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Paper text:
the human immunodeficiency virus ( hiv ) infects cd4 t lymphocytes and macrophages , eventually inducing the depletion of cd4 t cells , which is the defining feature of the acquired immune deficiency syndrome ( aids ) .
it is not clear precisely how the virus exploits the host cell to maximize viral particle production , but evidence is accumulating that hiv activates the cellular transcription machinery to achieve this aim .
while biochemical approaches have been extensively employed to study the intracellular response to hiv infection , the advent of lymphocyte microarrays has provided a powerful new tool to help illuminate the extensive effects of hiv on host - cell transcriptional responses .
biochemical studies have demonstrated that hiv is capable of modulating a variety of signal transduction pathways in the host cell at multiple stages in the infection process , beginning at entry when it engages two transmembrane receptors , cd4 plus either of the chemokine receptors ccr5 or cxcr4 , thereby activating intracellular protein tyrosine kinases .
indication that hiv gene products influence signaling processes in host cells also comes from analyses of transgenic mice that express portions of the hiv genome and display a variety of abnormalities , ranging from altered t - cell maturation   to the development of a systemic disease similar to aids .
because the long terminal repeats ( ltrs ) of hiv contain consensus recognition motifs for the nf-b and nfat families of transcriptional transactivators , it has been speculated that hiv may have evolved mechanisms to potentiate cellular activation pathways , thereby augmenting expression of its own genome . until now , however , there has been limited understanding of how hiv exerts control over specific transactivation responses of the host cell . because hiv employs host factors that are vital for its replication cycle , the virus may have evolved means of modulating their expression levels during infection , so as to favor its own replication .
one crucial host factor is the well - characterized transcription - elongation factor complex ptefb , which is recruited to the nascent hiv transcript by the rna - binding tat protein encoded by the virus .
this complex contains the cyclin - dependent kinase cdk.9 and cyclin t1 , and it phosphorylates the carboxy - terminal - domain repeats of rna polymerase ii , activating the polymerase and thus allowing processive transcription of the hiv genome .
other host proteins are required to facilitate transport of unspliced viral rna from the nucleus to the cytoplasm and to enhance viral assembly and release .
the identity of most of the host proteins involved in facilitating hiv replication has yet to be determined , however .
recent studies suggest that hiv infection can influence the expression of many host genes , and some of these may indeed have critical roles in the hiv replication cycle .
among the various hiv gene products implicated in modulation of cell signaling , nef appears to be the most potent .
the nef gene , expressed rapidly and abundantly following infection , is a major virulence factor both in vitro and in vivo .
rhesus macaques infected with simian immunodeficiency virus ( siv ) , a close relative of hiv , rarely progress to disease if the viral nef gene is deleted .
it has also been shown in infected macaques that there is very strong selective pressure for sivs with nef open reading frames . in humans ,
members of a cohort of individuals infected with a nef - deleted form of hiv have remained disease - free for many years . in primary t - cell cultures , hivs with intact nef genes replicate much better than nef - defective viruses .
while the precise function of the nef protein has remained elusive , the presence of an amino - terminal myristoyl linkage and a proline - rich sh3-binding domain suggest that it may interact with host proteins at the plasma membrane .
recent work has confirmed that these two regions of nef are required for its association with lipid rafts , cholesterol - rich membrane microdomains that concentrate potent signaling mediators .
one functional consequence of nef expression in t cells , as elucidated from in vitro studies , may be to enhance the levels of secreted interleukin-2 ( il-2 , a growth factor ) during activation .
nef has also been shown to associate with the -chain of the t - cell - receptor complex ( tcr- ) and concomitantly to induce expression of fas ligand , one of the mediators of apoptosis in differentiated cells , an outcome that may account for the high levels of apoptosis associated with hiv infection . in this and other studies ,
nef was also found to complex with a serine / threonine protein kinase , which in some cases has been identified as belonging to the pak ( p21-activated kinase ) family .
in their recent immunity paper , simmons et al .   describe results of an extensive microarray survey of expression levels of nef - responsive loci . as a model system , they have developed a clone of the t - cell - leukemia cell line jurkat that expresses nef in a tetracycline - inducible manner , thus minimizing the cytopathic effects of nef in long - term cultures . using arrays containing 3,528 genes , simmons et al .
