Mononuclear phagocytes and the human immunodeficiency virus

Mononuclear

phagocytes and the human

immunodeficiency H.E. Cendelman*t ‘The Henry

M. Jackson Foundation

Rockville, Maryland, Cellular Immunology,

for the Advancement

Opinion

in Immunology

Introduction The principal target cells for the human immunodeficiency virus (HIV) in the infected human host are CD4+ T cells and mononuclear phagocytes. The virus replicates continuously in both cell types despite an often vigorous immune response. The primary immunologic deficit, a relentless loss of CD4+ T cells, is inevitable and results in opportunistic infections, neoplastic change, and neurologic disease. There is now strong evidence that the numbers of productively infected cells in the central nervous system (CNS), lymphatics and lung tissues far outnumber those in blood. In each of these tissues, the predominant infected cell is the macrophage. Research efforts revolve around the identification and quantilication of infected tissue macrophages and the unique biologic, biochemical, and molecular mechanisms that un derlie these virus-cell Interactions. The probable role of the macrophage in the persistence of HIV infection and the unique features of the HIV life cycle that are related to macrophage viral tropism and cytopathology are discussed here.

that the macrophage

and M.S. Meltzert of Military

Medicine,

USA and THlV lmmunopathogenesis Program, Department of Waiter Reed Army Institute of Research, Washington DC, USA Current

Evidence

virus

is a major in

vivo target cell for HIV Numerous reports document tissue macrophage infection by HIV. Although the Iangerhans’ cells of skin (Tschacler et al., J Invest Dermutol 1987, 88:233-237), follicular dendritic cells of lymph nodes (Armstrong et aC, Lancet 1984, ii:37CF372; Tenner-Racz et al, Luncet 1985, 1:10>106; Tenner-Racz et al, Luncet 1988, i:774-775) macrophages of brain (Epstein et al,

1990, 2:414-419

AIDS Res 1985, 1:447454; Gartner et al., JAM4 1986, 256:2365-2371; Stoler et al., Jm 1986, 256:2381-2383; Vazeux et al, Am J Patbol 1987, 126:403-410; Gartner et al., Science 1986, 233:215-219; Koenig et al, Science 1986, 233:215219; Wiley et al, Proc Natl Acad Sci USA 1986, 83:708!&7093) [l] and spinal cord [2], interstitial and alveolar macrophages of lung (Chayt et aL, JAM4 1986, 256123562359; Plata et al, Nature 1987, 328:348351), and blood monocytes [3,4] (Ho et al., J Clin Invest 1986, 77:1712-1715; Popovic and Gartner, Luncet 1987, ik916) all support virus replication, only macrophages of the CNS, lymph nodes, and lung are productively infected at high frequencies in vivo. Neurologic disease associated with HIV Infection is characterized histologically by pallor of the white matter (the most common fmding) accompanied by a diffuse reactive astrocytosis, scattered microglial nodules, and multinucleated giant cells which are the histologic hallmarks of HIV infection in the CNS (Navia et al, Ann New-01 1986, 19:525-535) [ 51. Clinically, more than half the patients with the acquired immune deficiency syndrome (AIDS) develop some form of CNS morbidity including impaired memory, altered concentration, and psy chomotor retardation (Navia et al, Ann Neural 1986, 19:517-524). Numerous reports have shown that there is a persistent, productive viral infection (by detection of viral nucleic acid and progeny virions) in brains of HIV-infected individuals (Ho et al, N Engl J Med 1985,313:149%1497; Levy et al, Luncet 1985,2:586-588; Shaw et al, Science 1985, 227:177-182) [5]. This viral infection occurs predominantly, if not exclusively, in macrophages [1,5] (Gartner et al, 1986; Koenig et al., 1986, Wiley et al., 1986). Brain macrophages (subarachnoid, perivascular, and parenchymal cells), microglia, and macrophage-derived multinucleated giant cells are pro-

Abbreviations AIDS-acquired immune deficiency syndrome; CAT--chloramphenicol acetyl transferase; CMV-cytomegalovirus; CNS-central nervous system; CSF-colony-stimulating factor; EBV-Epstein-Barr virus; FACS-fluorescence-activated cell sorting FcR-Fc receptor; CM-CSF-granulocyte/macrophage CSF; HIV-human immunodeficiency virus; HSV-herpes simplex virus; HTLV-human T-cell leukemia virus; Ig-immunoglobulin; IL-interleukin; LA-lymphadenopathy-associated virus; LTI-long terminal repeat; M-CSF-macrophage CSF; mRNA-messenger RNA; PCR-polymerase chain reaction; RT-reverse transcriptase; srCDQ---soluble recombinant CD4; TCIDw-1 X IO5 tissue-culture-infected doses; TNF-tumor necrosis factor.

