Immunopathogenesis of HIV infection

2382 0892-6638/91/0005-2382/$01 .50. © FASEB

ZEDA F. ROSENBERG AND ANTHONY S. FAUCI

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

ABSTRACT The ultimate consequence of infectionwith HIV is profound immunosuppression that is theresult of both quantitative and qualitative abnormalitiesof the helper/inducer subset of T lymphocytes. The initialpathogenic event in HIV infection is binding of the enve-lope glycoprotein of HIV to the CD4 receptor moleculepresent on the surface of CD4 T lymphocytes and mono-cyte/macrophages. In vivo the reservoir for HIV infectionin the peripheral blood is the CD4 T cell, whereas inother tissues the monocyte/macrophage may play a sub-stantial role. As disease progresses in HIV-infected in-dividuals, the viral burden in the peripheral blood CD4T cells increases. An understanding of the mechanismsinvolved in the transition from an initially low viral bur-den during the asymptomatic phase of HIV infection tothe higher levels of virus expression detected in late stagedisease is being investigated intensively. A number ofpotential agents thay may influence regulation of HIV ex-pression have been identified including mitogens, anti-gens, heterologous viruses, cytokines, and physical fac-tors. The pathogenic mechanisms of HIV-inducedneurologic abnormalities and the potential role of HIV ina number of other clinical manifestations of HIV infec-tion are also discussed.-Rosenberg, Z. F.; Fauci, A. S.Immunopathogenesis of HIV infection. FASEB J. 5:2382-2390; 1991.

Key Words: CD4 T lymphocyte . HlVpathogenesis . viral acti-

vation

IN THE 10 YEARS SINCE THE acquired immunodeficiency syn-drome (AIDS)’ was first recognized, a complex array of im-munologic abnormalities and opportunistic diseases havebeen described in patients infected with the human im-munodeficiency virus (HIV). The central defect in AIDSwas soon shown to be a dramatic depletion of a specific sub-set of T lymphocytes known as CD4 T cells (1). The appar-ent paradox between the loss of a specific component of theimmune system and the global immune suppression thatAIDS patients exhibit is reconciled by the fact that the CD4T cell plays an instrumental role in inducing virtually all im-munologic responses (2). When HIV was discovered in 1983(3-5), the observation that CD4 T cells were a principal tar-get for HIV infection in vitro strengthened the associationbetween CD4 T cell depletion and development of AIDS.

The past decade has witnessed accumulation of an un-precedented amount of information on a new disease and anew pathogen. This paper examines what we have learnedabout the mechanisms that HIV uses to kill or impair CD4T cells. The role of HIV in the neurologic abnormalities thatfrequently accompany HIV infection are also discussed.This paper focuses also on some potential reasons why thetime between initial infection with HIV and the develop-ment of AIDS is often 10 years or longer. An understandingof this perplexing feature of HIV infection is a crucial com-ponent of strategies to halt progression of immunologic des-truction and prevent the onset of AIDS.

TARGET FOR HIV INFECTION

The in vitro observation that HIV infects and destroys CD4T cells, in conjunction with the progressive decrease in CD4T cells that occurs during HIV infection in vivo, ledresearchers to hypothesize that HIV was infecting anddirectly killing CD4 T cells in vivo and that this process wasresponsible for the immunosuppression characteristic ofAIDS. However, during early efforts to detect HIV in cir-culating peripheral blood mononuclear cells (PBMC) by insitu hybridization, it was found that only an extremely smallproportion of PBMC were actively expressing HIV (6).These results made it difficult to reconcile how the presenceof HIV in only I in 10,000 to 1 in 100,000 PBMC couldresult in the widespread CD4 T cell destruction noted inHIV-infected individuals. As a result, many differenthypotheses were developed to explain how HIV could des-troy CD4 T cells through indirect mechanisms (see below).

More recently, a direct role for HIV in CD4 T cellcytopathicity has received considerable attention. Severalstudies, using highly sensitive polymerase chain reaction(PCR) techniques to detect cells that are latently infectedwith HIV in addition to those that are actively expressingHIV, have found that HIV DNA is present in a much higherproportion of CD4 T cells than was previously reported (7,8). In patients with AIDS, at least 1 in 100 CD4 T cells hasbeen found to contain HIV DNA by PCR analysis. Inasymptomatic HIV-infected individuals, the proportion ofinfected CD4 T cells ranges between 1 in 100 and 1 in10,000. These data are consistent with viral culture studiesin which it was shown that HIV titers in AIDS patients wereapproximately two logs higher than in asymptomatic in-dividuals (9, 10).

A direct correlation between viral burden, decreasingCD4 T cell counts, and disease progression has beendemonstrated (11-13). By comparing the viral burden inasymptomatic infected individuals, half of whom progressed

to AIDS and half remained asymptomatic, it was found thatthe frequency of HIV DNA in CD4 T cells increased overtime in those patients who developed disease and remainedrelatively stable in the persistently asymptomatic patients(11). In these experiments, the increase in viral DNA was as-sociated with a decrease in CD4 T cells, suggesting thatHIV was directly involved in CD4 T cell destruction.

‘Abbrevjatjons: AIDS, acquired immunodeficiency syndrome;

HIV, human immunodeficiency virus; PBMC, peripheral bloodmononuclear cells; PCR, polymerase chain reaction; MHC, majorhistocompatibility complex; RT, reverse transcriptase; PHA, phyto-hemagglutinin; IL 2, interleukin 2; LTR, long-terminal repeat;HSV, herpes simplex virus; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HTLV, human T cell leukemia virus; HBV, hepatitis Bvirus; TNF, tumor necrosis factor; GMCSF, granulocyte-macrophage colony-stimulating factor; TGF, transforming growthfactor; UV, ultraviolet.

IMMUNOPATHOGENESIS OF HIV INFECTION 2383

Analyses of different subpopulations of cells in theperipheral blood of HIV-infected individuals have demon-strated that the circulating CD4 T cell is the principal celltype that contains HIV (7, 14). Another cell type in theperipheral blood that can also be infected with HIV is themonocyte/macrophage. The mechanism whereby HIV selec-tively infects these cell types is related to the presence of CD4molecules on the surface of CD4 T cells and monocyte/mac-rophages (15, 16). The initial step in HIV replication is theattachment of the virion to a specific receptor on the cell sur-face. This receptor is the CD4 molecule, which normallyfunctions by interacting with the class II major histocompati-bility complex (MHC) molecules on the surface of antigenpresenting cells during immune responses (17, 18).

LIFE CYCLE OF HIV

HIV uses the CD4 receptor to gain entry into the cell

through the high-affinity binding of the HIV envelopeglycoprotein, gpl2o, to a specific region of the CD4 molecule(19). Once bound to CD4, HIV is internalized into thecytoplasm of the cell. This process is not well understood butis thought to involve fusion of the cell membrane with anenvelope glycoprotein, gp4l, that is noncovalently associatedwith gpl2O. After the virus has gained entry into the cell, thevirion-associated reverse transcriptase (RT), in conjunctionwith ribonuclease H, transcribes the viral RNA into double-stranded DNA (20). The double-stranded HIV DNA thenenters the nucleus where it is inserted into the host cell ge-nome via action of the viral integrase. At this phase in theHIV life cycle, the HIV genome is designated a provirus.

Once the HIV provirus has been incorporated into the cel-lular DNA, both cellular and viral factors are required to in-itiate expression of viral genes (20). The cellular factors maybe constitutively produced by the cell or may be induced bya variety of activating signals including antigens, mitogens,heterologous gene products, cytokines, ultraviolet light, andheat (see below). After activation of the HIV provirus by cel-lular factors, the first viral genes to be expressed are thosethat encode nonstructural proteins with regulatory functions(reviewed in refs 21, 22). The most important of these pro-teins is Tat, which is a powerful transactivator of HIV geneexpression and is essential for HIV replication. Tat isthought to exert its effect in two ways: by initiating RNAtranscription of the HIV provirus or by stimulating produc-tion of full-length RNA transcripts.

