Nef (protein)
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Nef (Negative Regulatory Factor) is a small 27-35 kDa myristoylated
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
encoded by primate
lentiviruses ''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
. These include Human Immunodeficiency Viruses (HIV-1 and HIV-2) and
Simian Immunodeficiency Virus ''Simian immunodeficiency virus'' (''SIV'') is a species of retrovirus that cause persistent infections in at least 45 species of non-human primates. Based on analysis of strains found in four species of monkeys from Bioko Island, which was iso ...
(SIV). Nef localizes primarily to the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
but also partially to the Plasma membrane (PM) and is one of many
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
-expressed proteins, known as
virulence factors Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the followin ...
, which function to manipulate the host's cellular machinery and thus allow infection, survival or replication of the pathogen. Nef stands for "Negative Factor" and although it is often considered indispensable for HIV-1 replication, in infected hosts the viral protein markedly elevates viral titers.


Function

The expression of Nef early in the viral life cycle ensures
T-cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
activation and the establishment of a persistent state of infection, two basic attributes of
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
infection. Viral expression of Nef induces numerous changes within the infected cell including the modulation of protein cell surface expression,
cytoskeletal The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...
remodeling, and signal transduction. Since the activation state of the infected cell plays an important role in the success rate of HIV-1 infection, it is important that resting T-cells be primed to respond to
T-cell receptor The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding b ...
(TCR) stimuli. HIV-1 Nef lowers the threshold for activation of CD4+ lymphocytes, but is not sufficient to cause activation in the absence of exogenous stimuli. By down regulating cell surface expression of CD4 and
Lck Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...
, Nef creates a narrow TCR response which likely optimizes HIV-1 viral production and generates a susceptible population of cells to further infect. Nef retargets kinase-active Lck away from the plasma membrane to early and recycling
endosomes Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane ca ...
(RE) as well as the
Trans-Golgi network The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles in ...
(TGN). RE/TGN associated Lck sub-populations in Nef expressing cells are in the catalytically active conformation and thus signaling competent. While TCR signaling takes place at the plasma membrane (PM), activation of the
Ras Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...
-
GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
takes place in intracellular compartments including the Golgi apparatus. Nef induced enrichment of active Lck in these compartments results in an increase of localized RAS activity and enhanced activation of
Erk kinase In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and p ...
and the production of
Interleukin-2 Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16  kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible fo ...
(IL-2). Since IL-2 is known to activate the growth, proliferation, and differentiation of T-cells to become effector T-cells; this is a self-serving effect that creates a new population of cells which HIV-1 is able to infect. Self-activation of the infected cell by IL-2 also stimulates the cell to become an effector cell and initiate the machinery which HIV-1 relies upon for its own proliferation. To further evade the host immune response, Nef down-regulates the cell surface and total expression of the negative immune modulator
CTLA-4 CTLA-4 or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 ( cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively exp ...
by targeting the protein for
lysosomal A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pro ...
degradation. In contrast to CD28 which activates T-cells, CTLA-4 is essentially an “off-switch” which would inhibit the viral production if it were activated.
Lentiviruses ''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
such as HIV-1 have acquired proteins such as Nef which perform a wide array of functions including the identification of CTLA-4 before it reaches the PM and tagging it for degradation. Nef is also known to
phosphorylate In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...
and inactivate Bad, a
proapoptotic Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes inclu ...
member of the
Bcl-2 family The Bcl-2 familyTC# 1.A.21 consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion ...
thus protecting the infected cells from apoptosis. Cytoskeletal remodeling is thought to reduce TCR signaling during early infection and is also modulated to some degree by Nef.
Actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
remodeling is generally modulated by the actin severing factor cofilin. Nef is able to associate with the cellular kinase
PAK2 Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the ''PAK2'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''gen ...
which phosphorylates and inactivates
cofilin ADF/cofilin is a family of actin-binding proteins associated with the rapid depolymerization of actin microfilaments that give actin its characteristic dynamic instability. This dynamic instability is central to actin's role in muscle contractio ...
and interferes with early TCR signaling.


Clinical significance

The Sydney blood bank cohort (SBBC) were a group of eight patients who were asymptomatic many years after initial infection by transfusion from an infected blood donor. Later analyses showed that the virus strain was a Nef-deleted variant.


Vaccine

A ''Nef''-deleted virus vaccine has not been tried in humans although it was successfully tested in
Rhesus macaque The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally ...
s.


See also

* HIV structure and genome


References


Further reading

* *


External links

* {{Viral proteins HIV/AIDS Viral regulatory and accessory proteins