observed that a panoply of loci were up - regulated at multiple time points after nef induction ( figure 1a ) .
most remarkably , they observed significant induction of mrnas encoding many transcription factors that positively regulate the viral ltr , including nfatc , nf-b p52 and p100 , irf-1 and irf-2 , c - fos , and jun - d .
the cytokines transforming growth factor  ( tgf- ) and il-4 , which may function in an autocrine and/or paracrine manner to promote ltr transactivation , were also elicited , along with mip-1 and mip-1 , chemokines previously shown to be up - regulated by nef expression in macrophages .
because these soluble factors are likely to influence host gene responses , it will be interesting in future studies to distinguish transactivation cascades that are autonomous from those requiring new protein synthesis .
host cofactors implicated in potentiating other stages of the hiv life cycle , from the processing of viral transcripts to virion budding , were also elicited in response to nef expression .
it was also confirmed that the tat - cofactor cdk9 was elevated in nef - expressing cells . that these findings point to a role for nef in enhancing some of the earliest stages of
the viral life cycle is particularly intriguing in the context of a recent study showing that nef transcripts are produced prior to integration of the virus into the genome of resting t cells , resulting in accumulation of nef protein that primes viral synthesis upon t - cell activation . in view of previous work implicating nef in signaling at the plasma membrane , the ability of nef to influence expression of many loci suggested that it might function as an upstream regulator of multiple divergent cascades . to explore this issue , simmons et al .  
compared nef - responsive genes with those modulated when the t - cell line was activated with antibodies against the t - cell antigen - receptor ( tcr ) complex .
surprisingly , the spectrum of genes exhibited 97% overlap , indicating that a major function of nef may be to trigger the conventional t - cell activation program .
when nef was induced during antibody stimulation , the same loci were activated even more potently , with the exception of targets unique to either inducing factor . among the targets triggered only by nef
are several genes that may aid viral progression , including those encoding the transcription - elongation factor tat - sf1 , the transcription factor irf-2 , and the small nuclear riboprotein u1 snrnp a. in contrast , stimulation with anti - tcr antibody but not with nef induced two factors , the cytokine il-16 and the transcription factor yy1 , that are thought to negatively regulate viral transcription .
how a single viral gene can achieve such remarkable specificity will need to be addressed in future studies .
paper , nef expression also results in down - modulation of numerous positive effectors , including the kinases pkc- and zap-70 , the phospholipase plc-2 , and 40s ribosomal protein . one of the advantages of the in vitro system of simmons et al .  
for example , numerous jurkat mutants that lack the expression of proteins involved in t - cell activation have been generated .
inducibly expressed nef in two such lines , one that lacked tcr- and another deficient in zap-70 , a tyrosine kinase recruited to the tcr- chain upon activation .
expression profiling revealed that both proteins are required for the full - spectrum nef response ; in each of the mutant lines approximately half of the gene targets were not induced .
a similar magnitude of inhibition was achieved in wild - type jurkat cells in which nef was expressed in the presence of the drug cyclosporin a , which blocks the more downstream nfat effector calcineurin .
intriguingly , the genes inhibited by cyclosporin a only partially overlapped with those inhibited in the mutant jurkat lines
. caveats that must be considered when interpreting these results , however , are that the mutant lines may have undergone adaptive changes and the levels of nef protein in different jurkat lines may not be identical .
different levels of nef expression , and different nef alleles , may elicit dramatically different outcomes , as suggested by studies using both in vitro   and in vivo   models .
whereas the work of simmons et al .   paints a picture of nef as a ' master switch ' of cellular activation , a parallel study by corbeil et al .  
