Association of Virus Load, CD4 Cell Count, and Treatment with Clinical Progression in Human Immunodeficiency Virus–Infected Patients with Very Low CD4 Cell Counts

Miller, Veronica; Phillips, Andrew; Clotet, Bonaventura; Mocroft, Amanda; Ledergerber, Bruno; Kirk, Ole; Ormaasen, Vidar; Gargalianos‐Kakolyris, Panagiotis; Vella, Stefano; Lundgren, Jens D

doi:10.1086/341466

Cited by 56 publications

(44 citation statements)

References 30 publications

(31 reference statements)

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“…Our results are also in agreement with previous reports showing that baseline CD4 cell count and viral load can predict treatment responses in patients with advanced HIV-1 infection treated with effective HAART regimens [17,18]. Surprisingly, IL-7 independently predicted viral load at 48 weeks of treatment, and its prognostic value was not influenced by other baseline variables such as CD4 cell count, viral load and patient characteristics.…”

Section: Discussionsupporting

confidence: 92%

Interleukin‐7 levels may predict virological response in advanced HIV‐1‐infected patients receiving lopinavir/ritonavir‐based therapy

Boulassel

Smith²,

Gilmore³

et al. 2003

HIV Medicine

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ObjectivesTo examine the relationship between levels of the T-cell regulatory cytokine interleukin-7 (IL-7) and CD4 cell counts during immune reconstitution and to assess its prognostic value in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy. MethodsThirty-six HIV-1-infected adults who completed 48 weeks of follow-up visits were included in this prospective study. Patients having failed two or more antiretroviral therapy regimens were treated with lopinavir/ritonavir-based therapy. An enzyme-linked immunosorbent assay was used to determine IL-7 plasma levels, flow cytometry was used to analyse cell surface antigens, and polymerase chain reaction was used to quantify plasma HIV-1. ResultsPretreatment IL-7 levels were elevated in all patients (mean 11.0 pg/mL) and were negatively correlated with CD4 cell counts and age (r 5 À 0.59, Po0.001 and r 5 À 0.57, Po0.001, respectively). During the course of treatment, IL-7 levels decreased by 34% while CD4 cell numbers progressively increased by 88%. Multivariate regression analysis showed that only pretreatment IL-7 levels predicted viral load at 48 weeks when controlling for baseline CD4 cell counts, viral load and patient demographics. ConclusionsThese findings are consistent with regulation of T-cell recovery by IL-7, and suggest that IL-7 measurements might be used to predict virological response. IntroductionThe goal of highly active antiretroviral therapy (HAART) is to suppress HIV-1 replication, thereby permitting a restoration of CD4 cell counts. However, CD4 cell reconstitution is often only partial, and CD4 cell counts rarely return to normal values [1]. The reasons for this incomplete reconstitution are unknown. One possibility is inadequate levels or function of T-cell cytokines and/or growth hormones, as T-cell production is regulated by several cytokines and growth hormones that stimulate the maturation, differentiation and survival of T cells [2,3]. Interleukin-7 (IL-7) is one such cytokine crucial for the thymic production of naive T cells and the survival of mature T cells in blood and lymph nodes. In contrast to other type 1 cytokines, such as IL-2 and IL-4, which are produced mainly by T cells and macrophages, IL-7 is derived from thymic, lymph node and bone marrow epithelial and stromal cells [4]. Because of its particular sites of synthesis and its specific role in lymphopoeisis, IL-7 is considered a master regulator of T-cell homeostasis.T-cell depletion resulting from chemotherapy and bone marrow transplantation is associated with an increase in 315 the level of IL-7 and an increase in the regeneration and expansion of T cells [5]. In addition, elevated IL-7 levels have been observed in HIV-1-infected adults with low CD4 cell counts [6][7][8]. However, few reports have been published regarding changes in IL-7 levels following CD4 reconstitution in advanced HIV-1-infected subjects. In the current study, we examined the associations amongst IL-7 levels, CD4 cell counts and viral replication, over 48 weeks in a cohort of...

