Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

Abstract

Antiretroviral therapy (ART) for HIV-1 infection is lifelong. Stopping therapy typically leads to the reignition of infection and progressive disease. In a major breakthrough, recent studies have shown that early initiation of ART can lead to sustained post-treatment control of viremia, raising hopes of long-term HIV-1 remission. ART, however, elicits post-treatment control in a small fraction of individuals treated. Strikingly, passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 early in infection was found recently to elicit longterm control in a majority of SHIV-infected macaques, suggesting that HIV-1 remission may be more widely achievable. The mechanisms underlying the control elicited by bNAb therapy, however, remain unclear. Untreated infection typically leads to progressive disease. We hypothesized that viremic control represents an alternative but rarely realized outcome of the infection and that early bNAb therapy triggers a dynamical switch to this outcome. To test this hypothesis, we constructed a model of viral dynamics with bNAb therapy and applied it to analyse clinical data. The model fit quantitatively the complex longitudinal viral load data from macaques that achieved lasting control. The model predicted, consistently with our hypothesis, that the underlying system exhibited bistability, indicating two potential outcomes of infection. The first had high viremia, weak cytotoxic effector responses, and high effector exhaustion, marking progressive disease. The second had low viremia, strong effector responses, and low effector exhaustion, indicating lasting viremic control. Further, model predictions suggest that early bNAb therapy elicited lasting control via pleiotropic effects. bNAb therapy lowers viremia, which would also limit immune exhaustion. Simultaneously, it can improve effector stimulation via cross-presentation. Consequently, viremia may resurge post-therapy, but would encounter a primed effector population and eventually get controlled. ART suppresses viremia but does not enhance effector stimulation, explaining its limited ability to elicit post-treatment control relative to bNAb therapy.

Pre-existing resistance in the latent reservoir can compromise VRC01 therapy during chronic HIV-1 infection

“…The virions produced, being bNAb sensitive, would get neutralized and cleared by the bNAbs. Previous studies have argued that in the process bNAbs can stimulate CD8 T cells [ 20 , 87 ], improving the overall immune activation status, possibly explaining the higher latency reactivation rate we required to describe VRC01 failure than previously used to describe historical controls [ 38 ]. Our parameters would thus tend to underpredict the remission times in the historical controls.…”

“…The sample sizes involved in the clinical trials we studied were small,~10-15 patients each [17]. Nonlinear mixed-effects models have been used in recent studies to infer the effects of interventions by analyzing data from such trials [86][87][88]. For instance, bNAb therapy was argued to improve immune responses 8-fold over controls and not to synergize with the TLR7-agonist [86].…”

“…bNAbs are known to engage the immune system via multiple mechanisms [20,87,[89][90][91]. The result could be heightened activation, which for HIV-1 infection, could mean greater susceptibility of target CD4 T cells.…”

In silico dynamics of COVID-19 phenotypes for optimizing clinical management

“…inhibitors and hrACE2 for the diabetic patients, in particular. Interestingly, the fact that progression of viral infections can be generalized as the result of interactions between CD8 + T cells and antigens has been shown by mathematical models focused on other types of viruses, such as hepatitis C, HIV-1, and simian HIV (48)(49)(50)(51).…”

“…In case of patients with comorbidities (obesity, diabetes, hypertension) or dysregulated immunity, the treatment regimen could further include antiinflammatory drugs (e.g., anti-IL6/anti-IL6R) and RAS inhibitors and hrACE2 for the diabetic patients, in particular. Interestingly, the fact that progression of viral infections can be generalized as the result of interactions between CD8 + T cells and antigens has been shown by mathematical models focused on other types of viruses, such as hepatitis C, HIV-1, and simian HIV ( 48 – 51 ).…”