The full-length RNA transcripts are then multiply splicedand transported to the cytoplasm where the regulatory pro-teins of HIV are expressed. At this point in the viral life cy-cle, another essential regulatory protein, Rev, becomesdominant. The main function of Rev is to effect the transportof unspliced and singly spliced mRNA from the nucleus tothe cytoplasm. These unspliced and singly spliced mRNAsencode the structural and enzymatic proteins of HIV thatare essential for assembly of the infectious virion at the cellsurface (reviewed in refs 21, 22).

One unique feature of the retroviral life cycle is the abilityof the provirus to persist in a quiescent state without produc-tion of viral message or proteins (20). In infected individuals,it has been observed that for every one HIV-infected CD4T cell that is expressing viral proteins, there are approxi-mately 9 infected CD4 T cells that harbor latent HIVproviral DNA (7). As cellular factors are important for HIVexpression, these latently infected cells presumably lack thecritical cellular factors required for initiation of HIV RNAtranscription. The next section summarizes what is presently

known about the mechanisms involved in the transition be-tween a latently or low-level, chronically infected cell to a cellthat is actively expressing HIV.

REGULATION OF HIV EXPRESSION

The instrumental role that cellular factors play in the life cy-cle of HIV was evident when HIV was first discovered.Researchers found that isolation of HIV from the peripheralblood of AIDS patients required that patients’ cells be cocul-tured with allogeneic T cells that had been stimulated withphytohemagglutinin (PHA) and interleukin 2 (IL 2) (4, 5,23). In the absence of these activation signals, HIV repli-cated poorly in the target cells. PHA has also been shown toinduce high-level expression of HIV in infected cells thatnormally express little or no HIV (24).

In uninfected cells, exposure to PHA results in the induc-tion of cellular factors called NF-xB that bind to a specificsegment of certain cellular genes and initiate transcription ofthe host cell DNA. NF-xB binding sites are located in thepromotor region of the genes that encode for IL 2 and theIL 2 receptors. Thus, under normal circumstances mitogenstimulation of T cells causes production of IL 2 and IL 2receptor proteins (25). In the case of HIV-infected cells,however, the NF-xB proteins that are induced by PHA inter-act with the NF-xB binding sites located in the long-terminalrepeat (LTR) region of HIV. The HIV LTR contains twotandemly repeated NF-xB binding sites just upstream of thetranscription start sites (26). The binding of NF-xB proteinsto these binding sites in the HIV LTR results in the stimula-tion of HIV RNA transcription and the eventual productionof virions.

In addition to mitogens, antigens have also been shown toinfluence the level of HIV expression both in de novo infec-tion and in chronically or latently infected cells (reviewed inref 21). Although the precise mechanism for antigen-inducedenhancement of HIV expression has not been adequately ex-plored, it is likely that activation of NF-xB proteins are in-volved as both IL 2 and IL 2 receptor genes are instrumentalto antigen-induced T cell activation. It has recently beendemonstrated that lipopolysaccharide, a cell wall constituentof gram-negative bacteria, both potently enhances HIV ex-pression in chronically infected monocyte/macrophages andactivates NF-xB (27).

Viral cofactors in HIV infection

The HIV LTR also contains other sequences that bind cellu-lar transcription factors, such as the Spi binding sites andthe TATA box. It appears that these sites, in addition to NF-xB binding sites, are involved in activation of HIV expres-sion that follows exposure to heterologous viral genes. A vari-ety of heterologous viruses, including herpes simplex virus(HSV) type 1, cytomegalovirus (CMV), Epstein-Barr virus(EBV), adenovirus, hepatitis B virus (HBV), human herpes-virus (HHV) type 6, pseudorabies virus, and human T cellleukemia virus (HTLV) type I have been shown to enhanceHIV replication (reviewed in ref 21) (28) (Fig. 1) (29). TheHIV DNA binding sites implicated in the augmentation ofHIV expression by these viruses depend on the specific virusin question.

Initial experiments with heterologous viruses were per-formed with transfections of particular viral genes, includingthose from HSV, CMV, and HTLV-I (reviewed in 30) (28).Subsequently, it was shown that up-regulation of HIV ex-pression occurred after coinfection of CD4 T cells with HIV

0

C04+ Cell Latent Infection Productive Infection

Figure 2. Induction of HIV expression by cytokines (reprinted withpermission from ref 29).

2384 Vol. 5 July 1991 The FASEB Journal ROSENBERG AND FAUCI

#{149}cew micucCisMm...)

#{149}mmai. (clakki.s)

Figure 1. Progression from latent to productive HIV infection(reprinted with permission from ref 29).

and HSV-1 (31), CMV (32), HHV-6 (33), or HSV-2 (34). Inone study, it was reported recently that dual infection ofCD4 T cells with two clinical isolates of HIV and HHV-6resulted in an increase in CD4 T cell killing although HIVreplication was suppressed (35). As these viral pathogens areoften found in HIV-infected individuals, these experimentssuggest that in vivo infection with heterologous viruses mayact as a cofactor in HIV infection by directly influencingeither the level of HIV replication, its cytopathicity, or both.In addition, some of these viral pathogens may indirectlyaffect HIV expression by independently suppressing im-mune function (36).

Another potential mechanism by which herpesviruses canaffect the spread of HIV infection in vivo is via the inductionof Fc receptors. It has been reported that in vitro the Fcreceptor is the portal of entry for antibody-mediated uptakeof HIV. A recent study showed that CMV-induction of Fcreceptors in lung fibroblasts rendered the cells permissive forHIV infection. If Fc-receptor mediated infection by HIV inthe presence of anti-HIV antibody occurs in vivo, then her-pesviruses may permit more widespread HIV infection(reviewed in ref 36). Last, coinfecting viruses may modifyHIV expression by serving as antigens. As described previ-ously, antigen-induced activation of HIV-infected cellsresults in an increase in HIV replication. Moreover, antigen-induced activation of uninfected cells can render the cellsmore sensitive to de novo HIV infection and enhance thespread of HIV in vivo (reviewed in ref 37). In this regard,it has been shown that the supernatants of human monocytesthat had been exposed to EBV or CMV were able to up-regulate HIV expression in chronically HIV-infected cells(38).

Regulation of HIV expression by cytokines

The common denominator of antigen-, mitogen-, and heter-ologous viral gene-mediated induction of HIV expression isthe ability of these agents to induce or encode for proteinsthat bind to the HIV LTR and stimulate HIV RNA tran-scription. These proteins are customarily involved in a seriesof events that ultimately lead to T cell activation. Thus, it isreasonable to assume that other factors implicated in T cellactivation may also stimulate HIV. Cytokines are importantconstituents of immune cell activation that act as physiologicinductive signals in the regulation of immune responses.One such cytokine, tumor necrosis factor-a (TNFa) hasbeen shown to up-regulate HIV expression in chronicallyHIV-infected T and monocytic cell lines whereas two othercytokines, IL 6 and granulocyte-macrophage colony-stimulating factor (GMCSF), induce virus expression inmonocyte lineage cells only. Furthermore, TNFa actssynergistically with either IL 6 or GMCSF (reviewed in ref

39). These cytokines also induce HIV expression in primarymonocyte/macrophage cultures (40, 41) (Fig. 2).

