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Patients with discordant responses to antiretroviral therapy have impaired killing of HIV-infected T cells.

Natesampillai S, Nie Z, Cummins NW, Jochmans D, Bren GD, Angel JB, Badley AD - PLoS Pathog. (2010)

Bottom Line: The reductions in cell death occurred both within infected cells, as well as in uninfected bystander cells.These data indicate that single point mutations within HIV protease which are selected in vivo can significantly impact the ability of HIV to kill CD4 T cells, while not impacting viral replication.Therefore, HIV protease regulates both HIV replication as well as HIV induced T cell depletion, the hallmark of HIV pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA.

ABSTRACT
In medicine, understanding the pathophysiologic basis of exceptional circumstances has led to an enhanced understanding of biology. We have studied the circumstance of HIV-infected patients in whom antiretroviral therapy results in immunologic benefit, despite virologic failure. In such patients, two protease mutations, I54V and V82A, occur more frequently. Expressing HIV protease containing these mutations resulted in less cell death, caspase activation, and nuclear fragmentation than wild type (WT) HIV protease or HIV protease containing other mutations. The impaired induction of cell death was also associated with impaired cleavage of procaspase 8, a requisite event for HIV protease mediated cell death. Primary CD4 T cells expressing I54V or V82A protease underwent less cell death than with WT or other mutant proteases. Human T cells infected with HIV containing these mutations underwent less cell death and less Casp8p41 production than WT or HIV containing other protease mutations, despite similar degrees of viral replication. The reductions in cell death occurred both within infected cells, as well as in uninfected bystander cells. These data indicate that single point mutations within HIV protease which are selected in vivo can significantly impact the ability of HIV to kill CD4 T cells, while not impacting viral replication. Therefore, HIV protease regulates both HIV replication as well as HIV induced T cell depletion, the hallmark of HIV pathogenesis.

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HXB2 containing Discordance Associated Mutations (DAMs) are associated with reduced generation of TUNEL positivity and reduced Casp8p41 production.Cells were infected as in Figure 9 and analyzed for TUNEL positivity in the P24 positive (A) or P21 negative (B) cells, as well as for Casp8p41 (C). Results in (A) and (B) are pooled results from three independent experiments. Data in (C) is reflective of three independent replicates.
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ppat-1001213-g010: HXB2 containing Discordance Associated Mutations (DAMs) are associated with reduced generation of TUNEL positivity and reduced Casp8p41 production.Cells were infected as in Figure 9 and analyzed for TUNEL positivity in the P24 positive (A) or P21 negative (B) cells, as well as for Casp8p41 (C). Results in (A) and (B) are pooled results from three independent experiments. Data in (C) is reflective of three independent replicates.

Mentions: We next specifically analyzed cell death induced in HIV-infected cells, as well as in uninfected bystander cells by co-staining with TUNEL and P24 antigen, and comparing death in the infected (p24 positive, Figure 9C) and uninfected (p24 negative, Figure 9D) T cell subsets. Consistent with the premise that mutations in HIV protease will reduce the ability of HIV protease to kill infected cells, protease containing V82A or I54V induced less apoptosis in infected cells than either WT or L90M (Figure 10A). Of interest this trend was also observed in the uninfected cells, with less uninfected cell killing being observed with I54V, and a trend towards less death in the V82A protease mutant (Figure 10B).


Patients with discordant responses to antiretroviral therapy have impaired killing of HIV-infected T cells.

Natesampillai S, Nie Z, Cummins NW, Jochmans D, Bren GD, Angel JB, Badley AD - PLoS Pathog. (2010)

HXB2 containing Discordance Associated Mutations (DAMs) are associated with reduced generation of TUNEL positivity and reduced Casp8p41 production.Cells were infected as in Figure 9 and analyzed for TUNEL positivity in the P24 positive (A) or P21 negative (B) cells, as well as for Casp8p41 (C). Results in (A) and (B) are pooled results from three independent experiments. Data in (C) is reflective of three independent replicates.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2991267&req=5

ppat-1001213-g010: HXB2 containing Discordance Associated Mutations (DAMs) are associated with reduced generation of TUNEL positivity and reduced Casp8p41 production.Cells were infected as in Figure 9 and analyzed for TUNEL positivity in the P24 positive (A) or P21 negative (B) cells, as well as for Casp8p41 (C). Results in (A) and (B) are pooled results from three independent experiments. Data in (C) is reflective of three independent replicates.
Mentions: We next specifically analyzed cell death induced in HIV-infected cells, as well as in uninfected bystander cells by co-staining with TUNEL and P24 antigen, and comparing death in the infected (p24 positive, Figure 9C) and uninfected (p24 negative, Figure 9D) T cell subsets. Consistent with the premise that mutations in HIV protease will reduce the ability of HIV protease to kill infected cells, protease containing V82A or I54V induced less apoptosis in infected cells than either WT or L90M (Figure 10A). Of interest this trend was also observed in the uninfected cells, with less uninfected cell killing being observed with I54V, and a trend towards less death in the V82A protease mutant (Figure 10B).

Bottom Line: The reductions in cell death occurred both within infected cells, as well as in uninfected bystander cells.These data indicate that single point mutations within HIV protease which are selected in vivo can significantly impact the ability of HIV to kill CD4 T cells, while not impacting viral replication.Therefore, HIV protease regulates both HIV replication as well as HIV induced T cell depletion, the hallmark of HIV pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA.

ABSTRACT
In medicine, understanding the pathophysiologic basis of exceptional circumstances has led to an enhanced understanding of biology. We have studied the circumstance of HIV-infected patients in whom antiretroviral therapy results in immunologic benefit, despite virologic failure. In such patients, two protease mutations, I54V and V82A, occur more frequently. Expressing HIV protease containing these mutations resulted in less cell death, caspase activation, and nuclear fragmentation than wild type (WT) HIV protease or HIV protease containing other mutations. The impaired induction of cell death was also associated with impaired cleavage of procaspase 8, a requisite event for HIV protease mediated cell death. Primary CD4 T cells expressing I54V or V82A protease underwent less cell death than with WT or other mutant proteases. Human T cells infected with HIV containing these mutations underwent less cell death and less Casp8p41 production than WT or HIV containing other protease mutations, despite similar degrees of viral replication. The reductions in cell death occurred both within infected cells, as well as in uninfected bystander cells. These data indicate that single point mutations within HIV protease which are selected in vivo can significantly impact the ability of HIV to kill CD4 T cells, while not impacting viral replication. Therefore, HIV protease regulates both HIV replication as well as HIV induced T cell depletion, the hallmark of HIV pathogenesis.

Show MeSH
Related in: MedlinePlus