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Effects of neutralizing antibodies on escape from CD8+ T-cell responses in HIV-1 infection.

Wikramaratna PS, Lourenço J, Klenerman P, Pybus OG, Gupta S - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

Bottom Line: Despite substantial advances in our knowledge of immune responses against HIV-1 and of its evolution within the host, it remains unclear why control of the virus eventually breaks down.Here, we present a new theoretical framework for the infection dynamics of HIV-1 that combines antibody and CD8(+) T-cell responses, notably taking into account their different lifespans.Several apparent paradoxes in HIV pathogenesis and genetics of host susceptibility can be reconciled within this framework by assigning a crucial role to antibody responses in the control of viraemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.

ABSTRACT
Despite substantial advances in our knowledge of immune responses against HIV-1 and of its evolution within the host, it remains unclear why control of the virus eventually breaks down. Here, we present a new theoretical framework for the infection dynamics of HIV-1 that combines antibody and CD8(+) T-cell responses, notably taking into account their different lifespans. Several apparent paradoxes in HIV pathogenesis and genetics of host susceptibility can be reconciled within this framework by assigning a crucial role to antibody responses in the control of viraemia. We argue that, although escape from or progressive loss of quality of CD8(+) T-cell responses can accelerate disease progression, the underlying cause of the breakdown of virus control is the loss of antibody induction due to depletion of CD4(+) T cells. Furthermore, strong antibody responses can prevent CD8(+) T-cell escape from occurring for an extended period, even in the presence of highly efficacious CD8(+) T-cell responses.

No MeSH data available.


Related in: MedlinePlus

Model schematic. The population of viral variants of antigenic type i (vi) stimulates (shown by blue arrows) specific and partially cross-reactive antibodies as well as non-specific effector CD8+ T-cell responses. CD4+ T-cell help is essential for the induction of the antibody responses. vi can be attacked by all of these responses (shown by red bars) as well by partially cross-reactive antibodies (shown by green bars) raised against other variants j (stacked one behind the other) which share epitopes with i. CD4+ T-cells are attacked by all viral variants (as shown by pink bars): this is captured in the model by a reduction in CD4+ T-cell dependent strength of antibody induction, φ. All viral variants grow at a rate ρ; μu, μw and μz, respectively, represent the death rates of effector CD8+ T cells, specific and partially cross-reactive antibodies. See §5 Material and methods for further details.
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RSTB20140290F1: Model schematic. The population of viral variants of antigenic type i (vi) stimulates (shown by blue arrows) specific and partially cross-reactive antibodies as well as non-specific effector CD8+ T-cell responses. CD4+ T-cell help is essential for the induction of the antibody responses. vi can be attacked by all of these responses (shown by red bars) as well by partially cross-reactive antibodies (shown by green bars) raised against other variants j (stacked one behind the other) which share epitopes with i. CD4+ T-cells are attacked by all viral variants (as shown by pink bars): this is captured in the model by a reduction in CD4+ T-cell dependent strength of antibody induction, φ. All viral variants grow at a rate ρ; μu, μw and μz, respectively, represent the death rates of effector CD8+ T cells, specific and partially cross-reactive antibodies. See §5 Material and methods for further details.

Mentions: We visualize the virus as containing (i) CD8+ T-cell epitopes of limited variability that elicit cytotoxic responses [27] that decay rapidly in the absence of antigen [5,28], (ii) highly variable epitopes (specifically in the Env glycoprotein) that elicit both highly specific NAb responses maintained by long-lived plasma cells [29,30] and more broadly cross-reactive responses (CR-Ab) of shorter duration. Within our model, CD4+ T cells are necessary for the induction of the antibody responses but do not influence the induction of effector CD8+ T-cell responses (although they may have a role in the establishment of CD8+ T-cell memory). Finally, we assume that CD4+ cell counts decline at a rate proportional to viraemia. A schematic of the model structure is provided in figure 1 and the corresponding equations are shown in §5 Material and methods.Figure 1.


