Maximum suppression of HIV replication leads to the restoration of HIV-specific responses in early HIV disease

Al‐Harthi, Lena; Siegel, Joan N.; Spritzler, John; Pottage, John C.; Agnoli, Michelle; Landay, Alan

doi:10.1097/00002030-200005050-00001

Cited by 89 publications

(61 citation statements)

References 32 publications

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“…The clinical characteristics of the HIV-1-infected subjects are shown in Table 4. The 22 HIV-1-infected donors initially tested were receiving combination antiretroviral therapy (three or more agents), with peripheral CD4 counts ranging from 43 to 856 cells/mm 3 (mean, 482 cells/mm 3 ) and plasma HIV-1 RNA viral loads ranging from Ͻ20 to 89,520 viral copies/ml of plasma (73% with viral loads of Ͻ400 copies/ml of plasma HIV-1 RNA).…”

Section: Resultsmentioning

confidence: 99%

Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes

Wilson

Palmer

Southwood³

et al. 2001

J Virol

101

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Section: Resultsmentioning

confidence: 99%

Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes

Wilson

Palmer

Southwood³

et al. 2001

J Virol

101

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“…Hyperimmune activation, rather than direct cytopathic effects of the virus, is likely to be responsible for much of the dysregulation associated with HIV/AIDS. 47,48 Although we have classified HIV-infected p24 Ϫ cells as bystander cells that are not productively infected, these cells may indeed have been infected by HIV but either do not actively replicate the virus or have become p24 Ϫ . Nonetheless, these cells behaved very similarly to mock-infected cells for most parameters examined, suggesting that even if HIV entered these cells, it did not alter their biologic properties.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

Bahbouhi

Landay

Al‐Harthi

2004

Blood

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Using intracellular p24 staining to discriminate between bystander and HIV productively infected cells, we evaluated the properties of HIV productively infected cells in terms of cytokine expression, activation status, apoptosis, and cell proliferation. We demonstrate that HIV productively infected primary CD4 ؉ T cells express 12-to 47-fold higher type 1 cytokines than bystander or mock-infected cells. The frequency of HIV productive replication occurred predominantly in Thelper 1 (Th1), followed by Th0, then by Th2 cells. These productively infected cells expressed elevated levels of CD95, CD25, CXC chemokine receptor 4 (CXCR4), and CC chemokine receptor 5 (CCR5). While productively infected cells were only 1.8-fold higher in apoptosis frequency, they up-regulated the antiapoptotic protein B-cell leukemia 2 (Bcl-2) by 10-fold. Up-regulation of interleukin-2 (IL-2) and Bcl-2 were dependent on phosphatidylinositol-3-kinase signal transduction, given that it was down-regulated by Wortmanin treatment. Additionally, 60% of productively infected cells entered the cell cycle, as evaluated by Ki67 staining, but none divided, as evaluated by carboxyfluoresccin diacetate succinimidyl ester (CFSE) staining. Evaluation of cell cycle progression by costaining for DNA and RNA indicated that the cells were arrested in G 2 /M. Collectively, these data indicate that HIV replication occurs predominantly in Th1 cells and is associated with immune activation and up-regulation of Bcl-2, conferring a considerable degree of protection against apoptosis in the productively infected subpopulation. IntroductionThe interaction between cytokines and HIV expression is multifaceted. Approaches to evaluate the relationship between cytokines and HIV have relied on (1) evaluating the impact of a particular cytokine on HIV replication in vitro, [1][2][3][4][5] (2) comparing the cytokine expression profile of HIV-infected and uninfected donors, 6,7 and (3) measuring cytokine production from in vitro infected cells. [8][9][10] Analysis of the impact of cytokines on HIV-1 replication in vitro have generally demonstrated that a number of type 1 cytokines (interleukin-1 [IL-1], tumor necrosis factor-␣ [TNF-␣], IL-2, IL-12) up-regulate HIV replication while type 2 cytokines down-modulate HIV (IL-10, transforming growth factor-␤ [TGF-␤]). This relationship is not simplistic given that a combination of type 1 and type 2 cytokines may lead to a synergistic or antagonistic effects on HIV replication [11][12][13][14] ; this result often depends on the combination of cytokines and on the cell type examined, whether lymphocytic or monocytic.Earlier studies describing the cytokine profile in purified peripheral blood mononuclear cells (PBMCs) from HIV ϩ patients have led to discordant findings. Some suggested that HIV-1 infection leads to a shift from type 1 (IL-2, interferon-␥ [IFN-␥]) to type 2 (IL-4, IL-10) cytokines with HIV disease progression. 6 By contrast, others have not been able to document such a type 1-to-type 2 cytokine shift with disease pro...

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“…ART Intervention in primary HIV disease may protect HIV-specific T helper responses [30][31][32] but likewise treating patients in chronic HIV disease with CD4+ T cell count > 500 cells/mm 3 , also preserved CD4+ HIV-specific T-helper immune responses [33]. Hence, it is still not clear if there is an added benefit for treating acutely infected HIV+ patients [18].…”

Section: Discussionmentioning

confidence: 99%

Immunophenotypic alterations in acute and early HIV infection

Al‐Harthi¹,

MaWhinney²,

Connick³

et al. 2007

Clinical Immunology

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To understand the extent of immune dysregulation in primary HIV infection (PHI) and the impact of antiretroviral therapy (ART) on restoring these abnormalities, we longitudinally evaluated 52 subjects {Acute Treated (AT); Early Treated (ET); Early Untreated (EU)) for markers of activation, proliferation, and function on T cells. ET and AT patients differed by 0.54 log viral load (VL) at baseline but did not differ thereafter by more than 0.34 log10 VL. AT subjects had higher CD8+ T cell counts and expression of markers indicative of CD8+ T cell activation (CD38), and proliferation (Ki67), at baseline, than ET subjects but were not different post-48 weeks of ART. Although acute PHI is marked by higher level of immune activation than early PHI, virologic and immunologic responses were similar post-ART, suggesting that the extent of immunologic recovery is not negatively impacted by a delay of treatment beyond the acute stage of disease.

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Maximum suppression of HIV replication leads to the restoration of HIV-specific responses in early HIV disease

Abstract: This is one of the first studies to demonstrate the restoration of HIV-1 specific responses in non-acute HIV infection, suggesting early intervention with potent antiretroviral therapy may reverse immune-mediated damage not seen with treated patients who have more advanced disease.

Cited by 89 publications

References 32 publications

Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes

Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

Immunophenotypic alterations in acute and early HIV infection

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