this group infected the cem t - cell line for various lengths of time ( eight time points , from 0 to 72 hours ) with high levels of replication - competent hiv . after analyzing microarrays containing 6,800 loci
, they found that productive infection was associated with complex patterns of up- and down - regulated genes ( figure 1b ) . on average ,
more genes were induced early in infection ( up to 24 hours ) than later , when the cytotoxic effects of the virus resulted in dramatic repression of approximately one third of expressed host genes ( 33% of cells were apoptotic 72 hours after infection ) . among the genes augmented at consecutive early time points were interferon- ( ifn- ) and its target mxb , which serve anti - viral functions . nfib-2 , which encodes a factor involved in the transcription of both viral and cellular genes , was up - regulated , as confirmed by real - time pcr .
perusal of the supplementary data   reveals that a multitude of host genes are strongly up - regulated at individual time points , although the relevance and reproducibility of these findings remain uncertain until confirmed . other activated loci appeared to reflect a state of genotoxic stress , including the gene gadd45 , which is induced by dna damage .
both the mrna encoding the proapoptotic mediator bax and the protein itself were up - regulated in infected cells , as were numerous caspases .
it is worth noting that an earlier survey of hiv-1-induced genes by differential display revealed a variety of up- and down - regulated host genes , including some responses consistent with a cytopathic outcome .
, it is apparent that nef down - regulated the anti - apoptotic bcl-2 gene while up - regulating the proapoptotic mediator bad .
utilization of replication - competent hiv to study effects on host genes has advantages as well as disadvantages .
the most obvious merit is that the system is likely to reflect in vivo outcomes better ( although certainly the in vivo cellular microenvironment will exert a profound influence on gene responses ) .
the data obtained by this method are more difficult to interpret and dissociate from stress responses associated with apoptosis , however .
additional studies are now needed to dissect out the contributions of individual viral proteins by employing a variety of mutated hiv strains .
given that the envelope glycoprotein of hiv is cytotoxic , it will also be interesting to compare strains lacking expression of this product .
replication - defective hiv coated with envelopes specific for ccr5 or cxcr4 can be compared to replication - defective hiv enveloped with vesicular stomatitis virus ( vsv ) glycoprotein to address the provocative question of whether viral entry by means of different receptors may itself influence expression of various genes .
whereas viral products such as nef may have adapted to activate loci that favor viral progression , the acute phase of infection induces a cellular stress program associated with a generalized dampening of host - cell transcription and a shift towards the induction of the proapoptotic machinery .
the effects on host gene responses of defined nef mutations , changes in nef expression , and substitution of nef alleles can be powerfully addressed in future microarray experiments .
moreover , it will be crucial to examine the effects of clinical hiv isolates in primary t cells , as well as macrophages , in which the virus also perturbs activation cascades . as enlarged panels of gene arrays become available , more comprehensive genome scanning will be possible .
these studies might ultimately be extended to examine the effects of human genetic polymorphisms on hiv gene responses .
together , these approaches will prove crucial in developing new therapies that seek to suppress and eliminate hiv .
a ) expression of nef in t cells results in the induction of numerous viral permissivity factors as well as genes associated with t - cell activation .
the induction of secreted factors , such as il-4 and tgf- , may generate secondary signals that favor viral replication , while the up - regulation of chemokines such as mip-1 and mip-1 may attract cells to the site of infection , perhaps aiding transmission of the virus .
although the precise mechanisms through which nef modulates signaling have not been elucidated , it has been implicated in exerting controls on a number of membrane - proximal pathways . ( b ) infection of t cells with intact hiv induces gene responses that are more complex and include the up - regulation and suppression of functionally diverse host genes . as infection proceeds , host - cell genes
are increasingly suppressed , and there is a shift toward the induction of factors associated with a cytopathic response , including those regulating apoptosis and responses to genotoxic stress .
the anti - viral gene ifn- is induced relatively early in infection , and may modulate a variety of response cascades .
hiv may elicit these transcriptional changes through a wide variety of mechanisms , either directly ( though viral factors such as nef , env , and tat ) , or indirectly , by inducing cellular stress during the acute phase of infection .
the human immunodeficiency virus has evolved various mechanisms to exploit its host cells , including the interruption and augmentation of signal transduction pathways . recently , two dna microarray studies have illustrated a remarkably broad - based perturbation in host transcriptional responses , which is in part mediated by the hiv - encoded nef protein . 
 hiv therefore seems to function as a ' master regulator ' of cellular gene expression .