In the normal homeostatic mechanisms of immune systemregulation, cytokines function in both an autocrine andparacrine manner. Likewise, it has been shown that TNFafunctions in an autocrine/paracrine fashion in the inductionof HIV expression (42). These studies also demonstratedthat constitutive expression of HIV in chronically infectedmonocytic lines could be blocked by antibody to TNFa, in-dicting endogenous TNFa in maintenance of HIV expres-sion in certain systems (42). Other studies demonstrated thatseveral factors, including HIV itself, can induce monocytesto secrete TNFa, which in turn induces the expression ofboth HIV and TNFa in chronically infected cells (38). Otherstudies, however, failed to detect HIV-induced enhancementof TNFa production in macrophages or peripheral bloodmononuclear cells (43, 44). Recent work with IL 6 suggeststhat IL 6 may also function via autocrine/paracrine mechan-isms in the induction of HIV expression (40).

Since cytokine-induced regulation of HIV expression ap-pears to mimic the normal homeostatic control mechanismsof the human immune system, it is not surprising thatseveral groups of investigators have found that the molecularmechanisms of cytokine induction of HIV expression mimicsthose of the immune system as well. It has been shown thatTNFa triggers virus expression by induction of transcriptionactivating factors which bind to the NF-xB consensus se-quences in the promotor region of the HIV LTR similar tomechanisms of induction of IL 2 and IL 2 receptor gene ex-pression in T cells (reviewed in ref 37). In contrast, IL 6 andGMCSF induce HIV expression predominantly by posttran-scriptional mechanisms (40; G. Poli and A. S. Fauci, unpub-lished results).

The physiologic relevance of cytokine regulation of HIVexpression in vivo has been supported by recent experimentswhich showed that activated B cells from HIV infected in-

dividuals secrete TNFa and IL 6 which are capable of induc-ing expression of HIV in chronically infected cell lines aswell as in autologous infected T cells (45). This effect wasnoted both with supernatants of activated B cells and incoculture of infected T cells and monocytes with the acti-vated B cells. In addition, antibodies to TNFa and IL 6 wereable to block this inductive effect. Furthermore, HIV enve-lope protein could enhance the secretion of these inductivecytokines from B cells of infected individuals but not fromnormal controls. Studies of activated B cells have importantimplications in understanding the role of B cells in thepropagation of HIV infection among T cells, particularly inthe milieu of peripheral lymphoid organs where these celltypes are in close contact.

In addition to the up-regulation of HIV replication, it hasbeen shown that some cytokines possess the ability to sup-press HIV expression. For example, interferon-a potentlydecreases HIV expression in both acutely and chronically in-fected cells posttranslationally by inhibiting the budding of

IMMUNOPATHOGENESIS OF HIV INFECTION 2385

virions (46). Another cytokine, transforming growth factor-fl(TGFi3), down-regulates constitutive as well as induced ex-pression of HIV by blocking both transcriptional and post-transcriptional mechanisms depending on the inductive sig-nal in question (47).

The positive relationship between the level of HIV expres-sion in the peripheral blood, loss of CD4 T cells, andprogression to AIDS suggests that strategies to inhibit the in-duction of HIV expression may be instrumental to the con-trol of HIV disease. Given the potential for cytokine-inducedescalation of HIV replication in vivo, it becomes importantto identify pharmacologic agents that can inhibit thisprocess. In this regard, it has been demonstrated that N-acetyl cysteine and glutathione (48, 49), as well as retinoicacid and vitamin D3 (G. Poli and A. S. Fauci, unpublishedresults), were capable of suppressing the cytokine and PMAinduction of HIV expression in chronically infected celllines. These observations have potentially important ther-apeutic implications, especially since it has been clearlydemonstrated that immune competent cells of HIV-infectedindividuals have decreased levels of glutathione. Further-more, retinoic acid and vitamin D3 administered to humansfor conditions other than HIV resemble TGF/3 in the pat-terns and molecular mechanisms of its suppression of induc-tion of HIV expression (G. Poli and A. S. Fauci, unpublishedresults).

Stress-induced enhancement of HIV expression

Physical factors such as ultraviolet (UV) light and heat, aswell as compounds such as mitomycin C, have been studiedto determine the role that these stress-inducing agents mayplay in the regulation of HIV expression. Initial experimentswith HIV-LTR constructs showed that exposure of cells toUV light, sunlight, or mitomycin C resulted in the inductionof expression of an indicator gene that was under the controlof the HIV LTR (50). Ultraviolet light also increased therate of viral replication in de novo infection of T cells. It wassubsequently shown that UV light could induce the expres-sion of HIV in chronically infected cells (51). It has recentlybeen reported that UV light can activate the lac Z gene invivo in transgenic mice that carry the lac Z gene under thecontrol of the HIV LTR (52). NF-xB sequences have beenshown to be important in UV induction of HIV expression.In addition, a UV-induced cellular factor that can activatethe HIV LTR in nonirradiated cells also requires thepresence of NF-xB-binding sequences (53).

Stress responses can also be induced by cells by exposureto heat. Temperatures of 40.7-41#{176}Chave been found to en-hance HIV expression in chronically HIV-infected cells thatare simultaneously treated with IL 6. This up-regulation ofHIV expression occurred in a synergistic manner (54). Be-cause heat shock treatment of cells causes production of acellular DNA binding protein that binds to a sequence in thecellular genome that possesses considerable sequence homol-ogy to the NF-xB enhancer, it is possible that heat shock in-duction also involves NF-xB binding to the HIV LTR (55).

MECHANISMS OF CD4 T CELL KILLING

Although a direct relationship between HIV burden andCD4 T cell loss has been established (11-13), the precisemechanisms by which HIV causes a decrease in the numberof CD4 T cells is presently not well understood. Severaldifferent mechanisms have been considered in an attempt toshed light on this important area of HIV pathogenesis

(reviewed in ref 21). Clearly, as HIV causes extensive cell

death during in vitro infection of CD4 T cells, HIV maydestroy CD4 T cells in vivo as a direct result of infection andreplication. It has been suggested that massive budding ofHIV particles from the outer cell membrane damages the in-tegrity of the membrane leading to ionic imbalance anddeath. Another potential pathway for HIV-inducedcytopathicity may be similar to that observed in otherretroviral systems, namely a positive relationship betweenthe accumulation of cytoplasmic retroviral DNA and cellkilling. High levels of unintegrated viral DNA have been ob-served in the cytoplasm of HIV-infected cells and arethought to arise as a result of reinfection of the cell (56). Ithas recently been shown that unintegrated DNA can serveas a template for the production of HIV antigens which mayin turn impair cell viability or function (see below) (57).

The high-affinity binding of gpl2O to CD4 has also beenimplicated in HIV-induced cell killing (58). In addition togpI2O-CD4 binding that occurs on the cell surface during in-fection of the CD4 cell, the binding of these two proteins canalso occur intracellularly and interfere with normal cellmetabolism (59). The binding of gpl2O to CD4 can alsoresult in formation of multinucleated giant cells or syncytiathat result from the fusion of HIV-infected cells with unin-fected cells. A single HIV-infected CD4 T cell expressesenough gpl2O on its cell surface to bind to CD4 moleculeson the surface of tens or perhaps hundreds of uninfectedcells. It is thus conceivable that uninfected CD4 T cells canbe eliminated at the same time that infected cells are killed.In vivo data do not presently support the theory that HIV-

induced syncytia contribute substantially to cell death inHIV-infected individuals. Furthermore, researchers havefound that under certain conditions HIV can kill CD4 Tcells in culture in the absence of syncytia (reviewed in ref 21).

Several other mechanisms of indirect killing of uninfectedCD4 T cells have been proposed. The destruction ofbystander CD4 T cells by autoimmune phenomena is onesuch prospect. As the viral envelope proteins interact withthe CD4 molecule, it is possible that antibodies directedagainst certain epitopes of these viral proteins may cross-react with the usual ligand for CD4. In addition, uninfectedCD4 cells may bind free gpl2O molecules and become tar-gets for lysis by antibody-dependent cellular cytotoxicity in-volving anti-gpl20 antibodies (60). Furthermore, CD4 Tcells may process soluble gpl20 and, via antigen presenta-tion, again become targets for cytolysis (reviewed in (21)). Inthis regard, cytotoxic lymphocytes that can lyse uninfectedCD4 T cells have recently been found in HIV-infected in-dividuals but not in HIV-infected chimpanzees (61). It hasbeen postulated that this difference in human and chimpan-zee infection may be relevant to the lack of progression toAIDS in HIV-infected chimpanzees.