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Section: Discussionsupporting

confidence: 92%

Interleukin‐7 levels may predict virological response in advanced HIV‐1‐infected patients receiving lopinavir/ritonavir‐based therapy

Boulassel

Smith²,

Gilmore³

et al. 2003

HIV Medicine

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“…Thus, the association between CXCR4 tropism and inflammation appears to require active viral replication. Additionally, in viremic individuals, the presence of drug resistance mutations has been associated with lower levels of immune activation, rates of CD4 ϩ T cell depletion, and progression to AIDS, independently of HIV RNA levels (28)(29)(30)(31). Our study was the first to examine archived drug resistance mutations in individuals on fully suppressive treatment, and we did not identify a significant association between drug resistance mutations and inflammation.…”

Section: Discussionmentioning

confidence: 69%

“…For instance, the number of mutations conferring drug resistance was inversely correlated with levels of the proinflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-␣), and tumor necrosis factor receptor II (TNF-rII), independent of HIV-1 RNA levels (28). In addition, individuals with documented drug resistance have lower levels of CD4 ϩ and CD8 ϩ T cell activation, experience lower rates of CD4 ϩ depletion, and progress more slowly to AIDS than do untreated HIV-infected individuals, independently of plasma HIV RNA levels (28)(29)(30)(31)(32). The reduced ability of drug-resistant viruses to contribute to disease progression may result from particular drug resistance mutations that impede viral replicative capacity, thus decreasing the activation of bystander T cells (29,33).…”

mentioning

confidence: 99%

Association between Latent Proviral Characteristics and Immune Activation in Antiretrovirus-Treated Human Immunodeficiency Virus Type 1-Infected Adults

Liang

Sceats

Bayless

et al. 2014

J Virol

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Generalized immune activation during HIV infection is associated with an increased risk of cardiovascular disease, neurocognitive disease, osteoporosis, metabolic disorders, and physical frailty. The mechanisms driving this immune activation are poorly understood, particularly for individuals effectively treated with antiretroviral medications. We hypothesized that viral characteristics such as sequence diversity may play a role in driving HIV-associated immune activation. We therefore sequenced proviral DNA isolated from peripheral blood mononuclear cells from HIV-infected individuals on fully suppressive antiretroviral therapy. We performed phylogenetic analyses, calculated viral diversity and divergence in the env and pol genes, and determined coreceptor tropism and the frequency of drug resistance mutations. Comprehensive immune profiling included quantification of immune cell subsets, plasma cytokine levels, and intracellular signaling responses in T cells, B cells, and monocytes. These antiretroviral therapy-treated HIV-infected individuals exhibited a wide range of diversity and divergence in both env and pol genes. However, proviral diversity and divergence in env and pol, coreceptor tropism, and the level of drug resistance did not significantly correlate with markers of immune activation. A clinical history of virologic failure was also not significantly associated with levels of immune activation, indicating that a history of virologic failure does not inexorably lead to increased immune activation as long as suppressive antiretroviral medications are provided. Overall, this study demonstrates that latent viral diversity is unlikely to be a major driver of persistent HIV-associated immune activation. IMPORTANCEChronic immune activation, which is associated with cardiovascular disease, neurologic disease, and early aging, is likely to be a major driver of morbidity and mortality in HIV-infected individuals. Although treatment of HIV with antiretroviral medications decreases the level of immune activation, levels do not return to normal. The factors driving this persistent immune activation, particularly during effective treatment, are poorly understood. In this study, we investigated whether characteristics of the latent, integrated HIV provirus that persists during treatment are associated with immune activation. We found no relationship between latent viral characteristics and immune activation in treated individuals, indicating that qualities of the provirus are unlikely to be a major driver of persistent inflammation. We also found that individuals who had previously failed treatment but were currently effectively treated did not have significantly increased levels of immune activation, providing hope that past treatment failures do not have a lifelong "legacy" impact.

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“…Based on the results of randomized trials and observational cohorts which focused on the high risk of disease progression, the initiation of antiretroviral treatment is strongly recommended in all patients with a CD4+ T cell count < 200/mm 3 [4,8,21,29] (A-I). In these patients antiretroviral treatment should be started as soon as possible (A-II) and be coupled with both a previous comprehensive clinical as well as pharmacological evaluation and an accurate counseling program on adherence to treatment [30] (A-III).…”

Section: General Recommendationsmentioning

confidence: 99%

Italian Consensus Statement on Management of HIV-Infected Individuals with Advanced Disease Naïve to Antiretroviral Therapy

et al. 2009

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Association of Virus Load, CD4 Cell Count, and Treatment with Clinical Progression in Human Immunodeficiency Virus–Infected Patients with Very Low CD4 Cell Counts

Cited by 56 publications

References 30 publications

Interleukin‐7 levels may predict virological response in advanced HIV‐1‐infected patients receiving lopinavir/ritonavir‐based therapy

Interleukin‐7 levels may predict virological response in advanced HIV‐1‐infected patients receiving lopinavir/ritonavir‐based therapy

Association between Latent Proviral Characteristics and Immune Activation in Antiretrovirus-Treated Human Immunodeficiency Virus Type 1-Infected Adults

Italian Consensus Statement on Management of HIV-Infected Individuals with Advanced Disease Naïve to Antiretroviral Therapy

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