6 June 2023 HIV Capsid as target for antiviral treatment

Episode 335: HIV capsid inhibition as a target for anti-retroviral therapy (ART)

Dear colleagues,

The very abundant HIV capsid (CA or p24 protein) is highly conserved and has multiple functions in the cell cycle, interacting with various human proteins, either as (positive) co-factors or (negative) restrictions. It is therefore an ideal potential target of anti-viral therapy. As we will see in this Episode, a number of candidates has been tested against 5 different sites in the CA protein.  Of those only one has made it until now: GS-6207 = Lenacapavir (LEN) = Sunleca®).  LEN belongs to a novel class, very different from the entry/fusion-inhibitors as well as the enzyme (RT-INT and protease) antagonists.  Therefore it shows no cross-resistance and seems ideal for heavily pre-treated patients with m:ulti-drug resistant viruses. In addition, it has a very long half-life allowing a regimen with subcuteaneous dosing every 6 months.

See     

Par 1 Structure and function of capsid 

Ep 335-1: Eric Rossi Capsid protein structure and function Life 2021.pdf

Genetic organization

Capsid (CA or p24) is the major part of the Gag polyprotein

Overall structure

The capsid core (fullerene cone structure) is composed of capsid proteins (CA), also known as p24, that form pentameric and hexameric subunits, which assemble into the mature viral capsid.

It has a conical structure and surrounds the 2 viral genomic RNA + reverse transcriptase and integrase enzymes.  

CA within the viral particle

Viral cycle and functions of CA

Functions of capsid:

• CA shields the reverse transcription complex from cellular restriction factors
• It enables trafficking to the nucleus by hijacking various human adaptor proteins, such as FEZ1 and BICD2.
• It facilitates the import of the viral complex in the nucleus through interaction with NUP153, NUP358, TNPO3, and CPSF-6.
• In the later stages of the HIV-1 life cycle, CA plays an essential role in the maturation step as a constituent of the Gag polyprotein.
• Finally, Gag is cleaved, and CA is released, allowing for the assembly of CA into a fullerene cone, known as the capsid core.

Par 2 Development of CA-specific antivirals

Ep 335-2 : Mc Fadden Retrovirology 2021 Overview on potential antivirals targeting the HIV Capsid

Binding sites of CA-targeting antivirals in mature HIV-1 CA monomers and hexamers.

A The five CA-targeting antiviral binding sites are shown mapped onto the HIV-1 CA monomer.

CA N-terminal domains NTDs are shown in light gray, CA C-terminal domains CTDs are shown in dark gray.

Binding site 1 is shown in red, binding site 2 in orange, binding site 3 in yellow, binding site 4 in green, and binding site 5 in blue. The view is rotated by 180°.

B The same domains and five CA-targeting antiviral binding sites are shown mapped onto the HIV-1 CA hexamer. Colors are as described in A. The views are rotated by 90°.

C Schematic outlining the domains, binding sites, and secondary structure of HIV-1 CA. Compound binding sites are colored as

described in A, and the Cyclophilin A binding loop (CypA-BL) is shown as pink circles. The CA-NTD and CA-CTD are shown as light and dark gray bars, respectively. The β-hairpin (βPin) and α-helices (α) shown as gray arrows and twists, respectively.

Table 1 Chemical structures of each CA-targeting antiviral discussed

As can be seen, the compound GS-6207 that binds to site 1 (FG or Phenyl-Alanine dipeptide binding site):  

• Inhibits CA function both early and late (= maturation) in the cycle.
• Has a very favorable therapeutic index (50 % cytotoxicity / 50 % effective concentration = > 50,000).   
• Is active after either oral or subcutaneous administration
• Has a very long half-life allowing maintenance once in 6 months.

This compound was further developed by Gilead as Lenacapavir (or Sunlenca® in EU).

Ep 335-3: Segal‑Maurer NEJM Jan 2023 CAPELLA trial = Phase 3 of Lenacapavir in multi-resistant HIV-1 patients.   

Set-up

Cohort 1 is 36 pt with 24 on functional monotherapy (= oral Lenacapavir + failing ART)) and 12 on placebo (+failing ART) during 2 weeks, followed by lenacapavir subcutaneous every 6 months + optimized background therapy.

Cohort 2 is 36 pt with open label Lenacapvir + optimized background

Result:

Clear effect on viral load after 2 weeks of functional monotherapy

High rate (> 80 %) of viral suppression after 26 weeks with increase of CD4 T cell counts.

Ep 335-4: Samir Gupta Lancet HIV Jan 2023: Open label phase 2 of Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV.

Set-up: 4 groups

Result:

Conclusion: SC or oral Lenacapavir + Emtricitabine (3TC) + Tenofovir alafenamide (TAF), followed  TAF; Bictegravir or 3TC + TAF → high rates of virological suppression for 54 weeks in people with HIV who were starting therapy.  

Episode 335-5: EMA Aug 2022: Approval of Sunlenca® (Lenacapavir)

Indication: Sunlenca injection, in combination with other antiretroviral(s), is indicated for the treatment of adults

with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen.

HIV susceptibility and resistance

1. Lenacapavir antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, A1, AE, AG, B, BF, C, D, E, F, G, H. BUT was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1.

2. Resistance selections with lenacapavir in vitro identified 7 mutations in CA: L56I, M66I, Q67H, K70N, N74D/S, and T107N singly or in dual combination

Ep 335-6:  Nka JAC 2022 on natural resistance (DRM) in drug-naïve individuals

The overall prevalence of lenacapavir DRMs was 0.14% (3/2031)

M66I (0.05%) and Q67H (0.05%) observed in subtype C, and T107N (0.05%) observed in CRF01_AE.

Ep 335-7: Nicolas Margor JID Nov 2022: Resistance in highly experienced patients then treaten with Lenacapavir

Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection.

I hope you enjoyed this episode?

Best wishes,

Guido