Persistence and emergence of X4 virus in HIV infection
Approximately 50% of late-stage HIV patients develop CXCR4-tropic (X4) virus in addition to CCR5-tropic (R5) virus. X4 emergence occurs with a sharp decline in CD4+ T cell counts and accelerated time to AIDS. Why this phenotypic switch to X4 occurs is not well understood. Previously, we used numeri...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
AIMS Press
2011-03-01
|
| Series: | Mathematical Biosciences and Engineering |
| Subjects: | |
| Online Access: | https://www.aimspress.com/article/doi/10.3934/mbe.2011.8.605 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832590194356781056 |
|---|---|
| author | Ariel D. Weinberger Alan S. Perelson |
| author_facet | Ariel D. Weinberger Alan S. Perelson |
| author_sort | Ariel D. Weinberger |
| collection | DOAJ |
| description | Approximately 50% of late-stage HIV patients develop CXCR4-tropic (X4) virus in addition to CCR5-tropic (R5) virus. X4 emergence occurs with a sharp decline in CD4+ T cell counts and accelerated time to AIDS. Why this phenotypic switch to X4 occurs is not well understood. Previously, we used numerical simulations of a mathematical model to show that across much of parameter space a promising new class of antiretroviral treatments, CCR5 inhibitors, can accelerate X4 emergence and immunodeficiency. Here, we show that mathematical model to be a minimal activation-based HIV model that produces a spontaneous switch to X4 virus at a clinically-representative time point, while also matching in vivo data showing X4 and R5 coexisting and competing to infect memory CD4+ T cells. Our analysis shows that X4 avoids competitive exclusion from an initially fitter R5 virus due to X4v unique ability to productively infect nave CD4+ T cells. We further justify the generalized conditions under which this minimal model holds, implying that a phenotypic switch can even occur when the fraction of activated nave CD4+ T cells increases at a slower rate than the fraction of activated memory CD4+ T cells. We find that it is the ratio of the fractions of activated nave and memory CD4+ T cells that must increase above a threshold to produce a switch. This occurs as the concentration of CD4+ T cells drops beneath a threshold. Thus, highly active antiretroviral therapy (HAART), which increases CD4+ T cell counts and decreases cellular activation levels, inhibits X4 viral growth. However, we show here that even in the simplest dual-strain framework, competition between R5 and X4 viruses often results in accelerated X4 emergence in response to CCR5 inhibition, further highlighting the potential danger of anti-CCR5 monotherapy in multi-strain HIV infection. |
| format | Article |
| id | doaj-art-7b1148b91f7e49edb254d631d305f675 |
| institution | Kabale University |
| issn | 1551-0018 |
| language | English |
| publishDate | 2011-03-01 |
| publisher | AIMS Press |
| record_format | Article |
| series | Mathematical Biosciences and Engineering |
| spelling | doaj-art-7b1148b91f7e49edb254d631d305f6752025-01-24T02:01:39ZengAIMS PressMathematical Biosciences and Engineering1551-00182011-03-018260562610.3934/mbe.2011.8.605Persistence and emergence of X4 virus in HIV infectionAriel D. Weinberger0Alan S. Perelson1Graduate Group in Biophysics, University of California, Berkeley, Berkeley, CA 94720Graduate Group in Biophysics, University of California, Berkeley, Berkeley, CA 94720Approximately 50% of late-stage HIV patients develop CXCR4-tropic (X4) virus in addition to CCR5-tropic (R5) virus. X4 emergence occurs with a sharp decline in CD4+ T cell counts and accelerated time to AIDS. Why this phenotypic switch to X4 occurs is not well understood. Previously, we used numerical simulations of a mathematical model to show that across much of parameter space a promising new class of antiretroviral treatments, CCR5 inhibitors, can accelerate X4 emergence and immunodeficiency. Here, we show that mathematical model to be a minimal activation-based HIV model that produces a spontaneous switch to X4 virus at a clinically-representative time point, while also matching in vivo data showing X4 and R5 coexisting and competing to infect memory CD4+ T cells. Our analysis shows that X4 avoids competitive exclusion from an initially fitter R5 virus due to X4v unique ability to productively infect nave CD4+ T cells. We further justify the generalized conditions under which this minimal model holds, implying that a phenotypic switch can even occur when the fraction of activated nave CD4+ T cells increases at a slower rate than the fraction of activated memory CD4+ T cells. We find that it is the ratio of the fractions of activated nave and memory CD4+ T cells that must increase above a threshold to produce a switch. This occurs as the concentration of CD4+ T cells drops beneath a threshold. Thus, highly active antiretroviral therapy (HAART), which increases CD4+ T cell counts and decreases cellular activation levels, inhibits X4 viral growth. However, we show here that even in the simplest dual-strain framework, competition between R5 and X4 viruses often results in accelerated X4 emergence in response to CCR5 inhibition, further highlighting the potential danger of anti-CCR5 monotherapy in multi-strain HIV infection.https://www.aimspress.com/article/doi/10.3934/mbe.2011.8.605hivcoreceptorphenotypic switchx4r5. |
| spellingShingle | Ariel D. Weinberger Alan S. Perelson Persistence and emergence of X4 virus in HIV infection Mathematical Biosciences and Engineering hiv coreceptor phenotypic switch x4 r5. |
| title | Persistence and emergence of X4 virus in HIV infection |
| title_full | Persistence and emergence of X4 virus in HIV infection |
| title_fullStr | Persistence and emergence of X4 virus in HIV infection |
| title_full_unstemmed | Persistence and emergence of X4 virus in HIV infection |
| title_short | Persistence and emergence of X4 virus in HIV infection |
| title_sort | persistence and emergence of x4 virus in hiv infection |
| topic | hiv coreceptor phenotypic switch x4 r5. |
| url | https://www.aimspress.com/article/doi/10.3934/mbe.2011.8.605 |
| work_keys_str_mv | AT arieldweinberger persistenceandemergenceofx4virusinhivinfection AT alansperelson persistenceandemergenceofx4virusinhivinfection |