Immunophenotypic alterations in acute and early HIV infection

Al‐Harthi, Lena; MaWhinney, Sam; Connick, Elizabeth; Schooley, Robert T.; Forster, Jeri E.; Benson, Constance A.; Thompson, Melanie; Judson, Franklyn N.; Palella, Frank J.; Landay, Alan

doi:10.1016/j.clim.2007.08.011

Cited by 10 publications

(7 citation statements)

References 41 publications

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“…However, chronic immune activation remains a hallmark of pathogenic HIV infections and correlates with disease progression [110,114,115]. The activation of CD4+ T cells as determined by surface expression of activation markers like Ki67, HLA-DR, CD25 and CD38 [116,117] has been associated with HIV disease progression. In fact immune activation is a better predictor of disease progression than plasma viremia [118,119,120,121].…”

Section: Immune Activation In Hiv Disease Progressionmentioning

confidence: 99%

HIV-1 Induced Bystander Apoptosis

Garg

Mohl

Joshi

2012

Viruses

105

111

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Apoptosis of uninfected bystander cells is a key element of HIV pathogenesis and believed to be the driving force behind the selective depletion of CD4+ T cells leading to immunodeficiency. While several viral proteins have been implicated in this process the complex interaction between Env glycoprotein expressed on the surface of infected cells and the receptor and co-receptor expressing bystander cells has been proposed as a major mechanism. HIV-1 utilizes CD4 as the primary receptor for entry into cells; however, it is the viral co-receptor usage that greatly influences CD4 decline and progression to AIDS. This phenomenon is relatively simple for X4 viruses, which arise later during the course of the disease, are considered to be highly fusogenic, and cause a rapid CD4+ T cell decline. However, in contrast, R5 viruses in general have a greater transmissibility, are encountered early during the disease and have a lesser pathogenic potential than the former. The above generalization gets complicated in numerous situations where R5 viruses persist throughout the disease and are capable of causing a rigorous CD4+ T cell decline. This review will discuss the multiple factors that are reported to influence HIV induced bystander apoptosis and pathogenesis including Env glycoprotein phenotype, virus tropism, disease stage, co-receptor expression on CD4+ T cells, immune activation and therapies targeting the viral envelope.

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Section: Immune Activation In Hiv Disease Progressionmentioning

confidence: 99%

HIV-1 Induced Bystander Apoptosis

Garg

Mohl

Joshi

2012

Viruses

105

111

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“…Nevertheless, chronic immune activation remains a hallmark of pathogenic HIV infections [115;116]. The activation of CD4+ T cells as determined by surface expression of activations markers like Ki67, HLA-DR, CD25 and CD38 [117;118] have been associated with HIV disease progression. In fact immune activation is a better predictor of CD4 apoptosis than plasma viremia [119–122].…”

Section: Immune Activation and Hiv Pathogenesismentioning

confidence: 99%

Role of HIV Gp41 mediated fusion/hemifusion in bystander apoptosis

Garg

Blumenthal

2008

Cell. Mol. Life Sci.