414

@ Current

Science

Ltd ISSN 0952-7915

Mononuclear

phagocytes

and the human

ductively infected at infection frequencies of up to 10%. Although viral infection of brain parenchymal cells (endothelial cells, astrocytes and oligodendrocytes) has also been reported (Wiley et al, 1986;Stoler et al, JAMA 1986,256:2381-2383; Gyorkey et al, J Infect Db 1987, 155:87@876), most studies failed to demonstrate viral gene products in such cells. Productive and persistent infection of spinal cord macrophages is reported in HIV disease [2]. HIVinduced pathologic changes in the spinal cord are different from those in brain and are characterized by vacuolation of white matter with macrophage (multi nucleated and mononucleated cell) infiltrations. em munohistochemistry and electron microscopic analyses of HIV-infected macrophages in spinal cord show phagocytized myelin in the regions adjacent to tissue lesions. Follicular dendritic cells of lymph nodes are also infected in viva at frequencies similar to macrophages in the CNS. Progressive follicular destruction, low antibody titers and ultrastructural evidence of viral replication in follicular dendritic cells is a reproducible result in HIV infection (Cameron et al, Clin Eq Immunoll987,68:465-478). A unique phenotypic feature of the follicular dendritic cell compared with other cells of the mononuclear phagocyte system is the high level of cellsurface CD4. The striking and coincident depletion of circulating blood CD4+ T cells and these follicular dendritic cells during HIV infec tion may reflect the relatively high levels of CD4 in both cell types. HIV gene products are found in cells of bronchoalveolar lavage fluids ( > 90% macrophages) at high frequencies of infection (HIV gag gene products or nucleic acids are detected in up to 50% of macrophages (Ziza et al, New Engl J Med 1985,313:183; Plata et al., 1987). The predominant circulating HIV-infected blood leukocyte is the CD4+ T cell [6](Psallidopoulos et al., J Vi rol1989,63:462&4631). Recent analyses of blood leukocytes by sensitive techniques that can amplify a few copies of viral DNA (the polymerase chain reaction; PCR) have shown that up to 1% of blood mononuclear leukocytes harbor HIV proviral DNA Despite the relatively high frequency of infected cells, the number of productively infected cells in blood (cells with viral RNA or protein) is very low ( < 0.001%; Harper et al., Proc Nat1 Acad Sci USA 1986,83:772-776). The number of circulating blood monocytes latently or productively infected with HIV remains controversial. Ho et al. (1986)recovered the virus from HIV seropositive individuals from the adherent monocyte-enriched fractions of blood leukocytes, and not from the non-adherent T-lymphocyte-enriched fractions, after cocultivation with allogeneic, mitogen-stimulated lymphoblasts. Similarly, Popovic and Gartner (1987)compared monocyte and Tcell-enriched fractions of blood as sources of virus in the early stages of HIV infection. For each patient tested, the virus was successfully recovered from monocytes, but not from T cells. Using macrophage colony-stimulating factor (M-CSF)-treated monocytes from seronegative donors as target cells [ 31. recovery of HIV from the leukocytes of in-

