Longitudinal Analysis of Clinical Markers following Antiretroviral Therapy Initiated during Acute or Early HIV Type 1 Infection

Kassutto, Sigall; Maghsoudi, Kaveh; Johnston, Mary N.; Robbins, Gregory K.; Burgett, Nicole C.; Sax, Paul E.; Cohen, Daniel E.; Pae, Eunice; Davis, Ben; Zachary, Kimon C.; Basgoz, Nesli; D’Agata, Erika M. C.; DeGruttola, Victor; Walker, Bruce D.; Rosenberg, Eric S.

doi:10.1086/500410

Cited by 67 publications

(44 citation statements)

References 27 publications

(25 reference statements)

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“…While the mean viral loads during acute infection have been reported to be in excess of 5 ϫ 10 6 RNA copies/ml in other studies (31), the virus loads during acute phase in the HIV controllers studied here never exceeded 1 ϫ 10 6 RNA copies/ml ( Fig. 1A and B).…”

Section: Kinetics Of Plasma Viremia During Primary Infection In Per-contrasting

confidence: 61%

Impaired Replication Capacity of Acute/Early Viruses in Persons Who Become HIV Controllers

Miura

Brumme

Brockman

et al. 2010

J Virol

123

129

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were shown to exhibit impaired replication capacities, in part associated with escape mutations from cytotoxic-T-lymphocyte (CTL) responses. In contrast, little is known about viruses during acute/early infection in individuals who subsequently become HIV controllers. Here, we examine the viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection. gag-protease chimeric viruses constructed using the earliest postinfection samples displayed significantly lower replication capacities than isolates from persons who failed to control viremia (P ‫؍‬ 0.0003). Protective HLA class I alleles were not enriched in these early HIV controllers, but viral sequencing revealed a significantly higher prevalence of drug resistance mutations associated with impaired viral fitness in controllers than in noncontrollers (6/15 [40.0%] versus 10/80 [12.5%], P ‫؍‬ 0.018). Moreover, of two HLA-B57-positive (B57 ؉ ) controllers identified, both harbored, at the earliest time point tested, signature escape mutations within Gag that likewise impair viral replication capacity. Only five controllers did not express "protective" alleles or harbor viruses with drug resistance mutations; intriguingly, two of them displayed typical B57 signature mutations (T242N), suggesting the acquisition of attenuated viruses from B57 ؉ donors. These data indicate that acute/early stage viruses from persons who become controllers have evidence of reduced replication capacity during the initial stages of infection which is likely associated with transmitted or acquired CTL escape mutations or transmitted drug resistance mutations. These data suggest that viral dynamics during acute infection have a major impact on HIV disease outcome.

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Section: Kinetics Of Plasma Viremia During Primary Infection In Per-contrasting

confidence: 61%

Impaired Replication Capacity of Acute/Early Viruses in Persons Who Become HIV Controllers

Miura

Brumme

Brockman

et al. 2010

J Virol

123

129

View full text Add to dashboard Cite

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“…The data for our investigations come from Massachusetts General Hospital (MGH), where all the patients enrolled in the study are symptomatic with acute or early HIV-infection (for more detailed information of these data, the interested reader is referred to [3,23,30]). In summary, nearly all subjects in the study undergo combination therapy and many have at least one treatment interruption.…”

Section: Application Of the Model To Clinical Datamentioning

confidence: 99%

Modelling HIV immune response and validation with clinical data

Banks

Davidian

et al. 2008

Journal of Biological Dynamics

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A system of ordinary differential equations is formulated to describe the pathogenesis of HIV infection, wherein certain features that have been shown to be important by recent experimental research are incorporated in the model. These include the role of CD4+ memory cells that serve as a major reservoir of latently infected cells, a critical role for T-helper cells in the generation of CD8 memory cells capable of efficient recall response, and stimulation by antigens other than HIV. A stability analysis illustrates the capability of this model in admitting multiple locally asymptotically stable (locally a.s.) off-treatment equilibria. We show that this more biologically detailed model can exhibit the phenomenon of transient viremia experienced by some patients on therapy with viral load levels suppressed below the detection limit. We also show that the loss of CD4+ T-cell help in the generation of CD8+ memory cells leads to larger peak values for the viral load during transient viremia. Censored clinical data is used to obtain parameter estimates. We demonstrate that using a reduced set of 16 free parameters, obtained by fixing some parameters at their population averages, the model provides reasonable fits to the patient data and, moreover, that it exhibits good predictive capability. We further show that parameter values obtained for most clinical patients do not admit multiple locally a.s off-treatment equilibria. This suggests that treatment to move from a high viral load equilibrium state to an equilibrium state with a lower (or zero) viral load is not possible for these patients.

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“…The data for our investigations come from Massachusetts General Hospital (MGH), where all the patients enrolled in the study are symptomatic with acute or early HIV-infection (for more detailed information of these data, the interested reader is referred to [3,21,27]). In summary, nearly all subjects in the study undergo combination therapy and many have at least one treatment interruption.…”

Section: Fitting the Model To Clinical Datamentioning

confidence: 99%

Modeling HIV Immune Response and Validation with Clinical Data

Banks¹,

Davidian²,

Hu³

et al. 2007

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A system of ordinary differential equations is formulated to describe the pathogenesis of HIV infection, wherein certain important features that have been shown important by recent experimental research are incorporated in the model. These include the role of CD4+ memory cells that serve as a major reservoir of latently infected cells, a critical role for T-helper cells in the generation of CD8 memory cells capable of efficient recall response, and stimulation by antigens other than HIV. A stability analysis illustrates the capability of this model in admitting multiple locally asymptotically stable (locally a.s.) off-treatment equilibria. The phenomenon of "viral blips" experienced by some patients on therapy with viral load levels suppressed below the detection limit is also investigated. Censored clinical data is used to demonstrate that this model provides reasonable fits to all the patient data available for this study and, moreover, that it exhibits impressive predictive capability. Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number.

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Longitudinal Analysis of Clinical Markers following Antiretroviral Therapy Initiated during Acute or Early HIV Type 1 Infection

Cited by 67 publications

References 27 publications

Impaired Replication Capacity of Acute/Early Viruses in Persons Who Become HIV Controllers

Impaired Replication Capacity of Acute/Early Viruses in Persons Who Become HIV Controllers

Modelling HIV immune response and validation with clinical data

Modeling HIV Immune Response and Validation with Clinical Data

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