title: The CD8⁺ memory stem T cell (T(SCM)) subset is associated with improved prognosis in chronic HIV-1 infection.
abstract: Memory stem T cells (T(SCM)) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. The hallmarks of HIV-1 pathogenesis are CD4(+) T cell depletion and abnormal cellular activation. We investigated the impact of HIV-1 infection on the T(SCM) compartment, as well as any protective role these cells may have in disease progression, by characterizing this subset in a cohort of 113 subjects with various degrees of viral control on and off highly active antiretroviral therapy (HAART). We observed that the frequency of CD8(+) T(SCM) was decreased in all individuals with chronic, untreated HIV-1 infection and that HAART had a restorative effect on this subset. In contrast, natural controllers of HIV-1 had the highest absolute number of CD4(+) T(SCM) cells among all of the infected groups. The frequency of CD4(+) T(SCM) predicted higher CD8(+) T(SCM) frequencies, consistent with a role for the CD4(+) subset in helping to maintain CD8(+) memory T cells. In addition, T(SCM) appeared to be progenitors for effector T cells (TEM), as these two compartments were inversely correlated. Increased frequencies of CD8(+) T(SCM) predicted lower viral loads, higher CD4(+) counts, and less CD8(+) T cell activation. Finally, we found that T(SCM) express the mucosal homing integrin α4β7 and can be identified in gut-associated lymphoid tissue (GALT). The frequency of mucosal CD4(+) T(SCM) was inversely correlated with that in the blood, potentially reflecting the ability of these self-renewing cells to migrate to a crucial site of ongoing viral replication and CD4(+) T cell depletion.
  
  
  OBJECTIVE
  HIV-1 infection leads to profound impairment of the immune system. T(SCM) constitute a recently identified lymphocyte subset with stem cell-like qualities, including the ability to generate other memory T cell subtypes, and are therefore likely to play an important role in controlling viral infection. We investigated the relationship between the size of the CD8(+) T(SCM) compartment and HIV-1 disease progression in a cohort of chronically infected individuals. Our results suggest that HAART restores a normal frequency of CD8(+) T(SCM) and that the natural preservation of this subset in the setting of untreated HIV-1 infection is associated with improved viral control and immunity. Therefore, the CD8(+) T(SCM) population may represent a correlate of protection in chronic HIV-1 infection that is directly relevant to the design of T cell-based vaccines, adoptive immunotherapy approaches, or the pharmacologic induction of T(SCM).
authors.affiliation: Laboratory of Clinical Immunology and Allergy-LIM60, University of São Paulo School of Medicine, São Paulo, Brazil Institute of Investigation in Immunology-iii-INCT, São Paulo, Brazil.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Ribeiro
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Milush
authors.affiliation: Laboratory of Clinical Immunology and Allergy-LIM60, University of São Paulo School of Medicine, São Paulo, Brazil Institute of Investigation in Immunology-iii-INCT, São Paulo, Brazil Laboratory of Immunology, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Edecio
authors.initials: E
authors.lastname: Cunha-Neto
authors.affiliation: Laboratory of Clinical Immunology and Allergy-LIM60, University of São Paulo School of Medicine, São Paulo, Brazil Institute of Investigation in Immunology-iii-INCT, São Paulo, Brazil.
authors.forename: Esper G
authors.initials: EG
authors.lastname: Kallas
authors.affiliation: Laboratory of Clinical Immunology and Allergy-LIM60, University of São Paulo School of Medicine, São Paulo, Brazil Institute of Investigation in Immunology-iii-INCT, São Paulo, Brazil Laboratory of Immunology, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil Butantan Institute, Butantã, São Paulo-SP, Brazil.
authors.forename: Jorge
authors.initials: J
authors.lastname: Kalil
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Ma
authors.initials: M
authors.lastname: Somsouk
authors.affiliation: HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
authors.affiliation: HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Department of Microbiology, Immunology & Tropical Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA devi.sengupta@ucsf.edu.
authors.forename: Devi
authors.initials: D
authors.lastname: SenGupta
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D013234:Stem Cells / Q000276:immunology*