immunodeficiency

virus

Cendelman and Meltzer

fected individuals was successful in 25 out of 27 patients [ 71, This relatively high frequency of virus isolation was independent of zidovudine therapy, patient’s age, clinical stage of disease, and numbers of CD4+ T cells. Al though the cocultivation assays with mixed populations of leukocytes and M-CSF-treated monocytes precluded identification of the HIV-infected cells in blood, the preferential growth conditions for macrophages and the biologic characterization of the recovered virus (see below) suggest (but do not prove) that the recovered virus is of monocyte origin. Other studies suggest that blood monocytes are infected less frequently. In an analysis of 36 seropositive homosexual men, McElrath et al. [4]isolated HIV in T-cell-enriched fractions of blood twice as frequently as in monocytes. Schnittrnan et al. [6],combining fluorescence-activated cell sorting (FACS) analysis with PCR techniques, isolated and analyzed CD4+ (Thelper), CDS+ (T-suppressor), CD14+ (monocyte), and CD19+ (B-cell) subpopulations. Viral DNA was detected almost exclusively in the T-cell subpopulation. In other reports (Psallidopoulos et al, 1989),both CD4+ T cells and monocytes were found to be infected in vivo, but most of the infectious burden was in the T cells. These experiments, taken together, provide strong evidence for infection of both CD4 + lymphocytes and blood monocytes. Epidermal Iangerhans’ cells, the dendritic antigen-presenting cells of skin, are also targets for HIV. In skin biopsies of 40 seropositive patients, HIV-infected Iangerhans’ cells were detected in about half of the individuals (Tschacler et al, 1987). The frequency of infection in skin was lower than that reported for brain, lung or lymph nodes. Other investigators found that infection of Iangerhans’ cells was an even more infrequent event. In immunocytochemical studies of skin tissue from 44 patients, none were positive for HIV antigens [B] . In cells of the oral mucosa, viral proteins were infected in only two out of 26 seropositive patients (Becker et al, W-chows Arch (A/ 1988,412:413-419). The differing results reported in these studies may reflect patient selection, the method used, or possibly the anatomic location of the skin biopsies [ 81.

Isolation

and propagation

cultured

macrophages:

cell-virus

interactions

of HIV in tissue-

unique host

Early reports of HIV propagation onto monocytes or alveolar macrophages using a laboratory-adapted T-cell strain of the human T-cell leukemia virus (HTLV)IIIB/lym phadenopathy-associated virus (IAV) demonstrated a low-level infection in a small subset of cells (Nicholson et al, J Immunol 1986, 137:323-329; Ho et al., 1986). The levels of viral replication were just above the limits of p24 antigen and reverse transcriptase (RT) assays. Macrophages cultured with HTLV-IIIB/LAVqngested the viral particles into phagocytic vacuoles within 10 min of exposure. HIV persisted in such vacuoles, as judged by

415

416

lmmunudeficiency

transmission electron microscopic analysis for 3 days of culture, but no virions were observed budding from the plasma membrane and no cytopathic changes were evident in the cultured cell monolayers. The first evidence for productive HIV infection of monocytes developed from studies using primaty cultures of brain tissue or bronchoalveolar lavage-derived macrophages (Gartner et UC, 1986). Cultures of brain explants or cells in the bronchoalveolar lavage from infected patients that were enriched for macrophages by trypsin digestion showed evidence of virus replication, on the basis of increased RT activity in cell-free culture fluids and transmission electron microscopic analysis. Cell-free fluids passaged from these tissue explants onto blood macrophages from seronegative donors in duced a productive and sustained infection for 2 months of culture. Such infected macrophages showed a high frequency of infection ( > 20%) concomitant with profound cytopathic effects (multinucleated giant cells) not present in the uninfected control cells. Progeny virus from these infected macrophage cultures was passaged into both T-cell and macrophage target cells. Iaboratoty adapted HIV strains passaged in T-cell lines (HTLVIIB/IAV) grew poorly in cultured macrophages. Similarly, HIV isolated from the cerebrospinal fluid of a patient with the AIDSdementia complex was passaged in lymphoblasts but not in macrophages; an HIV isolate from the brain tissue of the same patient infected both lymphoblasts and macrophages (Koyanagi et al, Science 1987, 236:819-822). Detailed analysis of the HIVmonocyte interaction has been impeded by the inability to culture macrophages for extended intervals in vitro. Macrophages maintained in medium supplemented with M-CSF survive for months with little or no loss of cell viability [3]. Here, M-CSF is a sun&al and differentiation factor: cell proliferation

