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Simian-human immunodeficiency infection--is the course set in the acute phase?

Petravic J, Davenport MP - PLoS ONE (2011)

Bottom Line: We found that in most cases, the depletion of CD4+ T cells in chronic infection was consistent with the prediction from the acute CD4+ T cell loss.However, the animals with less than 3.3% of baseline CD4 T cells in the acute phase were approximately 20% more depleted late in the infection than expected based on constant level of virus control.This suggests that severe acute CD4 depletion indeed impairs the immune response.

View Article: PubMed Central - PubMed

Affiliation: Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Sydney, Australia.

ABSTRACT
Identifying early predictors of infection outcome is important for the clinical management of HIV infection, and both viral load and CD4+ T cell level have been found to be useful predictors of subsequent disease progression. Very high viral load or extensively depleted CD4+ T cells in the acute phase often result in failure of immune control, and a fast progression to AIDS. It is usually assumed that extensive loss of CD4+ T cells in the acute phase of HIV infection prevents the establishment of robust T cell help required for virus control in the chronic phase. We tested this hypothesis using viral load and CD4+ T cell number of SHIV-infected rhesus macaques. In acute infection, the lowest level of CD4+ T cells was a good predictor of later survival; animals having less than 3.3% of baseline CD4+ T cells progressed to severe disease, while animals with more than 3.3% of baseline CD4+ T cells experienced CD4+ T cell recovery. However, it is unclear if the disease progression was caused by early depletion, or was simply a result of a higher susceptibility of an animal to infection. We derived a simple relationship between the expected number of CD4+ T cells in the acute and chronic phases for a constant level of host susceptibility or resistance. We found that in most cases, the depletion of CD4+ T cells in chronic infection was consistent with the prediction from the acute CD4+ T cell loss. However, the animals with less than 3.3% of baseline CD4 T cells in the acute phase were approximately 20% more depleted late in the infection than expected based on constant level of virus control. This suggests that severe acute CD4 depletion indeed impairs the immune response.

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Measures of accuracy of the survival tests based on CD4 preservation and viral load in the chronic and acute phases of SHIV infection.(A–C) Chronic phase tests: (A) sensitivity and specificity of the test based on chronic level of CD4+ T cells; (B) sensitivity and specificity of the test based on set point viral load, vertical dashed line represents the best choice of threshold; (C) ROC areas of the chronic phase tests; (D–E) Acute phase tests: (D) sensitivity and specificity of the test based on acute level of CD4+ T cells; (E) sensitivity and specificity of the test based on peak viral load, (F) ROC areas of the acute phase tests.
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pone-0017180-g002: Measures of accuracy of the survival tests based on CD4 preservation and viral load in the chronic and acute phases of SHIV infection.(A–C) Chronic phase tests: (A) sensitivity and specificity of the test based on chronic level of CD4+ T cells; (B) sensitivity and specificity of the test based on set point viral load, vertical dashed line represents the best choice of threshold; (C) ROC areas of the chronic phase tests; (D–E) Acute phase tests: (D) sensitivity and specificity of the test based on acute level of CD4+ T cells; (E) sensitivity and specificity of the test based on peak viral load, (F) ROC areas of the acute phase tests.

Mentions: We considered progressors “positive” for early death and controllers “negative”. If we tested for early death using the chronic depletion of CD4+ T cells, for each choice of the threshold we would have a number of “true positives” (progressors that test positive), “false positives” (controllers that test positive), true negatives (controllers that test negative) and false negatives (progressors that test negative). We chose the best threshold value as the one that simultaneously maximized sensitivity, i.e. the fraction of true positives out of all animals that test positive (Eq.1), and the specificity, i.e. the fraction of true negatives out of all animals that test negative (Eq.2). The summary of the measures of accuracy of the two diagnostic tests is shown in Figure 2A-C (sensitivity – full triangles; specificity – open inverted triangles) and in Tables 1 and 2. The best classification was obtained with the threshold chronic CD4 preservation of 24.1% and viral load of 4.83×104 RNA copies/mL (dashed vertical lines in Figure 1A and B) when values of sensitivity and specificity were the closest. The overall accuracy of the tests based on chronic CD4 depletion or viral load is compared in Figure 1C. A more accurate test would be the one for which the area under the curve of sensitivity as a function of (1-specificity), or the so-called “ROC area”, is closer to unity. Tests based on both chronic phase quantities had ROC areas higher than 0.95, with CD4 preservation at 0.993 ranking a little better than viral load at 0.977 (only one animal wrongly classified at the best threshold of CD4 preservation, compared to two for viral set point). The ROC areas for the two chronic phase measures were not significantly different (p = 0.459)


Simian-human immunodeficiency infection--is the course set in the acute phase?

