Limits...
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.

Show MeSH

Related in: MedlinePlus

Protease resistance mutations differ between patients with concordant and discordant virologic failure.Protease genotype sequences were compared between 34 patients with concordant virologic failure, and 34 patients with discordant virologic failure, but immunologic improvement. *Indicates p value <0.05.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2991267&req=5

ppat-1001213-g001: Protease resistance mutations differ between patients with concordant and discordant virologic failure.Protease genotype sequences were compared between 34 patients with concordant virologic failure, and 34 patients with discordant virologic failure, but immunologic improvement. *Indicates p value <0.05.

Mentions: In response to subinhibitory concentrations of protease inhibitors, HIV protease resistance mutations are selected, which often involve both primary active site mutations that directly inhibit the action of PI, and a host of accessory resistance mutations that may occur far from the active site but may contribute to restoring the fitness or stability of protease activity [21]. We sought to determine whether the prevalence of PI mutations differed between patients with discordant virologic failure versus age matched ART treatment matched patients with concordant virologic failure. We used a strict definition of discordant failure [22], that is consistent with other published definitions [23] of increasing viral load over a period of three or more months, coincident with an increase in CD4 T cell number over the same timeframe in any patient receiving a combination of three or more antiviral agents. We compared the prevalence of mutations within protease of viral isolates from 34 patients with discordant virologic failure and immunologic responses, to 34 patients with virologic failure that was associated with immunologic decline. The clinical characteristics of these patients are described in Table 1. The median (interquartile range) increase in HIV viral load from the first measurement after initiating therapy to the peak after failure was1.17 (0.47–2.04) log10 copies/mL. Our rationale was that if protease mutations were unrelated to the generation of a discordant response, then the frequency of protease mutations should be similar between discordant patients and those with concordant failures. Conversely, if specific protease mutations predispose to the development of discordant response, then those mutations should occur with a significantly higher frequency in discordant compared to concordant virologic failures. Indeed in discordant patients a high frequency of mutations in protease were seen in selected sites that differed from that seen in patients with concordant failures. Differences were significant for mutations at amino acids 10 (p = 0.03) 54 (p = 0.001), and 82 (p = 0.008) (Figure 1). We termed these mutations Discordance Associated Mutations (DAMs).


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)

Protease resistance mutations differ between patients with concordant and discordant virologic failure.Protease genotype sequences were compared between 34 patients with concordant virologic failure, and 34 patients with discordant virologic failure, but immunologic improvement. *Indicates p value <0.05.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1001213-g001: Protease resistance mutations differ between patients with concordant and discordant virologic failure.Protease genotype sequences were compared between 34 patients with concordant virologic failure, and 34 patients with discordant virologic failure, but immunologic improvement. *Indicates p value <0.05.
Mentions: In response to subinhibitory concentrations of protease inhibitors, HIV protease resistance mutations are selected, which often involve both primary active site mutations that directly inhibit the action of PI, and a host of accessory resistance mutations that may occur far from the active site but may contribute to restoring the fitness or stability of protease activity [21]. We sought to determine whether the prevalence of PI mutations differed between patients with discordant virologic failure versus age matched ART treatment matched patients with concordant virologic failure. We used a strict definition of discordant failure [22], that is consistent with other published definitions [23] of increasing viral load over a period of three or more months, coincident with an increase in CD4 T cell number over the same timeframe in any patient receiving a combination of three or more antiviral agents. We compared the prevalence of mutations within protease of viral isolates from 34 patients with discordant virologic failure and immunologic responses, to 34 patients with virologic failure that was associated with immunologic decline. The clinical characteristics of these patients are described in Table 1. The median (interquartile range) increase in HIV viral load from the first measurement after initiating therapy to the peak after failure was1.17 (0.47–2.04) log10 copies/mL. Our rationale was that if protease mutations were unrelated to the generation of a discordant response, then the frequency of protease mutations should be similar between discordant patients and those with concordant failures. Conversely, if specific protease mutations predispose to the development of discordant response, then those mutations should occur with a significantly higher frequency in discordant compared to concordant virologic failures. Indeed in discordant patients a high frequency of mutations in protease were seen in selected sites that differed from that seen in patients with concordant failures. Differences were significant for mutations at amino acids 10 (p = 0.03) 54 (p = 0.001), and 82 (p = 0.008) (Figure 1). We termed these mutations Discordance Associated Mutations (DAMs).

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