2011, 8(2): 605-626. doi: 10.3934/mbe.2011.8.605

Persistence and emergence of X4 virus in HIV infection

1. 

Graduate Group in Biophysics, University of California, Berkeley, Berkeley, CA 94720, United States

2. 

Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM 87545, United States

Received  March 2010 Revised  November 2010 Published  April 2011

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.
Citation: Ariel D. Weinberger, Alan S. Perelson. Persistence and emergence of X4 virus in HIV infection. Mathematical Biosciences & Engineering, 2011, 8 (2) : 605-626. doi: 10.3934/mbe.2011.8.605
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show all references

References:
[1]

H. Blaak, A. B. van't Wout, M. Brouwer, B. Hooibrink, E. Hovenkamp and H. Schuitemaker, In vivo HIV-1 infection of CD45RA(+)CD4(+) T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4(+) T cell decline,, Proc. Natl. Acad. Sci. U.S.A., 97 (2000), 1269.

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[3]

C. H. Casper, P. Clevestig, E. Carlenor, T. Leitner, B. Anzén, K. Lidman, E. Belfrage, J. Albert, A. B. Bohlin, L. Navér, S. Lindgren, E. M. Fenyö and A. C. Ehrnst, Link between the X4 phenotype in human immunodeficiency virus type 1-infected mothers and their children, despite the early presence of R5 in the child,, J. Infect. Dis., 186 (2002), 914.

[4]

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[5]

H. Y. Chen, M. Di Mascio, A. S. Perelson, D. D. Ho and L. Zhang, Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques,, Proc. Natl. Acad. Sci. U.S.A., 104 (2007), 19079.

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E. Coakley, C. J. Petropoulos and J. M. Whitcomb, Assessing chemokine co-receptor usage in HIV,, Curr. Opin. Infect. Dis., 18 (2005), 9.

[7]

M. Cornelissen, G. Mulder-Kampinga, J. Veenstra, F. Zorgdrager, C. Kuiken, S. Hartman, J. Dekker, L. van der Hoek, C. Sol and R. Coutinho, Syncytium-inducing (SI) phenotype suppression at seroconversion after intramuscular inoculation of a non-syncytium-inducing/SI phenotypically mixed human immunodeficiency virus population,, J. Virol., 69 (1995), 1810.

[8]

M. P. Davenporta, J. J. Zaundersb, M. D. Hazenbergc, H. Schuitemakerc and R. P. van Rijc, Cell turnover and cell tropism in HIV-1 infection,, Trends Microbiol., 10 (2002), 275.

[9]

P. Delobel, K. Sandres-Sauné, M. Cazabat, C. Pasquier, B. Marchou, P. Massip and J. Izopet, R5 to X4 switch of the predominant HIV-1 population in cellular reservoirs during effective highly active antiretroviral therapy,, J. Acquir. Immune. Defic. Syndr., 38 (2005), 382.

[10]

D. C. Douek, Disrupting T-cell homeostasis: How HIV-1 infection causes disease,, AIDS Rev., 5 (2003), 172.

[11]

D. C. Douek, L. J. Picker and R. A. Koup, T cell dynamics in HIV-1 infection,, Annu. Rev. Immunol., 21 (2003), 265.

[12]

O. Equils, E. Garratty, L. S. Wei, S. Plaeger, M. Tapia, J. Deville, P. Krogstad, S. MyungShin, K. Nielsen and Y. J. Bryson, Recovery of replication-competent virus from CD4 T cell reservoirs and change in coreceptor use in human immunodeficiency virus type 1-infected children responding to highly active antiretroviral therapy,, J. Infect. Dis., 182 (2000), 751.

[13]

J. M. Farber and E. A. Berger, HIV's response to a CCR5 inhibitor: I'd rather tighten than switch!,, Proc. Natl. Acad. Sci. U.S.A., 99 (2002), 1749.

[14]

J. V. Giorgi, L. E. Hultin, J. A. McKeating, T. D. Johnson, B. Owens, L. P. Jacobson, R. Shih, J. Lewis, D. J. Wiley, J. P. Phair, S. M. Wolinsky and R. Detels, Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage,, J. Infect. Dis., 179 (1999), 859.

[15]

F. Gondois-Rey, A. Biancotto, M. A. Fernandez, L. Bettendroffer, J. Blazkova, K. Trejbalova, M. Pion and I. Hirsch, R5 variants of human immunodeficiency virus type 1 preferentially infect CD62L- CD4+ T cells and are potentially resistant to nucleoside reverse transcriptase inhibitors,, J. Virol., 80 (2006), 854.

[16]

F. Gondois-Rey, J. C. Grivel, A. Biancotto, M. Pion, R. Vigne, L. B. Margolis and I. Hirsch, Segregation of R5 and X4 HIV-1 variants to memory T cell subsets differentially expressing CD62L in ex vivo infected human lymphoid tissue,, AIDS, 16 (2002), 1245.

[17]

A. T. Haase, Population biology of HIV-1 infection: Viral and CD4+ T cell demographics and dynamics in lymphatic tissues,, Annu. Rev. Immunol., 17 (1999), 625.

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