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Drug-resistant HIV-1 has caused a growing concern in clinic and public health. Although combination antiretroviral therapy can contribute massively to the suppression of viral loads in patients with HIV-1, it cannot lead to viral eradication. Continuing viral replication during sub-optimal therapy (due to poor adherence or other reasons) may lead to the accumulation of drug resistance mutations, resulting in an increased risk of disease progression. Many studies also suggest that events occurring during the early stage of HIV-1 infection (i.e., the first few hours to days following HIV exposure) may determine whether the infection can be successfully established. However, the numbers of infected cells and viruses during the early stage are extremely low and stochasticity may play a critical role in dictating the fate of infection. In this paper, we use stochastic models to investigate viral infection and the emergence of drug resistance of HIV-1. The stochastic model is formulated by a continuous-time Markov chain (CTMC), which is derived based on an ordinary differential equation model proposed by Kitayimbwa et al. that includes both forward and backward mutations. An analytic estimate of the probability of the clearance of HIV infection of the CTMC model near the infection-free equilibrium is obtained by a multitype branching process approximation. The analytical predictions are validated by numerical simulations. Unlike the deterministic dynamics where the basic reproduction number $$ \mathcal{R}_0 $$ serves as a sharp threshold parameter (i.e., the disease dies out if $$ \mathcal{R}_0 < 1 $$ and persists if $$ \mathcal{R}_0 > 1 $$), the stochastic models indicate that there is always a positive probability for HIV infection to be eradicated in patients. In the presence of antiretroviral therapy, our results show that the chance of clearance of the infection tends to increase although drug resistance is likely to emerge.
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Sustained Delivery of the Antiviral Protein Griffithsin and Its Adhesion to a Biological Surface by a Silk Fibroin Scaffold
The protein Griffithsin (Grft) is a lectin that tightly binds to high-mannose glycosylation sites on viral surfaces. This property allows Grft to potently inhibit many viruses, including HIV-1. The major route of HIV infection is through sexual activity, so an important tool for reducing the risk of infection would be a film that could be inserted vaginally or rectally to inhibit transmission of the virus. We have previously shown that silk fibroin can encapsulate, stabilize, and release various antiviral proteins, including Grft. However, for broad utility as a prevention method, it would be useful for an insertable film to adhere to the mucosal surface so that it remains for several days or weeks to provide longer-term protection from infection. We show here that silk fibroin can be formulated with adhesive properties using the nontoxic polymer hydroxypropyl methylcellulose (HPMC) and glycerol, and that the resulting silk scaffold can both adhere to biological surfaces and release Grft over the course of at least one week. This work advances the possible use of silk fibroin as an anti-viral insertable device to prevent infection by sexually transmitted viruses, including HIV-1.
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- Award ID(s):
- 2112675
- PAR ID:
- 10527299
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- Materials
- Volume:
- 16
- Issue:
- 16
- ISSN:
- 1996-1944
- Page Range / eLocation ID:
- 5547
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/ma16165547