A particularly puzzling aspect of HIV infection is the lackof CD4 T cell regeneration early in the course of diseasewhen the viral burden is relatively low and CD4 T cell lossis progressing quite slowly. One possible explanation for whythe CD4 T cell pool is unable to regenerate and thus replacethe gradual attrition of circulating CD4 T cells pertains toinfection of CD4 T cell precursors. HIV infection of theseprecursor cells could lead to cell death or interference withthe differentiation to mature CD4 cells (62). In this regard,it has recently been demonstrated that intrathymic T cellprecursors and their progeny are susceptible to infection byHIV, including early CD3-, CD4-, CD8- thymocytes thathave subsequently been shown to express very low levels ofCD4 (63, 64).

2386 Vol. 5 July 1991 The FASEB Journal ROSENBERG AND FAUCI

MECHANISMS OF HIV-INDUCED CD4 T CELLABNORMALITIES

Although the focus of the previous section was HIV-inducedcell killing, it is well known that the effect of HIV on CD4T cells is not limited to cytopathicity. In vitro experimentshave demonstrated that HIV infection of cells in cultureresults in a suppression of antigen-specific responses. Im-pairment of CD4 T cell function during HIV infection, in-cluding a selective and early decrease in response to solubleantigens in the absence of dramatic CD4 T cell losses, hasbeen observed (64-66). One study has found that asympto-matic HIV-infected individuals exhibit a selective depletionof CD29 memory T cells primarily involved in antigen-specific responses (67). It has recently been shown that HIVpreferentially infects memory CD4 T cells at a 4- to 10-foldhigher level in vivo than naive T cells (68). Similarly, in SIV-infected macaques, SIV DNA has been foundpredominantly in resting memory T cells as well as in ac-tively proliferating cells (69).

In addition to HIV-induced suppression of CD4 T cellresponses that result from infection of the cells, it has alsobeen shown that in vitro exposure of CD4 T cells to specificHIV proteins (gpl2o, gp4l, and p24) in the absence of infec-tion of the cell is sufficient to inhibit antigen-specificresponses (reviewed in ref 21, 70) (71, 72). One mechanismwhereby HIV or its envelope proteins may impair T cell

function is by interfering with the interaction between CD4and MHC molecules that occurs during antigen presenta-tion. In addition, the binding of gpl2O to CD4 may disruptthe normal cellular postreceptor signal transduction path-ways (73-75). Another possible mechanism whereby HIVcan disturb CD4 T cell function is by interfering with eitherthe synthesis or expression of CD4. Although in vitro datasupport the theory that HIV suppresses CD4 expression onthe cell surface (76, 77), in vivo studies suggest that CD4 isnot down-regulated in HIV-infected cells (78). However,HIV-induced down-regulation of other cellular genes (i.e., IL2, IL 2 receptor, and T cell receptor genes) involved in T cellactivation has been reported and may contribute to thedefect in immune responses (reviewed in refs 21, 79).

As the memory T cell population is principally involved inantigen-specific responses, HIV-infection or exposure ofthese cells to HIV proteins may explain at least in part theetiology of the functional defect in HIV infection. However,the presence of functional defects during times of low viralburden would suggest that other mechanisms of T cell sup-pression may be operative.

HIV INFECTION OF OTHER CELL TYPES

The CD4 T lymphocyte is the principal cell type in theperipheral blood that is infected with HIV (7, 14). It is thegradual loss over time of the CD4 T cell population that isresponsible for the progressively severe immunosuppressioncharacteristic of HIV infection. However, HIV infection ofother cell types may be involved in a multitude of other clini-cal manifestations of HIV infection including neurologic,hematologic, and gastrointestinal abnormalities. One class ofCD4 cells that has been shown to be infected by HIV bothin vitro and in vivo is the monocyte/macrophage (reviewedin ref 21). HIV infection of monocyte/macrophages occursvia binding of HIV to the CD4 receptor. Phagocytosis ofHIV particles can contribute to the process of infection ofmonocyte/macrophages; however, this too is reported to bedependent on HIV binding to the CD4 molecule (80).

In contrast to HIV infection of CD4 T cells, in vitro in-fection of monocyte/macrophages does not lead readily to anapparent cytopathic effect. In fact, depending on the state ofdifferentiation of the cells, HIV particles may not budfrom the exterior cell surface of the monocyte/macrophagebut rather intracellularly from membranes within in-tracytoplasmic vesicles. Thus, under certain circumstances,HIV infected monocyte/macrophages may not be detectedby the immune system and may circulate throughout thebody. In this regard, HIV-infected cells of the monocyte line-age have been detected in the blood, lung, and brain of HIV-infected individuals (reviewed in ref 21). It has also beenshown that HIV-infected macrophages can transmit HIVthrough cell-cell contact to susceptible T cells, thus acting asa potential reservoir for HIV transmission (81). It has beenreported that other CD4 cells including dendritic cells,Langerhans cells, and thymocyte precursor cells (see above)can be infected with HIV (reviewed in refs 21, 82).

In an attempt to explain the wide range of hematologic ab-normalities in HIV-infected individuals, investigators havestudied bone marrow precursor cells in vivo and in vitro.Although it has been reported that CD34 hematopoieticprogenitor cells from patients with AIDS or AIDS-relatedcomplex are rarely positive for HIV DNA (83), a recentstudy of bone marrow samples from HIV-infected patientsrevealed that over half of the patients with advanced diseasehad viral DNA detectable in the progenitor cell population(S. Stanley et al., unpublished results). It has also beenshown that bone marrow progenitor cells can be infectedwith HIV in vitro and that the infection can be blocked byantibodies to CD4 (84) (S. Stanley et al., unpublishedresults). The in vitro HIV-infected bone marrow precursorcells exhibit characteristics of infection that are similar tothose observed during infection of monocyte/macrophages,specifically high levels of intracellular virus replication.

In essence, any human cell type that expresses CD4 is sus-ceptible to infection by HIV. In vitro, this includes a widerange of cell lines from B cells and glial cells to cervical cellsand colorectal cells (reviewed in ref 21). In vivo, HIV DNAhas been detected in glomerular and tubular epithelium (85)and in enterochromaffin cells (86). There have also been rarereports of HIV infection of cells that do not express detecta-ble levels of CD4 receptor antigen (87-90). However, asdescribed previously, it has been shown that the triple-negative thymocytes that were infected by HIV did indeedexpress very low levels of CD4 that were sufficient to allowHIV to enter the cells (63). Accordingly, in certain instancescells that are susceptible to HIV infection and reported to beCD4 negative may in fact be CD4 positive. In this regard,the susceptibility of a cell to HIV infection may be an ex-tremely sensitive tool for the detection of CD4. Nonetheless,it is possible that in rare circumstances CD4- cells may be in-fected by HIV. One potential mechanism for HIV infectionof CD4- cells involves presently unidentified accessorymolecules that may be required for HIV infection. Anotherpossible route of HIV entry into CD4- cells is via the induc-tion of expression of CD4 molecules by heterologous viruses(91) or by pseudotyping of the HIV genome into the envelopeof a virus with a broader range of cell infectivity (92, 93).The significance of these observations in the pathogenesis ofHIV infection remains unclear.

