Sousa, A. E., Carneiro, J., Meier-Schellersheim, M., Grossman, Z. & Victorino, R. M. CD4 T-cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J. Immunol. 169, 3400-3406

Clinical Immunology Unit/Institute of Molecular Medicine, Faculty of Medicine of Lisbon, Lisbon, Portugal.
The Journal of Immunology (Impact Factor: 4.92). 10/2002; 169(6):3400-6. DOI: 10.4049/jimmunol.169.6.3400
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The causal relationships among CD4 cell depletion, HIV replication, and immune activation are not well understood. HIV-2 infection, "nature's experiment" with inherently attenuated HIV disease, provides additional insights into this issue. We report the finding that in HIV-2 and HIV-1 patients with a comparable degree of CD4 depletion the imbalance in the relative sizes of the naive and memory T cell populations and the up-regulation of CD4 and CD8 cell activation markers (HLA-DR, CD38, CD69, Fas molecules) are similar, even though the viral load in the plasma of HIV-2-infected patients is two orders of magnitude lower than in HIV-1 patients and HIV-2 patients are known to have slower rates of CD4 T cell decline and a better clinical prognosis. Moreover, we found a similar increase in the frequency of cycling CD4 T cells (Ki67+), which was in strong correlation with the expression of activation markers. Finally, the level of T cell anergy, as assessed by the proliferative responses to CD3 stimulation and to a panel of microbial Ags, proved to be comparable in HIV-1 and HIV-2 patients with a similar degree of CD4 depletion despite large differences in viral load. Our data are consistent with a direct causal relationship between immune activation and CD4 cell depletion in HIV disease and an only indirect relation of these parameters to the virus replication rate. Invoking the concept of proximal immune activation and virus transmission, which links efficient transmission of virus to local cell activation and proliferation in response to Ags and inflammation, we propose an integrative interpretation of the data and suggest that strongly elevated immune activation induces CD4 cell depletion and not vice versa, with potential implications for the choice of treatment strategies.

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    • "Among other immunologic markers of HIV-1 pathogenesis, CD8 activation (Giorgi et al., 1999; Sousa et al., 2002), CD8 exhaustion (Eichbaum, 2011; Hinrichs et al., 2011), CD4:CD8 ratio (Taylor et al., 1989; Zaman et al., 2000; Margolick et al., 2006; Pahwa et al., 2008), and delayed-type hypersensitivity (DTH) to recall antigens (Dolan et al., 2007) can also serve as outcome measures that reflect immunologic health (or lack of). "
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    ABSTRACT: In individuals with human immunodeficiency virus type 1 (HIV-1) infection, CD4:CD8 lymphocyte ratio is often recognized as a quantitative outcome that reflects the critical role of both CD4(+) and CD8(+) T-cells in HIV-1 pathogenesis or disease progression. Our work aimed to first establish the dynamics and clinical relevance of CD4:CD8 ratio in a cohort of native Africans and then to examine its association with viral and host factors, including: (i) length of infection, (ii) demographics, (iii) HIV-1 viral load (VL), (iv) change in CD4(+) T-lymphocyte count (CD4 slope), (v) HIV-1 subtype, and (vi) host genetics, especially human leukocyte antigen (HLA) variants. Data from 499 HIV-1 seroconverters with frequent (monthly to quarterly) follow-up revealed that CD4:CD8 ratio was stable in the first 3 years of infection, with a modest correlation with VL and CD4 slope. A relatively normal CD4:CD8 ratio (>1.0) in early infection was associated with a substantial delay in disease progression to severe immunodeficiency (<350 CD4 cells/μl), regardless of other correlates of HIV-1 pathogenesis (adjusted hazards ratio (HR) = 0.43, 95% confidence interval (CI) = 0.29-0.63, P < 0.0001). Low VL (<10,000 copies/ml) and HLA-A*74:01 were the main predictors of CD4:CD8 ratio >1.0, but HLA variants (e.g., HLA-B*57 and HLA-B*81) previously associated with VL and/or CD4 trajectories in eastern and southern Africans had no obvious impact on CD4:CD8 ratio. Collectively, these findings suggest that CD4:CD8 ratio is a robust measure of immunologic health with both clinical and epidemiological implications.
    Frontiers in Microbiology 07/2015; 6:670. DOI:10.3389/fmicb.2015.00670 · 3.99 Impact Factor
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    • "Also transcriptional activation requires additional factors. These differences along with lower CD4 affinity seen with HIV-2's gp120 may account for the reason that makes HIV-2 infected individuals to have a lower viral load than those infected with HIV-1 (Sousa et al. 2002). Also HIV-2 shows enhanced sensitivity to neutralization due to its ability to infect host cell independent of CD4 interaction (Figure 1 & 2) (Reeves & Doms 2002). "
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    ABSTRACT: Acquired Immunodeficiency Syndrome (AIDS) is one of the most critically acclaimed endemic diseases, caused by two lentiviruses HIV-1 and 2. HIV-2 displays intimate serological and antigenic resemblance to Simian Immunodeficiency Virus (SIV) along with less pathogenicity, lower infectivity and appreciable cross reactivity with HIV-1 antigens. The present era is confronted with the challenge to fabricate a vaccine effective against all clades of both the species of HIV. But vaccine development against HIV-1 has proven highly intricate, moreover the laborious and deficient conventional approaches has slackened the pace regarding the development of new vaccines. These concerns may be tackled with the development of HIV-2 vaccine as a natural control of HIV-1 that has been found in ancestors of HIV-2 i.e. African monkeys, mangabeys and macaques. Thereby, suggesting the notion of cross protection among HIV-2 and HIV-1. Assistance of bioinformatics along with vaccinomics strategy can bring about a quantum leap in this direction for surpassing the bottleneck in conventional approaches. These specifics together can add to our conception that HIV-2 vaccine design by in silico strategy will surely be a constructive approach for HIV-1 targeting.
    SpringerPlus 12/2013; 2(1):7. DOI:10.1186/2193-1801-2-7
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    • "Many efforts have been devoted to better understanding the mechanism governing disease progression and non-progression during HIV infection. Besides the direct cytotoxic effect against CD4+ T cells caused by HIV, immune activation is widely accepted as a good predictor for disease progression [1], [2], [3], [4], [5]. Furthermore, some clinical studies using immunity suppressive drugs to suppress immune activation slowed down the diseases progression [6], [7]. "
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    ABSTRACT: Since statistical relationships between HIV load and CD4+ T cell loss have been demonstrated to be weak, searching for host factors contributing to the pathogenesis of HIV infection becomes a key point for both understanding the disease pathology and developing treatments. We applied Maximum Relevance Minimum Redundancy (mRMR) algorithm to a set of microarray data generated from the CD4+ T cells of viremic non-progressors (VNPs) and rapid progressors (RPs) to identify host factors associated with the different responses to HIV infection. Using mRMR algorithm, 147 gene had been identified. Furthermore, we constructed a weighted molecular interaction network with the existing protein-protein interaction data from STRING database and identified 1331 genes on the shortest-paths among the genes identified with mRMR. Functional analysis shows that the functions relating to apoptosis play important roles during the pathogenesis of HIV infection. These results bring new insights of understanding HIV progression.
    PLoS ONE 11/2013; 8(11):e78057. DOI:10.1371/journal.pone.0078057 · 3.23 Impact Factor
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