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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: 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.

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

Escape from CD8+ T-cell responses. (a) The colour of the line indicates the fraction of the viral population composed of escape mutants (growth rate, ρe = 7.6) or wild-type virus (ρ = 8.0), and changes from black (100% wild-type) to red (100% escape mutant). The dotted grey line shows the same time series where there is no escape possible from the CD8+ T-cell responses (ρe = 0), and with otherwise exactly the same parameters (parameters are identical to figure 2, except β = 0.8 (a(i)) and β = 0.3 (a(ii)). (b) Ratio of time of escape to time of progression to AIDS and its dependence on the strength of antibody and CD8+ T-cell responses. Time of escape is defined as the earliest time that the escape mutant achieves more than 50% prevalence, and time of progression to AIDS is defined as the time that φ reaches 0 (parameters are identical to figure 2).
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RSTB20140290F3: Escape from CD8+ T-cell responses. (a) The colour of the line indicates the fraction of the viral population composed of escape mutants (growth rate, ρe = 7.6) or wild-type virus (ρ = 8.0), and changes from black (100% wild-type) to red (100% escape mutant). The dotted grey line shows the same time series where there is no escape possible from the CD8+ T-cell responses (ρe = 0), and with otherwise exactly the same parameters (parameters are identical to figure 2, except β = 0.8 (a(i)) and β = 0.3 (a(ii)). (b) Ratio of time of escape to time of progression to AIDS and its dependence on the strength of antibody and CD8+ T-cell responses. Time of escape is defined as the earliest time that the escape mutant achieves more than 50% prevalence, and time of progression to AIDS is defined as the time that φ reaches 0 (parameters are identical to figure 2).

Mentions: Escape from CD8+ T-cell responses can be included within our framework by allowing for mutations that abrogate recognition but at a cost to viral fitness (see §5 Material and methods). However, due to the complex interplay between antibody and CD8+ T-cell responses, these escape mutants may only spread through the viral population long after first being generated by mutation (figure 3) and fluctuate in frequency thereafter—as has been observed in both HIV [41] and SIV [42] infection. In essence, the weakening of antibody responses increases the relative selection pressure exerted by CD8+ T cells, steadily tipping the evolutionary balance in favour of CD8+ T-cell escape mutants and ultimately leading to their dominance. Strong antibody responses can therefore prevent escape from occurring for an extended period, even in the presence of highly efficacious CD8+ T-cell responses (figure 3b). It is also clear in this model that the emergence of escape mutants is neither necessary nor sufficient for the transition to AIDS, but does lead to faster disease progression by precipitating an increase in set-point viraemia [43,44] and a consequently more rapid loss of CD4+ T cells. Once escape has occurred, time to AIDS is principally dependent on the potency of the antibody response (which explains why it is so similar between the examples of early and late escape shown in figure 3a), but may also be significantly affected by the relative fitness of the escape mutant (electronic supplementary material, figure S4).Figure 3.


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)

Escape from CD8+ T-cell responses. (a) The colour of the line indicates the fraction of the viral population composed of escape mutants (growth rate, ρe = 7.6) or wild-type virus (ρ = 8.0), and changes from black (100% wild-type) to red (100% escape mutant). The dotted grey line shows the same time series where there is no escape possible from the CD8+ T-cell responses (ρe = 0), and with otherwise exactly the same parameters (parameters are identical to figure 2, except β = 0.8 (a(i)) and β = 0.3 (a(ii)). (b) Ratio of time of escape to time of progression to AIDS and its dependence on the strength of antibody and CD8+ T-cell responses. Time of escape is defined as the earliest time that the escape mutant achieves more than 50% prevalence, and time of progression to AIDS is defined as the time that φ reaches 0 (parameters are identical to figure 2).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSTB20140290F3: Escape from CD8+ T-cell responses. (a) The colour of the line indicates the fraction of the viral population composed of escape mutants (growth rate, ρe = 7.6) or wild-type virus (ρ = 8.0), and changes from black (100% wild-type) to red (100% escape mutant). The dotted grey line shows the same time series where there is no escape possible from the CD8+ T-cell responses (ρe = 0), and with otherwise exactly the same parameters (parameters are identical to figure 2, except β = 0.8 (a(i)) and β = 0.3 (a(ii)). (b) Ratio of time of escape to time of progression to AIDS and its dependence on the strength of antibody and CD8+ T-cell responses. Time of escape is defined as the earliest time that the escape mutant achieves more than 50% prevalence, and time of progression to AIDS is defined as the time that φ reaches 0 (parameters are identical to figure 2).
Mentions: Escape from CD8+ T-cell responses can be included within our framework by allowing for mutations that abrogate recognition but at a cost to viral fitness (see §5 Material and methods). However, due to the complex interplay between antibody and CD8+ T-cell responses, these escape mutants may only spread through the viral population long after first being generated by mutation (figure 3) and fluctuate in frequency thereafter—as has been observed in both HIV [41] and SIV [42] infection. In essence, the weakening of antibody responses increases the relative selection pressure exerted by CD8+ T cells, steadily tipping the evolutionary balance in favour of CD8+ T-cell escape mutants and ultimately leading to their dominance. Strong antibody responses can therefore prevent escape from occurring for an extended period, even in the presence of highly efficacious CD8+ T-cell responses (figure 3b). It is also clear in this model that the emergence of escape mutants is neither necessary nor sufficient for the transition to AIDS, but does lead to faster disease progression by precipitating an increase in set-point viraemia [43,44] and a consequently more rapid loss of CD4+ T cells. Once escape has occurred, time to AIDS is principally dependent on the potency of the antibody response (which explains why it is so similar between the examples of early and late escape shown in figure 3a), but may also be significantly affected by the relative fitness of the escape mutant (electronic supplementary material, figure S4).Figure 3.

Bottom Line: 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.

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