was evident in < 3% of the total macrophage population. The CD4+ cell-surface epitope, the receptor for HIV on lymphoblasts, was not detected in M-CSF-treated macrophage populations. Although CD4 is present at low levels on monocytes, reports of the percentage of cells that display this determinant range from 5 to 95% 131 (Crowe et al, AIDS Res Hum Retrovir 1987, 3135138; Gartner et al., 1986). Using M-CSF-treated monocytes from seronegative donors as target cells, recovery of HIV from leukocytes was successful in 25 out of 27 patients (described above). Passage of cell-free culture fluids from these primary cocultures onto new seronegative donor macrophages induced sustained and high levels of viral replication. In such cultures, proviral DNA, messenger RNA (mRNA), p24 antigen and RT activity were all readily detected. Cytopathicity, as demonstrated by multinucleated giant cell formation, stellate cells and cell lysis were observed in these infected macrophage monolayers after serial viral passage [3] (Fig. 1). During viral isolation, progeny HIV was produced for 24 weeks at low levels in the absence of cytopathic changes. In such cultures, the viral p24 antigen was released in quantities that were often disproportionately higher than those of the progeny virions, as estimated by levels of RT activity. Anatysis of these chronically infected monocytes during the first virus passage by transmission electron rni croscopy showed predominant intracellular virus accumulation. Little or no progeny HIV was observed budding from the plasma membrane. These macrophages were > 50% infected, on the basis of several criteria, including in situ hybridization for HIV-specific mRNA and flow cytometry for viral proteins with specific antibodies. In fection of monocyte target cells by HIV serially passaged through monocytes induced a progressive increase in intracellular and extracellular RT activity and cytopathicity ]31. Fig. 1. Cytopathicity enger

RNA

munodeficiency and

viral

monocytes.

Periph-

cells cultured

in phytohaemagglutinin

/

2

infected

ADA

at

a

im-

(HWinfected

mononuclear

flymphoblasts),

mess-

in human

virus

lymphoblasts eral blood

and

expression

were

multiplicity

(MO0 = 0.01: virus-induced

interleukinof

with

infection

multinucle-

ated giant cells (a), and mRNA-expressrng cells (b), are illustrated. cultured

in monocyte

ing factor

were

infected

a MOI = 0.01; virus-induced ated

giant

illustrated cells in the

cells and cc). Viral cd).

with

ADA

at

multinucle-

stellate

cells are

mRNA-containing

HIV-infected

are also shown

Monocytes

colony-stimulat-

macrophages

Mononuclear

Mechanisms

of virion

phagocytes and the human immunodeficiency

assembly and entry into

macrophages Investigations of processing and biosynthesis of HIV proteins in infected macrophages have revealed unique mechanisms of viral assembly and virion structure. HIV encodes two glycoproteins, gp120 and gp41, which are cleavage products of a precursor gpl60. The external gp120 binds to CD4 on the T-cell surface, an obligatory event in T-cell infection, Quantitation of intracellular protein processing and virion assembly by radioimmunoprecipitation analysis of infected T cells reveals high levels of intracellular gpl60 envelope glycoproteins which are processed to mature gp120 and gp41. The viral gag protein precursor p55 is processed to the mature capsid proteins ~27, p25 and ~17. The major viral protein synthesized by HIV-infected T cells is the envelope protein gp120, and virions released into culture fluids contain high lev els of gp120. In contrast, the dominant viral proteins syrthesized in the HIVinfected macrophage and assembled into progeny tirions are capsid proteins [Hansen et al, Modem Approaches to New Vaccines, Cold Spring Harbor Laboratories, 1989 (abstract)]. There is a relative deficiency of env gene products both in the infected cell and in the released vii-ions. This relative lack of virus gp120 and of macrophage CD4 suggests that there might be other mechanisms of virus entry. The mechanisms of virus entry into macrophages were explored in studies with antibodies to CD4 and with soluble recombinant CD4 (srCD4). Prior treatment of cells with monoclonal antibodies directed against the gp120binding site on CD4 (Ieu3a or OKT4a) completely abrogated infection of macrophages by HIV. However, in seeming contrast to the preceding observation, srCD4 treatment of the infectious inoculum had little or no effect on viral replication in macrophages [9]. In these experiments, 1 x 105 tissue-culture-infected doses (TCIDs,) of HTLV-IIB in the H9 T-cell lyrnphoma line was completely inhibited by prior treatment with < 1 ug/ml of srCD4. Under similar conditions, I 6OOccg/mlsrCD4 had little or no effect on 1 X 103 TCID,, ADA, an HIV isolate that infects both monocytes and lyrnphoblasts [ 31. These data support the notion that inhibition of viral isolates with srCD4 is virus strain-specific. The absolute levels and processing of gp120 may dictate the gpl2ssrCD4 interac tion for both macrophages and lymphoblasts. The exis tence of an alternative CD4independent receptor for HIVon macrophages remains to be proven. The perpetuation of macrophage infection can be medi ated, in part, by antibody-mediated enhancement through the Fc receptor (FcR). Such a mechanism has recently been demonstrated in vitro with patient sera in both myeloid cell lines and primary human macrophages [lO,ll] (Homsy et al, Luncet 1988, i:1285-1286; Jauault et al, AIDS 1989, 3:125-133). In macrophages, antibody mediated enhancement of HIV infection is inhibited by monoclonal anti-F&III (this is the predominant FcR in tissue macrophages in culture, but is absent on circulating blood monocytes) but not monoclonal antibodies against FcRI or F&II. Antibody-mediated enhancement

