Efficient HIV-1 replication can occur in the absence of the viral matrix protein

Abstract

Matrix (MA), a major structural protein of retroviruses, is thought to play a critical role in several steps of the HIV-1 replication cycle, including the plasma membrane targeting of Gag, the incorporation of envelope (Env) glycoproteins into nascent particles, and the nuclear import of the viral genome in nondividing cells. We now show that the entire MA protein is dispensable for the incorporation of HIV-1 Env glycoproteins with a shortened cytoplasmic domain. Furthermore, efficient HIV-1 replication in the absence of up to 90% of MA was observed in a cell line in which the cytoplasmic domain of Env is not required. Additional compensatory changes in Gag permitted efficient virus replication even if all of MA was replaced by a heterologous membrane targeting signal. Viruses which lacked the globular domain of MA but retained its N-terminal myristyl anchor exhibited an increased ability to form both extracellular and intracellular virus particles, consistent with a myristyl switch model of Gag membrane targeting. Pseudotyped HIV-1 particles that lacked the structurally conserved globular head of MA efficiently infected macrophages, indicating that MA is dispensable for nuclear import in terminally differentiated cells.

Macrophages and HIV-1: dangerous liaisons

“…HIV-1 MA contains two sequences that could act as an NLS (Bukrinsky et al, 1993;Haffar et al, 2000). MA NLS mutants were found to be unable to replicate in macrophages in some studies but not in others (Fouchier et al, 1997;Reil et al, 1998;von Schwedler et al, 1994). The third viral protein involved in nuclear import of HIV-1 PIC is the viral protein R (Vpr) (Heinzinger et al, 1994;Popov et al, 1998) which is present only in lentiviruses.…”

A myristoyl switch regulates membrane binding of HIV-1 Gag

“…Conversely, cleavage of Gag by HIV-1 protease triggers the myristoyl switch ''in,'' thereby releasing MA from the membrane (14). Amino acid mutations near the N terminus of MA that block membrane binding can be suppressed by second site mutations downstream in MA (15,16). Some of these mutants exhibit enhanced membrane binding and particle production compared with wildtype Gag (15,17).…”

“…Amino acid mutations near the N terminus of MA that block membrane binding can be suppressed by second site mutations downstream in MA (15,16). Some of these mutants exhibit enhanced membrane binding and particle production compared with wildtype Gag (15,17). All of these studies are consistent with the existence of a myristoyl switch for HIV-1 Gag, but until now confirmation from structural biology studies was lacking.…”

Total chemical synthesis of N-myristoylated HIV-1 matrix protein p17: Structural and mechanistic implications of p17 myristoylation

“…Excised proteolytically during and immediately after budding of virus particles, p17 forms a protective shell associated directly with the inner leaflet of the viral membrane (5,6). In the early stages of the HIV-1 life cycle, p17 also can dissociate from the viral membrane and direct the core-derived preintegration complex to the host-cell nucleus (7)(8)(9), although the precise role of p17 in regulating HIV-1 nuclear import and enabling the virus to replicate in nondividing cells remains controversial (10)(11)(12)(13)(14). More recently, isolated p17 has been shown to enhance HIV-1 infection and replication in activated T lymphocytes by upregulating the secretion of proinflammatory cytokines through an extracellular receptor-mediated signaling pathway (15).…”