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In vivo CD8+ T-cell suppression of siv viremia is not mediated by CTL clearance of productively infected cells.

Wong JK, Strain MC, Porrata R, Reay E, Sankaran-Walters S, Ignacio CC, Russell T, Pillai SK, Looney DJ, Dandekar S - PLoS Pathog. (2010)

Bottom Line: The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms.As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication.These observations have important implications for future strategies to augment immune control of HIV.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV.

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Related in: MedlinePlus

Timeline of experiments.Plasma SIV RNA levels, immunophenotyping, GI biopsy and antibody treatment according to treatment group is shown. D = day post infection. Treatment phase with PMPA/FTC is indicated by the horizontal block-arrow in the right upper hand corner.
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ppat-1000748-g001: Timeline of experiments.Plasma SIV RNA levels, immunophenotyping, GI biopsy and antibody treatment according to treatment group is shown. D = day post infection. Treatment phase with PMPA/FTC is indicated by the horizontal block-arrow in the right upper hand corner.

Mentions: Animal studies were conducted in accordance with UC Davis IACUC approved protocols at the California National Primate Center. 8 healthy junvenile rhesus macaques were infected intravenously with 1000 TCID of SIVmac251 at time zero (D0). Viral load testing and immunophenotyping were performed as shown (Figure 1). At week 12 (D84), animals received mAb cMT-807, control antibody or no mAb. At week 13 (D91), animals were started on combination antitretroviral therapy consisting of PMPA (30 mg/Kg per day) and FTC (8 mg/Kg per day) given intramuscularly (IM) daily.


In vivo CD8+ T-cell suppression of siv viremia is not mediated by CTL clearance of productively infected cells.

Wong JK, Strain MC, Porrata R, Reay E, Sankaran-Walters S, Ignacio CC, Russell T, Pillai SK, Looney DJ, Dandekar S - PLoS Pathog. (2010)

Timeline of experiments.Plasma SIV RNA levels, immunophenotyping, GI biopsy and antibody treatment according to treatment group is shown. D = day post infection. Treatment phase with PMPA/FTC is indicated by the horizontal block-arrow in the right upper hand corner.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2813272&req=5

ppat-1000748-g001: Timeline of experiments.Plasma SIV RNA levels, immunophenotyping, GI biopsy and antibody treatment according to treatment group is shown. D = day post infection. Treatment phase with PMPA/FTC is indicated by the horizontal block-arrow in the right upper hand corner.
Mentions: Animal studies were conducted in accordance with UC Davis IACUC approved protocols at the California National Primate Center. 8 healthy junvenile rhesus macaques were infected intravenously with 1000 TCID of SIVmac251 at time zero (D0). Viral load testing and immunophenotyping were performed as shown (Figure 1). At week 12 (D84), animals received mAb cMT-807, control antibody or no mAb. At week 13 (D91), animals were started on combination antitretroviral therapy consisting of PMPA (30 mg/Kg per day) and FTC (8 mg/Kg per day) given intramuscularly (IM) daily.

Bottom Line: The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms.As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication.These observations have important implications for future strategies to augment immune control of HIV.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV.

Show MeSH
Related in: MedlinePlus