virus Cendelman

and Meltzer

of HIV infection in the myeloid cell line U937, which lacks F&III but does express FcRI and F&II, was blocked by heat-aggregated imrnunoglobulin (1g)G. It is unclear whether this Fc-mediated enhancement of virus infec tion is CD4dependent. Furthermore, several subsequent studies have questioned the magnitude (usually less than lo-fold) and even the existence of this pathway for viral entry. Certainly, more data are needed to determine whether antibody-mediated enhancement of infection in macrophages is relevant in HIV disease. Several other mechanisms have been postulated for the evasion of host immune surveillance by HIV-infected macrophages: (1) sustained latent or restricted infection; (2) intravacuolar accumulation of progeny HIV within cytoplasmic compartments (Orenstein et al., J Viral 1988, 62:257%2586); (3) infection of bone marrow stem cells [ 111; (4) virus induction of neutralizing antibodies that provide a selection pressure for the emergence of mutant viruses which, in turn, could escape serum neutralization (Narayan and Cork, Rev Infect Dis 1985, 7~89-98; Haase et al, Nature 1986, 322:130-136; Cheevers et al, Rev Infect Dis 1985, 7:83-88); (5) cell-to-cell spread of virus and formation of multinucleated giant cells in viva, and (6) infection and viral replication in an immunologically privileged CNS sanctuary.

Persistence

and regulation

of HIV replication

in macrophages: the role of cytokines

and

cofactors The interval between initial infection with HIV and the development of symptoms is long ( > 7 years) and vanable. In this relatively symptomless period of subclinical infection, the virus may be ‘dormant’. The existence of a true microbiologic latency in which there is no detectable viral expression of RNA or proteins in an infected cell is supported by the results of recent PCR studies [6,12]. Furthermore, a correlation between the levels of cell-free virus and viral proteins in serum and late stage of infec tion has also been reported. Mechanisms that augment viral expression in infected macrophages may have roles both in the onset and in the progression of clinical disease [ 13,141. Cytokines, which are involved as normal activation signals and induced during an immune response, might af feet HIV replication [ 16161. Transgenic mice that contain integrated but non-expressed HIV long terminal repeat (LTRtchloramphenicol acetyl transferase (CAT) plasmid DNA show increased LTRdirected viral expression in differentiated macrophages after exposure to sev eral different cytokines: M-CSF, granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1, IL-2 and IL-4 (Leonard et al, AIDS Res Hum Retroz& 1989,5:421-430). Moreover. viral production may be upregulated in HIV-infected myeloid cell lines or prirnaly macrophages by the addition of GM-CSF, M-CSF, tumor necrosis factor (TNP) or IL-3 [ 151 (Folks et al.. Sci-

ence

1987,238:800+02;

Matsuyna

et al, AIDS Res Hum

417

418

lmmunodeficiency

Retrovir 1989, 5:13!+146; Clouse et al., J Immunoll989,

Annotated

142:431-438). The viral strain, the target cells, the site of proviral DNA integration, and the concentration and duration of exposure of cytokines may all be critical in producing the effects on HIV gene expression in vivo.