Effects of neutralizing antibodies on escape from CD8+ T-cell responses in HIV-1 infection.

Wikramaratna PS, Lourenço J, Klenerman P, Pybus OG, Gupta S - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

Model schematic. The population of viral variants of antigenic type i (vi) stimulates (shown by blue arrows) specific and partially cross-reactive antibodies as well as non-specific effector CD8+ T-cell responses. CD4+ T-cell help is essential for the induction of the antibody responses. vi can be attacked by all of these responses (shown by red bars) as well by partially cross-reactive antibodies (shown by green bars) raised against other variants j (stacked one behind the other) which share epitopes with i. CD4+ T-cells are attacked by all viral variants (as shown by pink bars): this is captured in the model by a reduction in CD4+ T-cell dependent strength of antibody induction, φ. All viral variants grow at a rate ρ; μu, μw and μz, respectively, represent the death rates of effector CD8+ T cells, specific and partially cross-reactive antibodies. See §5 Material and methods for further details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528488&req=5

RSTB20140290F1: Model schematic. The population of viral variants of antigenic type i (vi) stimulates (shown by blue arrows) specific and partially cross-reactive antibodies as well as non-specific effector CD8+ T-cell responses. CD4+ T-cell help is essential for the induction of the antibody responses. vi can be attacked by all of these responses (shown by red bars) as well by partially cross-reactive antibodies (shown by green bars) raised against other variants j (stacked one behind the other) which share epitopes with i. CD4+ T-cells are attacked by all viral variants (as shown by pink bars): this is captured in the model by a reduction in CD4+ T-cell dependent strength of antibody induction, φ. All viral variants grow at a rate ρ; μu, μw and μz, respectively, represent the death rates of effector CD8+ T cells, specific and partially cross-reactive antibodies. See §5 Material and methods for further details.
Mentions: We visualize the virus as containing (i) CD8+ T-cell epitopes of limited variability that elicit cytotoxic responses [27] that decay rapidly in the absence of antigen [5,28], (ii) highly variable epitopes (specifically in the Env glycoprotein) that elicit both highly specific NAb responses maintained by long-lived plasma cells [29,30] and more broadly cross-reactive responses (CR-Ab) of shorter duration. Within our model, CD4+ T cells are necessary for the induction of the antibody responses but do not influence the induction of effector CD8+ T-cell responses (although they may have a role in the establishment of CD8+ T-cell memory). Finally, we assume that CD4+ cell counts decline at a rate proportional to viraemia. A schematic of the model structure is provided in figure 1 and the corresponding equations are shown in §5 Material and methods.Figure 1.

Bottom Line: Despite substantial advances in our knowledge of immune responses against HIV-1 and of its evolution within the host, it remains unclear why control of the virus eventually breaks down.Here, we present a new theoretical framework for the infection dynamics of HIV-1 that combines antibody and CD8(+) T-cell responses, notably taking into account their different lifespans.Several apparent paradoxes in HIV pathogenesis and genetics of host susceptibility can be reconciled within this framework by assigning a crucial role to antibody responses in the control of viraemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.

ABSTRACT
Despite substantial advances in our knowledge of immune responses against HIV-1 and of its evolution within the host, it remains unclear why control of the virus eventually breaks down. Here, we present a new theoretical framework for the infection dynamics of HIV-1 that combines antibody and CD8(+) T-cell responses, notably taking into account their different lifespans. Several apparent paradoxes in HIV pathogenesis and genetics of host susceptibility can be reconciled within this framework by assigning a crucial role to antibody responses in the control of viraemia. We argue that, although escape from or progressive loss of quality of CD8(+) T-cell responses can accelerate disease progression, the underlying cause of the breakdown of virus control is the loss of antibody induction due to depletion of CD4(+) T cells. Furthermore, strong antibody responses can prevent CD8(+) T-cell escape from occurring for an extended period, even in the presence of highly efficacious CD8(+) T-cell responses.

No MeSH data available.


Related in: MedlinePlus