PATHOGENESIS OF NEUROLOGICALABNORMALITIES

Neurologic abnormalities are commonly found in HIV-infected individuals (94). It has been well established that

IMMUNOPATHOGENESIS OF HIV INFECTION 2387

TABLE 1. Potential neuropathogenic mechanisms of HIV infection

1. Secretion of toxic factors by HIV-infected macrophages ormicroglial cells in the brain

2. Competitive inhibition of neurotrophic factors by gpl2O

3. Direct suppression of neuronal cell function by gpl2O

4. Direct infection of neuronal tissue (no evidence to date)

macrophages may also be responsible for many of the neuro-logic abnormalities seen in this devastating disease. The roleof HIV infection of other cell types in the multitude of clini-cal manifestations of HIV infection remains to be deter-mined. E!iI

REFERENCES

HIV is present in the brain and cerebrospinal fluid of in-fected individuals at all stages of infection (reviewed in ref21). In the brain, the predominant cell type that harborsHIV or HIV DNA is the macrophage or microglial cell.Although infrequent reports of HIV infection of other cellstypes in the brain have been made, the macrophage is gener-ally thought to be the key cell in the pathogenesis of HIV in-fection in the brain (Table 1). Data in support of this theoryhave recently been generated by HIV-infection of primaryhuman brain cultures. In these studies, microglial cells wereinfected with HIV while neighboring astrocytes remaineduninfected (95).

As macrophages in general, and HIV-infected macro-phages in particular, produce a number of different cytokinesit is thought that the release of high levels of cytokines by in-fected cells may result in direct damage to nearby neuronsor in an inflammatory response that indirectly compromisesneurons (94, 96). In this regard, it has recently been shownthat HIV-infected cells of the monocyte/macrophage lineagesecrete toxins that kill neurons (97). Other researchers havefound that supernatants from HIV-infected primary macro-phages but not HIV-infected T cells can kill a number ofdifferent types of brain cells (98).

HIV gpl2O may also play a role in the neuropathogenesisof HIV infection by interfering with the binding of neuro-tropic factors to the surface of the neuron. In this regard itis known that gpl20 shares a region of homology with neuro-leukin, a neurotropic factor for spinal and sensory neurons(99). It has also been reported that gpl20 can kill neuronalcells by interfering with the binding of another neurotropicfactor, vasoactive intestinal peptide (100). Gp120 may alsodirectly cause injury to neurons. Researchers have foundthat gpl20 increases the level of intracellular free calcium inrodent ganglion and neural cells in culture, and that calciumchannel antagonists were able to inhibit HIV-induced celldamage (101).

SUMMARY

Since the beginning of the AIDS pandemic, the CD4 T lym-phocyte has taken center stage in its role in the pathogenesisof AIDS. With the advent of new, more sensitive techniquesfor HIV detection, it has become apparent that HIV infec-tion of CD4 T cells is, in large part, directly responsible forthe quantitative and qualitative defects observed in this dis-ease. Through studies aimed at dissecting out the mechan-isms responsible for the long and variable asymptomaticphase of HIV infection, researchers have found that by in-fecting CD4 T cells and monocyte/macrophages, HIV caninsert itself into the immune system and use mechanismsnormally used in immune system activation and im-munoregulation to its own replicative advantage. Thus, thesystem that under normal circumstances is responsible forthe elimination of an infecting pathogen, becomes an accom-plice in disease progression. HIV infection of monocyte/

1. Lane, H. C., and Fauci, A. 5. (1985) Immunologic abnormali-ties in the acquired immunodeficiency syndrome. Annu. Rev.Immunol. 3, 477-500

2. Bowen, D. L., Lane, H. C., and Fauci, A. S. (1985) Im-munopathogenesis of the acquired immunodeficiency syn-drome. Ann. Intern. Med. 103, 704-709

3. Barre-Sinoussi, F., Cherrnann,J. C., Rey, F, Nugeyre, M. T.,Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C.,Vezinet-Brun, F., Rouzioux, C., Rozenbaum, W., and Mon-tagnier, L. (1983) Isolation of a T-lymphotropic retrovirus froma patient at risk for acquired immune deficiency syndrome(AIDS). Science 220, 868-871

4. Popovic, M., Sarngadharan, M. G., Read, E., and Gallo,R. C. (1984) Detection, isolation, and continuous productionof cytopathic retroviruses (HTLV-III) from patients withAIDS and pre-AIDS. Science 224, 497-500

5. Levy, J. A., Hoffman, A. D., Kramer, S. M., Landis, J. A.,Shimabukuro,J. M., and Oshiro, L. S. (1984) Isolation of lym-phocytopathic retroviruses from San Francisco patients withAIDS. Science 225, 840-842

6. Harper, M. E., Marselle, L. M., Gallo, R. C., and Wong-Staal, F (1986) Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph notes and peripheralblood from infected individuals by in situ hybridization. Proc.Nat!. Acad. Sci. USA 83, 772-776

7. Schnittman, S. M., Psallidopoulos, M. C., Lane, H. C.,Thompson, L., Baseler, M., Massari, F., Fox, C. H., Salzman,N. P., and Fauci, A. S. (1989) The reservoir for HIV-1 in hu-man peripheral blood is a T cell that maintains expression ofCD4. Science 245, 305-308

8. McElrath, M. J., Steinman, R. M., and Cohn, Z. A. (1991) La-tent HIV-1 infection in enriched populations of blood mono-cytes and T cells from seropositive patients.]. Clin. Invest. 87,27-30

9. Coombs, R. W., Collier, A. C., Allain, J. P., Nikora, B.,Leuther, M., Gjerset, G. F, and Corey, L. (1989) Plasma vire-mia in human immunodeficiency virus infection. N Engl. J.Med. 321, 1626-1631

10. Ho, D. D., Moudgil, T., and Alam, M. (1989) Quantitation ofhuman immunodeficiency virus type 1 in the blood of infectedpersons. N EngI. J. Med. 321, 1621-1625

11. Schnittman, S. M., Greenhouse, J. J., Psallidopoulos, M. C.,Baseler, M., Salzman, N. P., Fauci, A. S., and Lane, H. C.(1990) Increasing viral burden in CD4 T cells from patientswith human immunodeficiency virus (HIV) infection reflectsrapidly progressive immunosuppression and clinical disease.Ann. Intern. Med. 113, 438-443

12. Simmonds, P., Balfe, P., Peutherer, J. F., Ludlam, C. A.,Bishop, J. 0., and Brown, A. J. L. (1990) Human im-munodeficiency virus-infected individuals contain provirus insmall numbers of peripheral mononuclear cells and at low copynumbers. J. Viral. 64, 864-872

13. Genesca, J., Wang, R. Y., Alter, H. J., and Shih, J. W. (1990)Clinical correlation and genetic polymorphism of the humanimmunodeficiency virus proviral DNA obtained after poly-merase chain reaction amplification. j Infect. Dis. 162,1025-1030

14. McElrath, M. J., Pruett, J. E., and Cohn, Z. A. (1989)Mononuclear phagocytes of blood and bone marrow: com-parative roles as viral reservoirs in human immunodeficiencyvirus type I infections. Proc. Nat!. Acad. Sci. USA 86, 675-679

15. Dalgleish, A. G., Beverly, P. C., Clapham, P. R., Crawford, D.H., Greaves, M. F., and Weiss, R. A. (1984) The CD4 (T4) an-

2388 Vol. 5 july 1991 The FASEB journal ROSENBERG AND FAUCI

tigen is an essential component of the receptor for the AIDSretrovirus. Nature (London) 312, 763-767

16. Klatzmann, D., Champagne, E., Chamaret, S., Gruest, J.,Guetard, D., Hercend, T., Gluckman, J. C., and Montagnier,L. (1984) T-Lymphocyte T4 molecule behaves as the receptorfor human retrovirus LAV. Nature (London) 312, 767-768

