Post-treatment control of HIV infection

Abstract

Antiretroviral therapy (ART) for HIV is not a cure. However, recent studies suggest that ART, initiated early during primary infection, may induce post-treatment control (PTC) of HIV infection with HIV RNA maintained at <50 copies per mL. We investigate the hypothesis that ART initiated early during primary infection permits PTC by limiting the size of the latent reservoir, which, if small enough at treatment termination, may allow the adaptive immune response to prevent viral rebound (VR) and control infection. We use a mathematical model of within host HIV dynamics to capture interactions among target cells, productively infected cells, latently infected cells, virus, and cytotoxic T lymphocytes (CTLs). Analysis of our model reveals a range in CTL response strengths where a patient may show either VR or PTC, depending on the size of the latent reservoir at treatment termination. Below this range, patients will always rebound, whereas above this range, patients are predicted to behave like elite controllers. Using data on latent reservoir sizes in patients treated during primary infection, we also predict population-level VR times for noncontrollers consistent with observations.

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

“…As the infection was cleared, the CTL population declined and reached a new steady state corresponding to the level in the absence of infection and exhaustion (Figure 2c). (Note that immunological memory is not explicitly considered in this model, in keeping with extant models of CTL exhaustion 34, 36…”

“…The description has been employed successfully to explain the post‐treatment control of HIV‐1 infection 36. More sophisticated models that incorporate the dependence of exhaustion on sustained antigenic stimulation have been proposed,35, 37 but have been argued to have similar qualitative features as the simpler model employed here 36. Third, studies have argued that in addition to CTL function, NK cell function is restored during IFN‐free DAA therapy,53 which we did not consider.…”

“…Second, we considered the simplest model of CTL dynamics that includes antigen‐driven activation and exhaustion. The description has been employed successfully to explain the post‐treatment control of HIV‐1 infection 36. More sophisticated models that incorporate the dependence of exhaustion on sustained antigenic stimulation have been proposed,35, 37 but have been argued to have similar qualitative features as the simpler model employed here 36.…”

“…We let the death rate of infected cells other than by CTL killing be the same as the natural death rate of target cells, neglecting any HCV‐induced cytopathicity; thus, ω =  d T . We let the CTL production, death and activation rates be λ = 1 cell mL −1 day −1 , μ = 2 day −1 , b E  = 1 day −1 and k B  = 10 3  cells mL −1 35, 36. The viral production and clearance rates, p and c , the drug efficacy, ε, the strength of CTL killing, m , and the parameters governing CTL exhaustion, d E , k D and n , are expected to vary across individuals.…”

“…Data of viral load changes past the EOT were not available to define these parameters uniquely. To restrict choices, we let n  =   3, a value used previously 36. (Using n  =   1, also used previously,36 did not alter the stability properties; see Supplementary figure 5.)…”