Advances in HIV-1 Assembly and Release

Advances in HIV-1 Assembly and Release

The past decade has witnessed a tremendous advance in our understanding of HIV-1
replication at the molecular level. Rapid progress in this fi eld has been made possible
by important developments in several key scientifi c disciplines. Superresolution
microscopy has greatly increased our ability to pinpoint the localization
of proteins in cells and on the surface of virus particles. Novel fl uorescent tagging
methods have provided insights into the movement of viral RNAs within living cells
and their association with assembling Gag complexes. Cryo-electron microscopy
techniques now allow the visualization of protein complexes in heterogeneous
structures like retroviral particles at low-nm resolutions. Integrating cryo-electron
microscopy density maps with high-resolution structures derived from X-ray crystallography
and nuclear magnetic resonance spectroscopy has enabled the derivation
of near atomic-resolution models of complex structures like those of the HIV-1
envelope (Env) glycoprotein spikes and the immature retroviral Gag lattice.
Increased application of RNAi technology has led to genome-wide screens that
have identifi ed host factors required for the replication of a number of pathogens,
including HIV-1.
Despite these advances, many basic aspects of the HIV-1 replication cycle remain
poorly understood: how do viral Gag proteins traffi c to the site of assembly, what
role does the genomic RNA play in modulating assembly events, by what mechanism
are the viral Env glycoproteins enriched at sites of assembly and incorporated
into nascent virions, and what role do host cell components play in Env incorporation?
Although high-resolution structures have been solved for many individual
Gag domains and the structure of the capsid lattice is well understood, the structures
of other regions of Gag in the virus particle (e.g., the matrix lattice underlying the
lipid bilayer, and the spacer peptide that connects the capsid and nucleocapsid
domains) are still the topics of speculation.
The major advances that have been made in understanding basic HIV-1 biology
have been paralleled by, and in some cases have led to, remarkable successes in
developing drugs capable of potently blocking HIV-1 replication in infected patients.
Where these drugs are widely available, the prognosis for infected individuals has
improved tremendously. However, there is legitimate concern that issues of