Modeling HIV Pre-Exposure Prophylaxis

Straubinger, Thomas; Kay, Katherine; Bies, Robert R.

doi:10.3389/fphar.2019.01514

Cited by 7 publications

(4 citation statements)

References 62 publications

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“…At the individual level, prophylactic treatment may decrease or ideally prevent viraemia, which may consequently reduce or prevent progression to clinical disease 3 , 21 . At the community level, it might exert its effect through the prevention or reduction of DENV transmission from human to mosquito and, therefore, potentially stop dengue outbreaks 37 . Nevertheless, the long-term use of a prophylactic agent may facilitate the development of resistant variants when residual virus is still propagating.…”

Section: Discussionmentioning

confidence: 99%

Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates

Goethals

Kaptein

Kesteleyn

et al. 2023

Nature

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Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802—a highly potent DENV inhibitor that blocks the NS3–NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.

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Section: Discussionmentioning

confidence: 99%

Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates

Goethals

Kaptein

Kesteleyn

et al. 2023

Nature

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“…Moreover, as HIV patients need long-term medication, metabolic concerns, tissue damage and associated aging emerge as a challenge for new drugs and ART regimes (Chawla et al, 2018;Gu et al, 2020). Thus, promising results have been obtained with pre-exposure prophylaxis (PrEP) strategies, which aim to prevent both HIV-1 infection and transmission and are highly dependent on patient adherence (Straubinger et al, 2019), or by using broadly neutralizing antibodies (bnAbs) that could achieve prolonged viral suppression by directly targeting different epitopes from key viral proteins and activating the immune response in order to remove Ab-targeted infected cells (Carrillo et al, 2018;Kumar et al, 2018;Grobben et al, 2019).…”

Section: Introduction a General Overview Of Hiv: Factors Related To The Control Of The Infection And Pathogenesismentioning

confidence: 99%

The Interplay of HIV and Autophagy in Early Infection

et al. 2021

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HIV/AIDS is still a global threat despite the notable efforts made by the scientific and health communities to understand viral infection, to design new drugs or to improve existing ones, as well as to develop advanced therapies and vaccine designs for functional cure and viral eradication. The identification and analysis of HIV-1 positive individuals that naturally control viral replication in the absence of antiretroviral treatment has provided clues about cellular processes that could interact with viral proteins and RNA and define subsequent viral replication and clinical progression. This is the case of autophagy, a degradative process that not only maintains cell homeostasis by recycling misfolded/old cellular elements to obtain nutrients, but is also relevant in the innate and adaptive immunity against viruses, such as HIV-1. Several studies suggest that early steps of HIV-1 infection, such as virus binding to CD4 or membrane fusion, allow the virus to modulate autophagy pathways preparing cells to be permissive for viral infection. Confirming this interplay, strategies based on autophagy modulation are able to inhibit early steps of HIV-1 infection. Moreover, autophagy dysregulation in late steps of the HIV-1 replication cycle may promote autophagic cell-death of CD4+ T cells or control of HIV-1 latency, likely contributing to disease progression and HIV persistence in infected individuals. In this scenario, understanding the molecular mechanisms underlying HIV/autophagy interplay may contribute to the development of new strategies to control HIV-1 replication. Therefore, the aim of this review is to summarize the knowledge of the interplay between autophagy and the early events of HIV-1 infection, and how autophagy modulation could impair or benefit HIV-1 infection and persistence, impacting viral pathogenesis, immune control of viral replication, and clinical progression of HIV-1 infected patients.

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“…The availability of a topical microbicide against HIV-1 infection would offer an alternative to condoms as the most feasible method for HIV-1 prevention and would greatly contribute to a decrease in the new cases of HIV-1 infections worldwide and halt the epidemic [ 3 ]. In spite of the knowledge of successful HIV-1 prevention strategies, such as condom use, reduction of sexual partners, pre-exposure prophylaxis (PrEP) [ 19 , 20 ] and early diagnosis and treatment [ 21 ], HIV-1 continues to spread at an alarming rate, especially in developing countries, where women are a remarkably vulnerable. Microbicides are a potential HIV-1 prophylactic method that women can easily control and do not require the cooperation, consent or even knowledge of the partner, and thus, it would empower women in developing countries or resource-poor settings to protect themselves and their partners.…”

Section: Discussionmentioning

confidence: 99%

Safety of G2-S16 Polyanionic Carbosilane Dendrimer as Possible HIV-1 Vaginal Microbicide

Martín-Moreno

Ceña-Díez

Serramía

et al. 2022

IJMS

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The UNAIDS objective for 2020 was 500,000 new HIV-1 infections per year; however, the latest annual reported data confirmed 1.7 million new HIV-1 infections in that year. Those data evidences the need for new prevention strategies and prophylactic treatments. This prevention crisis occurred in spite of the knowledge and availability of efficient prevention strategies. The G2-S16 is a microbicidal polyanionic carbosilane dendrimer currently being tested for topical vaginal application, which has been shown to be efficient in the prevention of HIV-1 infection. However, safety tests were lacked. For this purpose, we injected intravenously G2-S16 dendrimer to CD1 mice, thereby analyzing the hemogram, blood biochemical markers of systemic damage, accumulation in the organs and organ-tissue damage in heart, spleen, kidney, liver and brain. This work shows that even if the G2-S16 dendrimer penetrates the epithelial tissue, it does not cause vaginal irritation or tissue damage. Moreover, the i.v. injection of the G2-S16 dendrimer did not cause a damaging effect on the studied organs and it did not modify the hemogram or the biochemical plasma markers. In conclusion, the G2-S16 dendrimer has a very good safety profile, indicating that this molecule can be a very safe and efficient vaginal microbicide.

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Modeling HIV Pre-Exposure Prophylaxis

Cited by 7 publications

References 62 publications

Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates

Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates

The Interplay of HIV and Autophagy in Early Infection

Safety of G2-S16 Polyanionic Carbosilane Dendrimer as Possible HIV-1 Vaginal Microbicide

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