17. Gay, D., Buus, S., Pasternak, J., Kappler, J., and Marrack, P.(1988) The T-cell accessory molecule CD4 recognizes a mono-morphic determinant on isolated Ia. Proc. Nati. Acad Sci. USA85, 5629-5633

18. Doyle, C., and Strominger, J. L. (1987) Interaction betweenCD4 and class II MHC molecules mediates cell adhesion. Na-ture (London) 330, 256-259

19. McDougal, J. S., Kennedy, M. S., Sligh, J. M., Cort, S. P.,Mawle, A., and Nicholson, J. K. (1986) Binding of HTLV-III/LAV to CD4 T cells by a complex of the 110K viral proteinand the T4 molecule. Science 231, 382-385

20. Varmus, H. (1988) Retroviruses. Science 240, 1427-143521. Rosenberg, Z. F., and Fauci, A. S. (1989) The immunopatho-

genesis of HIV infection. Adv. Immunol. 47, 377-43122. Greene, W. C. (1991) The molecular biology of human im-

munodeficiency virus type I infection. N Engl. j Med. 324,308-317

23. Barre-Sinoussi, F., Mathur-Wagh, U., Rey, F., Brun-Vezinet,Fl, Yancovitz, S. R., Rouzioux, C., Montagnier, L., Mildvan,D., and Chermann,J. C. (1985) Isolation of lymphadenopathy-associated virus (LAV) and detection of LAV antibodies fromUS Datients with AIDS. F. Am. Med. Assoc. 253, 1737-1739

24. Zagury, D., Bernard, J., Leonard, R., Cheynier, R., Feldman,M., Sarin, P. S., and Gallo, R. C. (1986) Long-term culturesof HTLV-III-infected T cells: a model of cytopathology ofT-cell depletion in AIDS. Science 231, 850-853

25. Greene, W. C., Bohnlein, E., and Ballard, D. W. (1989) HIV-1,HTLV-I and normal T-cell growth: transcriptional strategiesand surprises. Immuno!. Today 10, 272-278

26. Nabel, G., and Baltimore, D. (1987) An inducible transcriptionfactor activates expression of human immunodeficiency virusin T cells. Nature (London) 326, 711-713

27. Pomerantz, R. J., Feinberg, M. B., Trono, D., and Baltimore,D. (1990) Lipopolysaccharide is a potent monocyte/macrophage-specific stimulator of human immunodeficiencyvirus type 1 expression. J. Exp. Med. 172, 253-261

28. Bohnlein, E., Siekevitz, M., Ballard, D. W., Lowenthal, J. W.,Rimsky, K., Bogerd, H., Hoffman, J., Wano, Y., Franza,B. R., and Greene, W. C. (1989) Stimulation of the human im-munodeficiency virus type 1 enhancer by the human T-cellleukemia virus type I tax gene product involves the action ofinducible cellular proteins. j Virol. 63, 1578-1586

29. Rosenberg, Z. F, and Fauci, A. S. (1990) Immunopathologyand pathogenesis of HIV infection. In Pediatric AIDS (Pizzo,P. A., and Wilfert, C. M., eds) Williams & Wilkins, Baltimore,Md.

30. Rosenberg, Z. F., and Fauci, A. 5. (1989) Induction of expres-sion of HIV in latently or chronically infected cells. AIDS Res.Hum. Retroviruses 5, 1-4

31. Albrecht, M. A., DeLuca, N. A., Byrn, R. A., Schaffer, P. A.,and Hammer, S. M. (1989) The herpes simplex virusimmediate-early protein. ICP4, is required to potentiate repli-cation of human immunodeficiency virus in CD4 lympho-cytes. j Viral. 63, 1861-1868

32. Casareale, D., Fiala, M., Chang, C. M., Cone, L. A., andMacarski, E. S. (1989) Cytomegalovirus enhances lysis of HIV-infected T lymphoblasts. Int. J Cancer 44, 124-130

33. Lusso, P., Ensoli, B., Markham, P. D., Ablashi, D. V., Sala-huddin, S. Z., Tschachler, E., Wong-Staal, F., and Gallo, R. C.(1989) Productive dual infection of human CD4 T lympho-cytes by HIV-l and HHV-6. Nature (London) 337, 370-373

34. Kucera, L. S., Leake, E., Iyer, N., Raben, D., and Myrvik,Q N. (1990) Human immunodeficiency virus type 1 (HIV-l)and herpes simplex virus 2 (HSV-2) can coinfect and simul-taneously replicate in the same human CD4 cell: effect ofcoinfection on infectious HSV-2 and HIV-1 replication. AIDS

Res. Hum. Retroviruses 6, 641-647

35. Carrigan, D. R., Knox, K. K., and Tapper, M. A. (1990) Sup-pression of human immunodeficiency virus type 1 replicationby human herpesvirus-6. j Infect. Dis. 162, 844-851

36. Laurence, J. (1990) Molecular interactions among herpes-viruses and human immunodeficiency viruses. j Infect. Dis.162, 338-346

37. Rosenberg, Z. F, and Fauci, A. S., (1990) Activation of latentHIV infection. j NIH Res. 2, 41-45

38. Clouse, K. A., Robbins, P. B., Fernie, B., Ostrove, J. M., andFauci, A. 5. (1989) Viral antigen stimulation of the productionof human monokines capable of regulating HIV1 expression.j Immunol. 143, 470-475

39. Rosenberg, Z. F, and Fauci, A. 5. (1990) Immunopathogenicmechanisms of HIV infection: cytokine induction of HIV ex-pression. Immunol. Today 11, 176-180

40. Poli, G., Bressler, P., Kinter, A., Duh, E., Timmer, W. C.,Rabson, A., Justement, J. S., Stanley, S., and Fauci, A. S.(1990) Interleukin 6 induces human immunodeficiency virusexpression in monocytic cells alone and in synergy with tumornecrosis factor alpha by transcriptional and post-transcriptional mechanisms. j Exp. Med 172, 151-158

41. Mellors, J. W., Griffith, B. P., Ortiz, M. A., Landry, M. L.,and Ryan, J. L. (1991) Tumor necrosis factor-aipha/cachectinenhances human immunodeficiency virus type 1 replication inprimary macrophages. j Infect. Dis. 163, 78-82

42. Poli, G., Kinter, A., Justement, J. S., Kehrl, J. H., Bressler, P.,Stanley, S., and Fauci, A. S. (1990) Tumor necrosis factor alphafunctions in an autocrine manner in the induction of humanimmunodeficiency virus expression. Proc. Nat!. Acad Sci. USA

87, 782-78543. Munis, J. R., Richman, D. D., and Kornbluth, R. S. (1990)

Human immunodeficiency virus-I infection of macrophages invitro neither induces tumor necrosis factor (TNF)/cachectingene expression nor alters TNF/cachectin induction bylipopolysaccharide. j C!in. Invest. 85, 591-596

44. Molina, J. M., Scadden, D. T., Amirault, C., Woon, A., Van-nier, E., Dinarello, C. A., and Groopman, J. E. (1990) Humanimmunodeficiency virus does not induce interleukin- 1,interleukin-6, or tumor necrosis factor in mononuclear cells. jViral. 64, 2901-2906

45. Rieckman, P., Poli, G., Kehrl, J. H., and Fauci, A. S. (1991)Activated B lymphocytes from human immunodeficiencyvirus-infected individuals induce virus expression in infected Tcells and a promonocytic cell line, Ui. j Exp. Med. 173, 1-5

46. Poli, G., Orenstein, J. M., Kinter, A., Folks, T. M., and Fauci,A. S. (1989) Interferon-alpha but not AZT suppresses HIV ex-pression in chronically infected cell lines. Science 244, 575-577