reading

Patients infected with HIV are often co-infected with a variety of DNA viruses. Co-infection with herpes simplex virus (HSV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), are commonly found in people with AIDS or at risk for it. The role of such DNA viruses in stirrulation of HIV gene expression was examined in model systems (Gendelman et al, Proc NatLAcud Sci USA 1986, 83:975+9763; Mosca et al, Nature 1987, 325:67-70). When plasmids containing the immediate-early genes of heterologous DNA viruses were co-transfected into cells with plasmids containing the CAT gene linked to the HIV LTR, CAT activity was markedly increased. As HS\’ and CMV replicate in macrophages and dual infection of macrophages by HIV and CMV has been reported in vivo (Nelson et al., Virology 1988, 165:286290), these dually infected cells could have a role in the progression of HIV disease. Suppression of HIV expression may underlie viral latency and be related to several factors including methylation of LTR sequences (Bednarik et al, J Viral 1987, 61:12%1257) and exposure to circulating interferons [ 171 (Poli et al, Science 1989, 244:575577; Gendelman et al, 1989). Demethylation and active viral replication may follow exposure of cells to activating agents, such as mitogens. Interferons have been shown to suppress HIV replication in human monocytes. In this respect, the high levels of an acid-labile interferon found in HIV-infected patients might reflect the pathophysiologic mechanisms involved in restricting viral gene expression in man.

0

Acknowledgements We thank Drs Gerald Eddy, Donald Skillman, Jim Turpin, D. Chester Kalter, Lisa Baca, Brian Hansen and Steve Joe for helpful discussion and members of the Walter Reed RetroviraJ Research group for excellent patient management. Dr Gendeiman is a Carter-Wallace fellow of The Johns Hopkins University School of Public Health and Hygiene in the Department of Immunology and Infectious Diseases. These studies were supported in part by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Rtxkville, MD. The opinions of the authors do not necessarily reflect those of the Department of Defense

and recommended

?? b

Of interest Of outstanding

1.

MK: Microglia in the giant MICHAEISJ, PRICERW, ROSENBLUM

0

cell encephalitis of acquired immune deficiency syndrome: proliferation, infection and fusion. Actu Neuropatbol 1988,

interest

76375379. Characterization of microglia 2. a

as target cells in AIDS encephalopathy.

EILBO’~~DJ, PERESSN, BURGERH, LANEYED, ORENSTEIN J. GENDELMAN HE, SEIDMANR, WEISERB: Human immunoceficiency virus type 1 in spinal cords of acquired immunodeticiency patients with myelopathy: expression and replication in macrophages. Proc Natl Acud Sci 1J.U 1989.

a6:3337-3341. Description of spinal cord macrophages HIV infection. 3. a

in the vacuolar myelopathy

of

GENDELMAN HE, ORENSTEINJM, MARTINMA, FERRUA C, MrmA R, PHIPPS T, WAHLrq LANEHC, FAUCIAS, BURKEDS, SKKLMAND, MELTZER MS: Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor l-treated monocytes. J Exp Med 1988, 167:1428-1441.

An efficient tissue culture system for the isolation and propagation of HIV on blood-derived monocyt~macrophages is described. Viral budding into intracytoplasmic vacuoles of macrophages is reported. 4. 0

MCEIRATHMJ, PRUETIJE, COHN ZA: Mononuclear phagocytes of blood and bone marrow: comparative roles as viral reservoirs in human immunodeliciency virus type 1 infections.

Proc Nat1 Acad Sci USA 1989, 86675-679. of HIV isolation from blood monocytes and T lymphocytes of seropositive individuals. The frequency of viral isolates obtained from T lymphocytes is greater than that for blood monoqtes.

A comparison

5. .a

MICHAELS J, SHARER LR, EPSTEIN LG: Human immunodeficiency virus type 1 (HIV-l) infection of the nervous system: a review. Immun Rev 1988, 1:71-104.

An extraordinarily well-written and comprehensive review on the pathogenesis of CNS disease associated with HIV infection. 6.

SCHN~-~MANSM, PSAU.UXIPOULOS MC, IANE HC, THOMPKIN

. .

L, BA~EL!~R M, MA%ARI F, Fox CH, SAI~~~ANNP, FA~JCIAS: The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4 Science 1989.

Summary Macrophages are an important in vivo reservoir for HIV [ 16,1%20]. Conclusive evidence that CNS, pulmonary, lymph node and blood-derived mononuclear phagoqtes harbor and support HIV replication is supported by numerous independent studies. HIV variants which preferentially replicate in macrophages have been recovered from infected individuals, suggesting that these cells and variant viruses are involved in the establishment and progression of HIV-related disease.

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