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Mechanisms of HIV-mediated CD4+ T cell loss leading to immunodeficiency are amongst the most extensively studied yet unanswered questions in HIV biology. The level of CD4+ T cell depletion in HIV infected patients far exceeds the number of infected T cells suggesting an indirect mechanism of HIV pathogenesis termed bystander cell death. Evidence is accumulating that the HIV envelope glycoprotein (Env) is a major determinant of HIV pathogenesis and plays a critical role in bystander cell death. The complex structure and function of HIV Env makes the determination of the mechanism of Env mediated apoptosis more complex than previously thought. This review will examine the complex relationship between HIV Env phenotype, coreceptor expression and immune activation in determining HIV pathogenesis. We review data here corresponding to the role of HIV Env (hemi) fusion activity in HIV pathogenesis and how it interplays with other AIDS associated factors like chemokine receptor expression and immune activation. KeywordsHIV-1; Env; pathogenesis; fusion; hemifusion; apoptosis Envelope glycoprotein structure and functionThe Envelope glycoprotein (Env) of HIV is arranged on the surface of the virus and virusinfected cells as a hetero-trimer. Each monomer is composed of a receptor-binding surface unit (gp120) and a fusogenic gp41 transmembrane unit [1]. The gp120 subunit binds to CD4 and a coreceptor either CXCR4 or CCR5 on T helper cells. Binding of HIV gp120 to CD4 triggers a complex sequence of events ( Figure 1) involving several conformational changes in gp120 that result in exposure of coreceptor binding sites on gp120 and the N-terminal and C-terminal heptad repeat regions of gp41. Following engagement of gp120 with coreceptor, the gp41 heptad repeat domains interact with each other to form a six helix bundle catalyzing fusion of target and viral membranes [2]. Elucidation of mechanisms of fusion mediated by gp41 has been facilitated by high resolution determination of the gp41 core structure and by inhibition studies using peptides that mimic N or C-terminal heptad repeat sequences and interact with intermediate conformations of gp41 [3][4][5][6][7]. Although the function of HIV Env glycoprotein is to facilitate the entry of viral nucleocapsid into the target cell, its role in HIV pathogenesis is becoming increasingly evident [8]. . These steps include hemifusion and the opening of small fusion pores [10]. Hemifusion is defined as a membrane fusion event characterized by the mixing of the outer leaflets of the lipid bilayer without progression to fusion pore formation [11]. In the case of influenza hemagglutinin-expressing cells that fuse with red blood cells, stable hemifusion intermediates have been identified [12][13][14][15][16]. In the case if HIV-1 Env mediated cell fusion lipid mixing has been observed which is followed by separation of cells and the process does not progress to syncytia formation [17][18][19]. Although the latter process would represent "stunted" fusion rather than hemifusion from a f...

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“…Primary infection with the human immunodeficiency virus type-1 (HIV) is a crucial moment for establishing relationships between virus and host [1], [2], [3]. The high plasma viral load (pVL) causes a relevant and persistent immune activation that can trigger apoptosis [6]–[8], and becomes chronic in the absence of a valid immune response or without efficient antiretroviral therapy.…”

Section: Introductionmentioning

confidence: 99%

T Cell Activation but Not Polyfunctionality after Primary HIV Infection Predicts Control of Viral Load and Length of the Time without Therapy

et al. 2012

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ObjectiveImmune changes occurring after primary HIV infection (PHI) have a pivotal relevance. Our objective was to characterize the polyfunctionality of immune response triggered by PHI, and to characterize immune activation and regulatory T cells, correlating such features to disease progression.Patients and MethodsWe followed 11 patients experiencing PHI for 4 years. By polychromatic flow cytometry, we studied every month, for the first 6 months, T lymphocyte polyfunctionality after cell stimulation with peptides derived from HIV-1 gag and nef. Tregs were identified by flow cytometry, and T cell activation studied by CD38 and HLA-DR expression.ResultsAn increase of anti-gag and anti-nef CD8+ specific T cells was observed 3 months after PHI; however, truly polyfunctional T cells, also able to produce IL-2, were never found. No gross changes in Tregs were present. T lymphocyte activation was maximal 1 and 2 months after PHI, and significantly decreased in the following period. The level of activation two months after PHI was strictly correlated to the plasma viral load 1 year after infection, and significantly influenced the length of period without therapy. Indeed, 80% of patients with less than the median value of activated CD8+ (15.5%) or CD4+ (0.9%) T cells remained free of therapy for >46 months, while all patients over the median value had to start treatment within 26 months.ConclusionsT cell activation after PHI, more than T cell polyfunctionality or Tregs, is a predictive marker for the control of viral load and for the time required to start treatment.

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Immunophenotypic alterations in acute and early HIV infection

Cited by 10 publications

References 41 publications

HIV-1 Induced Bystander Apoptosis

HIV-1 Induced Bystander Apoptosis

Role of HIV Gp41 mediated fusion/hemifusion in bystander apoptosis

T Cell Activation but Not Polyfunctionality after Primary HIV Infection Predicts Control of Viral Load and Length of the Time without Therapy

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