replication. HIV controllers maintain a large proportion of Gag-specific expandable memory CD8(+) T cells involved in ongoing viral suppression. These data suggest that induction of this cell subset by future HIV vaccines may be important for narrowing possible routes of rapid escape from vaccine-induced CD8(+) T cell responses.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
Zaza M
ZM
Ndhlovu
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
Eleni
E
Stampouloglou
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
Kevin
K
Cesa
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
Orestes
O
Mavrothalassitis
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
Donna Marie
DM
Alvino
Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Jonathan Z
JZ
Li
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
Shannon
S
Wilton
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
Daniel
D
Karel
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
Alicja
A
Piechocka-Trocha
Vaccine and Immunotherapy Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Huabiao
H
Chen
Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Florencia
F
Pereyra
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa bwalker@mgh.harvard.edu.
Bruce D
BD
Walker
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D015683:Gene Products, gag / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D008404:Massachusetts; D016133:Polymerase Chain Reaction / Q000379:methods; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D019562:Viral Load
D015683:Gene Products, gag