Limited HIV infection of central memory and stem cell memory CD4+ T cells is associated with lack of progression in viremic individuals (original) (raw)
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Journal of Experimental Medicine, 2003
CD4 ϩ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester-based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4 ϩ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4 ϩ T cells were identified in aviremic patients, CD45RA Ϫ CCR7 ϩ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA Ϫ CCR7 Ϫ effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-␥ . In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-␥ . Longitudinal analysis of HIV epitope-specific CD4 ϩ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-␥producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4 ϩ T cell memory depends on IL-2-producing CD4 ϩ T cells and that IFN-␥ only-producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-␥ only-producing cells that lack self-renewal capacity.
AIDS Research and Treatment, 2012
Objectives. We investigated immune phenotypes of HIV+ patients who present late, considering late presenters (LPs, CD4+ < 350/μL and/or AIDS), advanced HIV disease (AHD, CD4+ < 200/μL and/or AIDS), and AIDS presenters (AIDS-defining condition at presentation, independently from CD4+).Methods. Patients newly diagnosed with HIV at our clinic between 2007–2011 were enrolled. Mann-Whitney/Chi-squared tests and logistic regression were used for statistics.Results. 275 patients were newly diagnosed with HIV between January/2007–March/2011. 130 (47%) were LPs, 79 (29%) showed AHD, and 49 (18%) were AIDS presenters. LP, AHD, and AIDS presenters were older and more frequently heterosexuals. Higher CD8+%, lower CD127+CD4+%, higher CD95+CD8+%, CD38+CD8+%, and CD45R0+CD38+CD8+% characterized LP/AHD/AIDS presentation. In multivariate analysis, older age, heterosexuality, higher CD8+%, and lower CD127+CD4+% were confirmed associated with LP/AHD. Lower CD4+ and higher CD38+CD8+% resulted ind...
The Journal of Immunology, 2010
The functional integrity of CD4 + T cells is crucial for well-orchestrated immunity and control of HIV-1 infection, but their selective depletion during infection creates a paradox for understanding a protective response. We used multiparameter flow cytometry to measure activation, memory maturation, and multiple functions of total and Ag-specific CD4 + T cells in 14 HIV-1-and CMVcoinfected individuals at 3 and 12 mo post HIV-1 infection. Primary HIV-1 infection was characterized by elevated levels of CD38, HLA-DR, and Ki67 in total memory and Gag-specific CD4 + and CD8 + T cells. In both HIV-infected and 15 uninfected controls, the frequency of activated cells was uniformly distributed among early differentiated (ED; CD45RO + CD27 + ), late differentiated (CD45RO + CD27 2 ), and fully differentiated effector (CD45RO 2 CD27 2 ) memory CD4 + T cells. In HIV-1-infected individuals, activated CD4 + T cells significantly correlated with viremia at 3 mo postinfection (r = 0.79, p = 0.0007) and also harbored more gag provirus DNA copies than nonactivated cells (p = 0.04). Moreover, Gag-specific ED CD4 + T cells inversely associated with plasma viral load (r = 20.87, p , 0.0001). Overall, we show that low copy numbers of gag provirus and plasma RNA copies associated with low CD4 activation as well as accumulation of ED HIV-specific CD4 + memory. Significant positive correlations between 3 and 12 mo activation and memory events highlighted that a steady state of CD4 + T cell activation and memory maturation was established during primary infection and that these cells were unlikely to be involved in influencing the course of viremia in the first 12 mo of HIV-1 infection.
Cells
Several studies have identified main changes in T- and B-lymphocyte subsets during chronic HIV infection, but few data exist on how these subsets behave during the initial phase of HIV infection. We enrolled 22 HIV-infected patients during the acute stage of infection before the initiation of antiretroviral therapy (ART). Patients had blood samples drawn previous to ART initiation (T0), and at 2 (T1) and 12 (T2) months after ART initiation. We quantified cellular HIV-DNA content in sorted naïve and effector memory CD4 T cells and identified the main subsets of T- and B-lymphocytes using an 18-parameter flow cytometry panel. We identified correlations between the patients’ clinical and immunological data using PCA. Effective HIV treatment reduces integrated HIV DNA in effector memory T cells after 12 months (T2) of ART. The main changes in CD4+ T cells occurred at T2, with a reduction of activated memory, cytolytic and activated/exhausted stem cell memory T (TSCM) cells. Changes were...
Viruses, 2014
CD4 + T cells are principal targets for human immunodeficiency virus type 1 (HIV-1) infection. CD4 + T cell subsets are heterogeneous cell populations, divided by functional and phenotypic differences into naï ve and memory T cells. The memory CD4 + T cells are further segregated into central, effector and transitional memory cell subsets by functional, phenotypic and homeostatic characteristics. Defining the distribution of HIV-1 infection in different T cell subsets is important, as this can play a role in determining the size and composition of the viral reservoir. Both central memory and transitional memory CD4 + T cells have been described as long-lived viral reservoirs for HIV. Recently, the newly described stem memory T cell subset has also been implicated as a long-lived HIV
Nature Communications, 2014
In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4+ T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. Here we provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory (TSCM) CD4+ T cells). This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the TSCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies.