Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load

Abstract

Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation "set point" is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4 ؉ and CD8 ؉ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviraltreated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8 ؉ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10 000 copies/mL. Among untreated patients, the level of CD8 ؉ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8 ؉ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4 ؉ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4 ؉ T cells are lost over time. IntroductionUntreated HIV-1 infection is associated with a gradual loss of peripheral CD4 ϩ T cells. Although the direct cytopathic effect of HIV-1 on CD4 ϩ T cells almost certainly contributes to this gradual depletion, 1 most cells destined to die in vivo as a consequence of HIV infection are not productively infected with HIV. 2 This observation has led to the hypothesis that progressive CD4 ϩ T-cell depletion occurs due to indirect effects of viral replication. [3][4][5][6] The mechanism for these indirect effects of HIV replication on CD4 ϩ T-cell depletion is not understood.One widely accepted model postulates that HIV causes accelerated proliferation, expansion, and death of T cells, and that this heightened T-cell turnover eventually results in depletion or exhaustion of the regenerative capacity of the immune system. 4,5 Multiple studies have shown that HIV infection results in a state of high T-cell turnover (ie, the rates of T-cell proliferation and death are increased). For example, in vivo labeling of T cells indicates that HIV infection results in increased numbers of rapidly cycling CD4 ϩ and CD8 ϩ T cells. 7,8 These cells are primarily of memoryeffector phenotype, and are destined to proliferate and die rapidly. 9 The rate at which HIV recruits cells into this rapid turnover state is directly proportional to the level of viremia, 8 which in turn is directly related to the rate at which CD4 ϩ T cells are lost. 10 In the absence of antiretroviral treatment, markers of T-cell activation and T-cell turnover predict the rate of disease progression 11-14 and the rate of CD4 ϩ T-cell loss. 15 When antiretroviral therapy is initiated, the rate of T-cell turnover and the degree of generalized T-cell activation both decrease, suggest...

Inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in SIVmac239-infected Chinese rhesus macaques

“…1 Recently, it has been accepted that in addition to the direct infection of CD4 1 T lymphocytes by HIV virions, chronic immune activation in HIV-infected human and simian immunodeficiency virus (SIV)-infected non-natural hosts, such as rhesus macaques and cynomolgus macaques, may greatly contribute to the pathogenesis of AIDS. [2][3][4][5][6][7] Accumulated evidence suggests that large amounts of type I interferons (IFNs) produced by activated plasmacytoid dendritic cells (pDCs) might play a critical role in this chronic immune activation during HIV-1 infection. Clinical strategies aimed at inhibiting pDC activation could effectively counter disease progression in HIV patients.…”

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…Importantly, the tempo of HIV-and SIV-associated CD4 ϩ T-cell depletion is related to both the set-point level of viremia and the magnitude of virus-associated chronic immune activation (1,5). HIV/ SIV-associated chronic immune activation is characterized by polyclonal B-cell activation (6), high T-cell turnover of both CD4 ϩ and CD8 ϩ T cells with an enhanced cell surface expression of molecules indicative of cell activation (7), and high levels of circulating proinflammatory cytokines and chemokines (8).…”

Lymphocyte Subset (CD3, CD4 and CD8 Cells) and their Ratios in HIV patients on Highly Active Antiretroviral Therapy (HAART) and HAART Naïve Patients

“…Clinical studies conducted by Golgi and colleagues concluded that excessive immune activation leads to immune dysfunction in chronic HIV patients. The findings showed that CD38 a maker of CD8 T cell and HLA-DR expression negatively correlate better with the worse condition of HIV infected persons than viral load [3][4][5]. So as CD4+ T-cell numbers decrease in HIV condition, HLA-DR+ and CD38+ CD8+ T lymphocytes rather appreciate in numbers [5].…”

“…However, the ratio of CD4/CD3 was significantly lower among treatment and treatment naïve HIV infected participants compared to control. The low level of CD4/CD3 exhibit a steady progression of the HIV infection [5,7] and is used to monitor some forms of immunodeficiency [4]. The association between low CD4+ T-cell count may possibly be explained by chronic inflammation in immunosuppressed HIV-infected individuals [21].…”