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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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CD4+ T cells remaining in the chronic phase (as % of baseline) and their recovery as functions of the CD4+ T cells remaining at nadir.Full line represents the relationship expected for constant level of immune control. Grey area is the level of CD4+ T cells at nadir lower than the acute survival threshold of 3.3% of baseline. (A) Survival threshold of 24.1% of baseline based on chronic phase CD4 T cell level (dashed line bordering the red area) almost exactly corresponds to the acute threshold, based on the assumption of constant immune response. The animals with data points below the full line have less CD4+ T cells remaining in the chronic phase than expected from the nadir. (B) CD4+ recovery is defined as the difference between the nadir and the chronic level. The points above the curve represent better than expected recovery. All animals with the level of remaining CD4+ T cells lower than the survival threshold recover considerably less than expected.
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pone-0017180-g003: CD4+ T cells remaining in the chronic phase (as % of baseline) and their recovery as functions of the CD4+ T cells remaining at nadir.Full line represents the relationship expected for constant level of immune control. Grey area is the level of CD4+ T cells at nadir lower than the acute survival threshold of 3.3% of baseline. (A) Survival threshold of 24.1% of baseline based on chronic phase CD4 T cell level (dashed line bordering the red area) almost exactly corresponds to the acute threshold, based on the assumption of constant immune response. The animals with data points below the full line have less CD4+ T cells remaining in the chronic phase than expected from the nadir. (B) CD4+ recovery is defined as the difference between the nadir and the chronic level. The points above the curve represent better than expected recovery. All animals with the level of remaining CD4+ T cells lower than the survival threshold recover considerably less than expected.

Mentions: We can make this estimate using the standard model of viral dynamics (Eq.3–5). If we plot CD4+ T cell level in the chronic phase T*/T0 as a function of the fraction remaining in the acute phase Tmin/T0, we obtain the universal curve shown as solid black line in Figure 3A. Full circles represent the data for the controllers, and open circles represent the progressors. The grey area encloses CD4+ T cell levels in the acute phase lower than the survival threshold, as determined by the ROC analysis. The pink area is the fraction of remaining CD4 T cells in the chronic phase corresponding to the acute levels in the grey interval, as predicted by the model, if we assume constant immune response during the whole course of disease. It is immediately obvious that, for very low fractions of remaining CD4+ T cells in the acute phase, small improvement in CD4 preservation results in much larger improvement in the long-term outcome.


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

Petravic J, Davenport MP - PLoS ONE (2011)

CD4+ T cells remaining in the chronic phase (as % of baseline) and their recovery as functions of the CD4+ T cells remaining at nadir.Full line represents the relationship expected for constant level of immune control. Grey area is the level of CD4+ T cells at nadir lower than the acute survival threshold of 3.3% of baseline. (A) Survival threshold of 24.1% of baseline based on chronic phase CD4 T cell level (dashed line bordering the red area) almost exactly corresponds to the acute threshold, based on the assumption of constant immune response. The animals with data points below the full line have less CD4+ T cells remaining in the chronic phase than expected from the nadir. (B) CD4+ recovery is defined as the difference between the nadir and the chronic level. The points above the curve represent better than expected recovery. All animals with the level of remaining CD4+ T cells lower than the survival threshold recover considerably less than expected.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017180-g003: CD4+ T cells remaining in the chronic phase (as % of baseline) and their recovery as functions of the CD4+ T cells remaining at nadir.Full line represents the relationship expected for constant level of immune control. Grey area is the level of CD4+ T cells at nadir lower than the acute survival threshold of 3.3% of baseline. (A) Survival threshold of 24.1% of baseline based on chronic phase CD4 T cell level (dashed line bordering the red area) almost exactly corresponds to the acute threshold, based on the assumption of constant immune response. The animals with data points below the full line have less CD4+ T cells remaining in the chronic phase than expected from the nadir. (B) CD4+ recovery is defined as the difference between the nadir and the chronic level. The points above the curve represent better than expected recovery. All animals with the level of remaining CD4+ T cells lower than the survival threshold recover considerably less than expected.
Mentions: We can make this estimate using the standard model of viral dynamics (Eq.3–5). If we plot CD4+ T cell level in the chronic phase T*/T0 as a function of the fraction remaining in the acute phase Tmin/T0, we obtain the universal curve shown as solid black line in Figure 3A. Full circles represent the data for the controllers, and open circles represent the progressors. The grey area encloses CD4+ T cell levels in the acute phase lower than the survival threshold, as determined by the ROC analysis. The pink area is the fraction of remaining CD4 T cells in the chronic phase corresponding to the acute levels in the grey interval, as predicted by the model, if we assume constant immune response during the whole course of disease. It is immediately obvious that, for very low fractions of remaining CD4+ T cells in the acute phase, small improvement in CD4 preservation results in much larger improvement in the long-term outcome.

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