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: 5.36). 10/2002; 169(6):3400-6. DOI: 10.4049/jimmunol.169.6.3400
Source: PubMed

ABSTRACT 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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Available from: Zvi Grossman, Aug 23, 2015
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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.
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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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    SpringerPlus 12/2013; 2(1):7. DOI:10.1186/2193-1801-2-7
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    • "Early work showed that cross-linking of CD4 molecules on T cells by the HIV envelope glycoprotein gp120 or anti-gp120 immune complexes, primes or sensitizes the cell for AICD [23] and gp120/gp41 was shown to be a powerful inducer of cell death in uninfected CD4 + target cells [24]. The discovery that the number of cells dying in lymph nodes correlated neither with the clinical stage of the disease nor with viral burden, but rather with the degree of activation of the lymphoid tissue, represented a significant conundrum in the understanding of HIV pathogenesis [25]. Studies from the natural hosts of the simian immunodeficiency virus (SIV), namely the African green monkeys and the sooty mangabeys supported these findings [26] [27]. "
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