Petravic J, Davenport MP - PLoS ONE (2011)

Measures of accuracy of the survival tests based on CD4 preservation and viral load in the chronic and acute phases of SHIV infection.(A–C) Chronic phase tests: (A) sensitivity and specificity of the test based on chronic level of CD4+ T cells; (B) sensitivity and specificity of the test based on set point viral load, vertical dashed line represents the best choice of threshold; (C) ROC areas of the chronic phase tests; (D–E) Acute phase tests: (D) sensitivity and specificity of the test based on acute level of CD4+ T cells; (E) sensitivity and specificity of the test based on peak viral load, (F) ROC areas of the acute phase tests.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040775&req=5

pone-0017180-g002: Measures of accuracy of the survival tests based on CD4 preservation and viral load in the chronic and acute phases of SHIV infection.(A–C) Chronic phase tests: (A) sensitivity and specificity of the test based on chronic level of CD4+ T cells; (B) sensitivity and specificity of the test based on set point viral load, vertical dashed line represents the best choice of threshold; (C) ROC areas of the chronic phase tests; (D–E) Acute phase tests: (D) sensitivity and specificity of the test based on acute level of CD4+ T cells; (E) sensitivity and specificity of the test based on peak viral load, (F) ROC areas of the acute phase tests.
Mentions: We considered progressors “positive” for early death and controllers “negative”. If we tested for early death using the chronic depletion of CD4+ T cells, for each choice of the threshold we would have a number of “true positives” (progressors that test positive), “false positives” (controllers that test positive), true negatives (controllers that test negative) and false negatives (progressors that test negative). We chose the best threshold value as the one that simultaneously maximized sensitivity, i.e. the fraction of true positives out of all animals that test positive (Eq.1), and the specificity, i.e. the fraction of true negatives out of all animals that test negative (Eq.2). The summary of the measures of accuracy of the two diagnostic tests is shown in Figure 2A-C (sensitivity – full triangles; specificity – open inverted triangles) and in Tables 1 and 2. The best classification was obtained with the threshold chronic CD4 preservation of 24.1% and viral load of 4.83×104 RNA copies/mL (dashed vertical lines in Figure 1A and B) when values of sensitivity and specificity were the closest. The overall accuracy of the tests based on chronic CD4 depletion or viral load is compared in Figure 1C. A more accurate test would be the one for which the area under the curve of sensitivity as a function of (1-specificity), or the so-called “ROC area”, is closer to unity. Tests based on both chronic phase quantities had ROC areas higher than 0.95, with CD4 preservation at 0.993 ranking a little better than viral load at 0.977 (only one animal wrongly classified at the best threshold of CD4 preservation, compared to two for viral set point). The ROC areas for the two chronic phase measures were not significantly different (p = 0.459)

Bottom Line: We found that in most cases, the depletion of CD4+ T cells in chronic infection was consistent with the prediction from the acute CD4+ T cell loss.However, the animals with less than 3.3% of baseline CD4 T cells in the acute phase were approximately 20% more depleted late in the infection than expected based on constant level of virus control.This suggests that severe acute CD4 depletion indeed impairs the immune response.

View Article: PubMed Central - PubMed

Affiliation: Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Sydney, Australia.

ABSTRACT
Identifying early predictors of infection outcome is important for the clinical management of HIV infection, and both viral load and CD4+ T cell level have been found to be useful predictors of subsequent disease progression. Very high viral load or extensively depleted CD4+ T cells in the acute phase often result in failure of immune control, and a fast progression to AIDS. It is usually assumed that extensive loss of CD4+ T cells in the acute phase of HIV infection prevents the establishment of robust T cell help required for virus control in the chronic phase. We tested this hypothesis using viral load and CD4+ T cell number of SHIV-infected rhesus macaques. In acute infection, the lowest level of CD4+ T cells was a good predictor of later survival; animals having less than 3.3% of baseline CD4+ T cells progressed to severe disease, while animals with more than 3.3% of baseline CD4+ T cells experienced CD4+ T cell recovery. However, it is unclear if the disease progression was caused by early depletion, or was simply a result of a higher susceptibility of an animal to infection. We derived a simple relationship between the expected number of CD4+ T cells in the acute and chronic phases for a constant level of host susceptibility or resistance. We found that in most cases, the depletion of CD4+ T cells in chronic infection was consistent with the prediction from the acute CD4+ T cell loss. However, the animals with less than 3.3% of baseline CD4 T cells in the acute phase were approximately 20% more depleted late in the infection than expected based on constant level of virus control. This suggests that severe acute CD4 depletion indeed impairs the immune response.

Show MeSH
Related in: MedlinePlus