Capsid-Dependent Host Factors in HIV-1 Infection

Abstract

After invasion of a susceptible target cell, HIV-1 completes the early phase of its life cycle upon integration of reverse-transcribed viral DNA into host chromatin. The viral capsid, a conical shell encasing the viral ribonucleoprotein complex, along with its constitutive capsid protein, plays essential roles at virtually every step in the early phase of the viral life cycle. Recent work has begun to reveal how the viral capsid interacts with specific cellular proteins to promote these processes. At the same time, cellular restriction factors target the viral capsid to thwart infection. Comprehensive understanding of capsid-host interactions that promote or impede HIV-1 infection may provide unique insight to exploit for novel therapeutic interventions.

Keywords: HIV/AIDS; capsid; host proteins; post-entry events; virus integration; virus–host interactions.

Figure 1. HIV-1 CA structures and common host factor interaction sites

(a) Monomeric CA (NTD, green; CTD, cyan; flexible loop, black) highlighting the CypA-binding loop (dashed oval) as well as residues and secondary structural elements that mediate CPSF6 or NUP153 binding (gray circle). Protein database (PDB) accession code 4XFY [146]. (b) CA hexamer (PDB code 4U0D) [69] views from the cytoplasmic face of the capsid (top) or rotated 90° up into the plane (bottom). Residues highlighted in (a) are shown in space fill in two adjacent gray monomers. Coloring highlights NTD (green and yellow) and CTD (cyan and orange) interactions between adjacent monomers. (c) Close up view of the CypA (light gray)-CA NTD interaction (PDB code 1AK4) [20]. Host factor residues are denoted by italic type; dashed lines, hydrogen bonds. (d) The NUP358 CHD (light gray)-CA NTD interaction (PDB code 4LQW) [81]. (e) Primary interaction site between CPSF6_313-327 (magenta) and the CA NTD (PDB code 4U0B) [69]. (f) Co-crystal structure of NUP153_1407-1423 (magenta) with hexameric CA (PDB code 4U0D) [69]. In (e) and (f), HIV-1 CA Asn57 engages similarly positioned hotspot Phe residues (F321 in CPSF6; F1417 in NUP153). Yellow and orange in (f) are the NTD and CTD, respectively, of an adjacent CA monomer (see panel b).

Figure 2. Capsid-dependent host factors for post-entry events of HIV-1 infection

Incoming viral capsids traffic towards the nuclear membrane, and subviral complexes can directly interact with NPC components such as NUP358 and NUP153. HIV-1 nuclear entry is mediated by these NUPs as well as soluble import receptors such as CPSF6/TNPO3. Intranuclear localization of PICs is regulated by CPSF6. Cellular proteins can promote (shown in blue) or block (shown in red) HIV-1 infection. The intact capsid near the cell periphery is depicted partially uncoated at the NPC, and more fully uncoated after nuclear entry. Host factors known to interact with the capsid or modulate uncoating or integration site selection are shown in this illustration. The positioning of the different factors in the figure is not meant to necessarily imply the location or timing of the virus-host interaction.