47. Poli, G., Kinter, A., Justement, J. S., Bressler, P., Kehrl, J. H.,and Fauci, A. 5. (1991) Transforming growth factor B sup-presses human immunodeficiency virus expression and repli-cation in infected cells of the monocyte/macrophage lineage. jExp. Med. 173, 589-597

48. Roederer, M., Staal, F J., Raju, P. A., Ela, S. W., and Herzen-berg, L. A. (1990) Cytokine-stimulated human immuno-deficiency virus replication is inhibited by N-acetyl-L-cysteine.Proc. Nat!. Acad. Sci. USA 87, 4884-4888

49. Kalebic, T., Kinter, A., Poli, G., Anderson, M. E., Meister, A.,and Fauci, A. S. (1991) Suppression of human im-munodeficiency virus expression in chronically infected mono-cytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc. Natl. Acad. Sci. USA 88, 986-990

50. Valerie, K., Delers, A., Bruck, C., Thiriart, C., Rosenberg, H.,Debouck, C., and Rosenberg, M. (1988) Activation of humanimmunodeficiency virus type 1 by DNA damage in humancells. Nature (London) 333, 78-81

51. Stanley, S. K., Folks, T. M., and Fauci, A. S. (1989) Inductionof expression of human immunodeficiency virus in a chroni-cally infected promonocytic cell line by ultraviolet irradiation.AIDS Res. Hum. Retroviruses 5, 375-384

52. Cavard, C., Zider, A., Vernet, M., Bennoun, M., Saragosti, S.,Grimber, G., and Briand, P. (1990) In vivo activation byultraviolet rays of the human immunodeficiency virus type 1long terminal repeat. j Clin. Invest. 86, 1369-1374

IMMUNOPATHOGENESIS OF HIV INFECTION 2389

53. Stein, B., Kramer, M., Rahmsdorf, H. J., Ponta, H., and Her-rlich, P. (1989) UV-Induced transcription from the human im-munodeficiency virus type 1 (HIV-I) long terminal repeat andUV-induced secretion of a factor that induces HIV-i transcrip-tion in nonirradiated cells. j Viral. 63, 4540-4544

54. Stanley, S. K., Bressler, P. B., Poli, G., and Fauci, A. S. (1990)Heat shock induction of HIV production from chronically in-fected promonocytic and T cell lines. J. Immuno!. 145,1120-1126

55. Geelen, J. L., Minnaar, R. P., Boom, R., Van der NoordaaJ.,and Goudsmit, J. (1988) Heat-shock induction of the humanimmunodeficiency virus long terminal repeat.j Cen. Vim!. 69,2913-2917

56. Pauza, C. D., Galindo, J. E., and Richman, D. D. (1990) Rein-fection results in accumulation of unintegrated viral DNA incytopathic and persistent human immunodeficiency virus typeI infection of CEM cells. j Exp. Med. 172, 1035-1042

57. Stevenson, M., Haggerty, S., Lamonica, C. A., Meier, C. M.,Welch, S. K., and Wasiak, A. J. (1990) Integration is not neces-sary for expression of human immunodeficiency virus type 1protein products. j Viral. 64, 2421-2425

58. Hoxie, J. A., Alpers, J. D., Rackowski, J. L., Huebner, K.,1-laggarty, B. S., Cedarbaum, A. J., and Reed, J. C. (1986) Al-

terations in T4 (CD4) protein and mRNA synthesis in cells in-fected with HIV. Science 234, 1123-1127

59. Koga, Y., Sasaki, M., Nakamura, K., Kimura, G., andNomoto, K. (1990) Intracellular distribution of the envelopeglycoprotein of human immunodeficiency virus and its role inthe production of cytopathic effect in CD4 and CD4- humancell lines. j Viral. 64, 4661-4671

60. Weinhold, K. J., Lyerly, H. K., Stanley, S. D., Austin, A. A.,Matthews, T. J., and Bolognesi, D. P. (1989) HIV-1GP12O-mediated immune suppression and lymphocyte des-truction in the absence of viral infection. j Immunol. 142,3091-3097

61. Zarling, J. M., Ledbetter, J. A., Sias, J., Fultz, P., Eichberg,J., Gjerset, G., and Moran, P. A. (1990) HIV-infected humans,but not chimpanzees, have circulating cytotoxic T lymphocytesthat lyse uninfected CD4 cells. J. Immunol. 144, 2992-2998

62. Fauci, A. 5. (1987) AIDS: immunopathogenic mechanismsand research strategies. Clin. Res. 35, 503-510

63. Schnittman, S. M., Denning, S. M., Greenhouse, J. J., Juste-ment, J. S., Baseler, M., Kurtzberg, J., Haynes, B. F, andFauci, A. S. (1990) Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen recep-tor phenotypes TCR alpha beta + and TCR gamma delta +

to human immunodeficiency virus infection: a mechanism forCD4 (T4) lymphocyte depletion. Proc. NatI. Acad. Sci. USA 87,7727-7731

64. Lane, H. C., Depper, J. M., Greene, W. C., Whalen, G.,Waldmann, T. A., and Fauci, A. S. (1985) Qualitative analysisof immune function in patients with the acquired im-munodeficiency syndrome. Evidence for a selective defect insoluble antigen recognition. N Engl. j Med. 313, 79-84

65. Miedema, F, Tersmette, M., and van Lier, R. A. (1990) AIDSpathogenesis: a dynamic interaction between HIV and the im-

mune system. Immunol. Today 11, 293-297

66. Teeuwsen, V. J., Siebelink, K. H., de Wolf, F., Goudsmit, J.,Uytdehaag, F G., and Osterhaus, A. D. (1990) Impairment ofin vitro immune responses occurs within 3 months after HIV-lseroconversion. AIDS 4, 77-81

67. van Noesel, C. J., Gruters, R. A., Terpstra, F G., Schellekens,P. T., van Lier, R. A., and Miedema, F (1990) Functional andphenotypic evidence for a selective loss of memory Tin asymp-tomatic human immunodeficiency virus-infected men. j C!in.Invest. 86, 293-299

68. Schnittman, S. M., Lane, H. C., Greenhouse, J., Justement,J. S., Baseler, M., and Fauci, A. 5. (1990) Preferential infectionof CD4 memory T cells by human immunodeficiency virustype 1: evidence for a role in the selective T-cell functionaldefects observed in infected individuals. Proc. Nat!. Acad. Sci.USA 87, 6058-6062

69. Willerford, D. M., Gale, M. J., Jr., Benveniste, R. E., Clark,E. A., and Gallatin, W. M. (1990) Simian immunodeficiency

virus is restricted to a subset of blood CD4 lymphocytes thatincludes memory cells. j Immunol. 144, 3779-3783

70. Habeshaw,J. A., Dalgleish, A. G., Bountiff, L., Newell, A. L.,Wilks, D., Walker, L. C., and Manca, F (1991) AIDS patho-

genesis: HIV envelope and its interaction with cell proteins.Immunol. Today 11, 418-425

71. Nong, Y., Kandil, 0., Tobin, E. H., Rose, R. M., and Remold,H. G. (1991) The HIV core protein p24 inhibits interferon-

gamma-induced increase of HLA-DR and cytochrome b heavychain mRNA levels in the human monocyte-like cell lineTHP1. Ce!! Immunol. 132, 10-16

72. Ruegg, C. L., and Strand, M. (1990) Inhibition of proteinkinase C and anti-CD3-induced Ca2 influx in Jurkat T cellsby a synthetic peptide with sequence identity to HIV-1 gp4l.

j Immuno!. 144, 3928-393573. Horak, I. D., Popovic, M., Horak, E. M., Lucas, P. J., Gress,

R. E., June, C. H., and Bolen, J. B. (1990) No T-cell tyrosineprotein kinase signalling or calcium mobilization after CD4 as-sociation with HIV-1 or HIV-1 gpl2O. Nature (London) 348,557-560

74. Cefai, D., Debre, P., Kaczorek, M., Idziorek, T., Autran, B.,and Bismuth, G. (1990) Human immunodeficiency virus-lglycoproteins gpl2O and gplfiO specifically inhibit the CD3/Tcell-antigen receptor phosphoinositide transduction pathway.j C!in. Invest. 86, 2117-2124

75. Hofmann, B., Nishanian, P., Baldwin, R. L., Insixiengmay, P.,Nd, A., and Fahey, J. L. (1990) HIV inhibits the early stepsof lymphocyte activation, including initiation of inositol phos-pholipid metabolism. j Immuno!. 145, 3699-3705

76. Folks, T., Benn, S., Rabson, A., Theodore, T., Hoggan, M. D.,Martin, M., Lightfoote, M., and Sell, K. (1985) Characteriza-tion of a continuous T-cell line susceptible to the cytopathiceffects of the acquired immunodeficiency syndrome (AIDS)-associated retrovirus. Prac. Nat!. Acad Sci. USA 82, 4539-4543

77. Hoxie, J. A., Haggarty, B. S., Rackowski, J. L., Pillsbury, N.,and Levy, J. A. (1985) Persistent noncytopathic infection ofnormal human T lymphocytes with AIDS-associated retrovi-rus. Science 229, 1400-1402

78. Psallidopoulos, M. C., Schnittman, S. M., Thompson, L. M.,III, Baseler, M., Fauci, A. S., Lane, H. C., and Salzman,N. P. (1989) Integrated proviral human immunodeficiency vi-rus type 1 is present in CD4 peripheral blood lymphocytes inhealthy seropositive individuals. Proc. Nat!. Acad Sci. USA 63,

4626-463179. Willard-Gallo, K. E., Van de Keere, F., and Kettmann, R.

(1990) A specific defect in CD3 gamma-chain gene transcrip-tion results in loss of T-cell receptor/CD3 expression late afterhuman immunodeficiency virus infection of a CD4 T-cell line.Proc. Nat!. Acad. Sci. USA 87, 6713-6717

80. Clapham, P. R., Weber, J. N., Whitby, D., McIntosh, K., Dal-gleish, A. G., Maddon, P. J., Deen, K. C., Sweet, R. W., andWeiss, R. A. (1989) Soluble CD4 blocks the infectivity of

diverse strains of HIV and SIV for T cells and monocytes butnot for brain and muscle cells. Nature (London) 337, 368-370

81. Mikovits, J. A., Raziuddin, Gonda, M., Ruta, M., Lohrey,N. C., King, H. F, and Ruscetti, F W. (1990) Negative regula-

tion of human immune deficiency virus replication in mono-cytes. Distinctions between restricted and latent expression incells. j Exp. Med. 171, 1705-1720

82. Macatonia, S. E., Lau, R., Patterson, S., Pinching, A. J., andKnight, S. C. (1990) Dendritic cell infection, depletion and

dysfunction in HIV-infected individuals. Immunology 71, 38-4583. von Laer, D., Hufert, F T., Fenner, T. E., Schwander, S.,

Dietrich, M., Schmitz, H., and Kern, P. (1990) CD34hematopoietic progenitor cells are not a major reservoir of thehuman immunodeficiency virus. Blood 76, 1281-1286

84. Folks, T. M., Kessler, S. W., Orenstein, J. M., Justement,J. S., Jaffe, E. S., and Fauci, A. S. (1988) Infection and replica-tion of HIV-I in purified progenitor cells of normal humanbone marrow. Science 242, 919-922

85. Cohen, A. H., Sun, N. C., Shapshak, P., and Imagawa, D. T.(1989) Demonstration of human immunodeficiency virus inrenal epithelium in HIV-associated nephropathy. Mod Pathol.2, 125-128

2390 Vol. 5 July 1991 The FASEB Journal ROSENBERG AND FAUCI

86. Levy, J. A., Margaretten, W., and Nelson, J. (1989) Detectionof HIV in enterochromaffin cells in the rectal mucosa of anAIDS patient. Am. j Gastroenterol. 84, 787-789

87. Cao, Y. Z., Friedman-Kien, A. E., Huang, Y. X., Li, X. L.,Mirabile, M., Moudgil, T., Zucker-Franklin, D., and Ho,D. D. (1990) CD4-Independent, productive human immuno-deficiency virus type 1 infection of hepatoma cell lines in vitro.j Viral. 64, 2553-2559

88. Werner, A., Winskowsky, G., Cichutek, K., Norley, S. G., andKurth, R. (1990) Productive infection of both CD4 and CD4-human cell lines with HIV-1, HIV-2 and SIVagm. AIDS 4,537-544

89. Ikeuchi, K., Kim, S., Byrn, R. A., Goldring, S. R., andGroopman, J. E. (1990) Infection of nonlymphoid cells by hu-man immunodeficiency virus type 1 or type 2. j Viral. 64,4226-4231

90. Kunsch, C., Hartle, H. T., and Wigdahl, B. (1989) Infectionof human fetal dorsal root ganglion glial cells with human im-munodeficiency virus type 1 involves an entry mechanism in-dependent of the CD4 T4A epitope. j Viral. 63, 5054-5061

91. Lusso, P., DeMaria, A., Malnati, M., Lori, F, DeRocco, S. E.,Baseler, M., and Gallo, R. C. (1991) Induction of CD4 andHIV-1 susceptibility in human CD8 T lymphocytes byHHV-6. Nature (London)349, 533-535

92. Canivet, M., Hoffman, A. D., Hardy, D., Sernatinger, J., andLevy, J. A. (1990) Replication of HIV-1 in a wide variety ofanimal cells following phenotypic mixing with murineretroviruses. Virology 178, 543-551

93. Landau, N. R., Page, K. A., and Littman, D. R. (1991) Pseu-dotype with human T-cell leukemia virus type 1 broadens the

human immunodeficiency virus host range. j Vim!. 65,162-169

94. Price, R. W., Brew, B., Sidtis, J., Rosenblum, M., Scheck,A. C., and Cleary, P. (1988) The brain in AIDS: central ner-vous system HIV-1 infection and AIDS dementia complex.

Science 239, 586-59295. Watkins, B. A., Dorn, H. H., Kelly, W. B., Armstrong, R. C.,

Potts, B. J., Michaels, F, Kufta, C. V., and Dubois-Dalcq, M.(1990) Specific tropism of HIV-1 for microglial cells in primaryhuman brain cultures. Science 249, 549-53

96. Fauci, A. 5. (1988) The human immunodeficiency virus: infec-tivity and mechanisms of pathogenesis. Science 239, 617-622

97. Giulian, D., Vaca, K., and Noonan, C. A. (1990) Secretion ofneurotoxins by mononuclear phagocytes infected with HIV-1.Science 250, 1593-1596

98. Pulliam, L., Herndier, B. G., Tang, N. M., and McGrath,M. S. (1991) Human immunodeficiency virus-infected macro-phages produce soluble factors that cause histological and neu-rochemical alterations in cultured human brain. j Clin. Invest.87, 503-512

99. Lee, M. R., Ho, D. D., and Gurney, M. E. (1987) Functionalinteraction and partial homology between human im-munodeficiency virus and neuroleukin. Science 237, 1047-1051

100. Brenneman, D. E., Westbrook, G. L., Fitzgerald, S. P., Ennist,D. L., Elkins, K. L., Ruff, M. R., and Pert, C. B. (1998) Neu-ronal cell killing by the envelope protein of HIV and itsprevention by vasoactive intestinal peptide. Nature (London)335, 639-642

101. Dreyer, E. B., Kaiser, P. K., Offermann, J. T., and Lipton,S. A. (1990) HIV-1 coat protein neurotoxicity prevented by cal-cium channel antagonists. Science 248, 364-367