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(Journal of Leukocyte Biology. 2000;68:311-317.)
© 2000 by Society for Leukocyte Biology

The level of HIV infection of macrophages is determined by interaction of viral and host cell genotypes

A. L. Cunningham, S Li, J Juarez, G Lynch, M. Alali and H. Naif

Centre for Virus Research, The Westmead Millennium Institute, University of Sydney, and The Australian National Centre for HIV Research, Sydney, Australia

Correspondence: Anthony L. Cunningham, The Westmead Millennium Institute, P.O. Box 412, Westmead NSW 2145, Sydney, Australia. E-mail: tony_cunningham{at}wmi.usyd.edu.au


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ABSTRACT
 
The outcome of HIV infection in vivo and in vitro depends on the interaction of viral and cellular genotypes. Analysis of infection of blood monocyte-derived macrophages by primary HIV strains shows that approximately one-third of 32 isolates was consistently high-replicating, one-third was consistently low-replicating, and one-third was dependent on the donor of the macrophages (i.e., variable). HIV isolates from patients with AIDS showed enhanced replication within macrophages and predominant use of CCR5 for entry, although 13% did use CXCR4. Tissue isolates from brain and CSF showed an enhanced ability to infect 1-day-old monocytes compared with blood isolates from patients with AIDS. The ability of primary isolates to infect neonatal or adult monocytes maturing into macrophages or placental macrophages correlated directly with the extent of CCR5 expression. Studies of macrophages from pairs of identical twins and unrelated donors showed genetic control over CCR5 expression, which was independent of the CCR5{triangleup}32 genotype. Furthermore, these studies showed a marked host-cell genetic effect on the variable primary HIV strains. Although CCR5 was essential for the entry of most primary isolates, it was not the essential "bottleneck" determining productivity of infection. The location of this bottleneck in the HIV replication cycle differs according to viral strain and host-cell donor, but it was exerted before the stage of reverse transcription in 80–90% of cases. Such host-cell genetic factors may affect viral load in vivo where macrophages are the predominant target cells.

Key Words: genetics • twins • monocytes


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INTRODUCTION
 
Human immunodeficiency virus (HIV) infection of any cell type results in a series of viral- and host-cell protein interactions as the virus proceeds through its replication cycle. These interactions will differ according to host and viral genotype (Fig. 1 ).



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  		Figure 1. Effect of genetics of cell donor on HIV infection of macrophages. "Bottlenecks" may occur at different places in different cells with the same HIV strain. RT, Reverse transcription.

Furthermore, the process of infection, commencing with envelope protein-CD4/chemokine-receptor interactions, also induces activation of various cell pathways, leading to endogenous host-cell, protein-protein interactions and secretion of cytokines or chemokines resulting in exogenous effects, which, in turn, affect viral-cell protein interactions. The complexity of the host-cell effects on HIV replication makes them difficult to study unless individual viral effects dominate, resulting in consistent interactions with the cells of individual donors (Fig. 2 ).



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  		Figure 2. Differences in sequences of HIV proteins [1 , 2 ] or macrophage [1 2 3 ] proteins (A), or differences in macrophage protein-protein interactions (B) may result in differences in binding of HIV to macrophage proteins and thus influence the replicative cycle.

HIV tropism for, and the level of, productive infection in T lymphocytes and macrophages is determined by these processes.


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BIOLOGICAL EFFECTS OF VIRAL GENOTYPES
 
The investigation of biological effects of HIV is complicated by its ability to generate variants resulting in quasispecies in vivo and in vitro (as "isolates") and also by differences in composition of the quasispecies between anatomical sites, between different infected cell types, and after isolation in different patients’ cells [3 ]. Interactions such as coninfections, complementation, and recombination may occur. Heterogeneity could be reduced by studying infectious molecular clones, but such studies would need to be very comprehensive; otherwise, they would be too selective and would not allow for the interactive effects. Practically, very low passage isolates in pooled donor cells are best used for biological studies, because they allow a reasonable approximation to the blood quasispecies in vivo.

In our studies of HIV infection of macrophages by primary chemokine receptor 5 (CCR5)-utilizing HIV (R5) macrophage (M)-tropic strains, unpassaged after initial isolation in pooled mononuclear cells, ~65% of such strains were observed to be consistently high- or low-replicating in any donor macrophage, but 35% replicated to a markedly different degree in macrophages from different donors (Tables 1 and 2 ). The consistently low-replicating isolates (extracellular p24 antigen <500 pg/ml) were examined for the stage of restriction. In blood monocyte-derived macrophages (MDMs), this occurred mainly prereverse transcription (low or absent viral DNA levels <100 copies/105 cells), presumably at viral entry/uncoating, and less frequently, post-reverse transcription (moderate–high viral DNA, low or absent extracellular p24 antigen) [1 , 2 ].


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  		Table 1. HIV Strains Used in These Studies and Their Source


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  		Table 2. Classification of the Ability of R5 Primary HIV Strains to Productively Infect Macrophages from Different Donors

In a cross-sectional study of primary HIV isolates from patients at different stages of HIV disease, these low-replicating R5 isolates were mainly from patients at an early or asymptomatic stage without marked depression of blood-CD4 concentrations. Most isolates from patients with AIDS appeared to have evolved in vivo to a predominant genotype, which was unrestricted at any stage in the replication cycle and produced moderate-to-high levels of productive infection in macrophages. These isolates showed greater diversity in the envelope gene by heteroduplex mobility shift assay (HMA) than isolates from early stages. Although there was a significant correlation between stage of disease and this envelope-gene diversity or productivity of macrophage infection, the correlation between the latter two showed only a nonsignificant trend [2 ]. Presumably the "noise" of enhanced diversity in late-stage disease obscured the specific changes in envelope and other genes responsible for enhanced replication.

In late-stage disease, HIV isolates show broadened coreceptor usage, mainly of CXCR4 [2 , 4 , 5 ]. Higher levels than the observed 13% of isolates might be expected because of the frequency of envelope-gene mutations, the selective inhibition of high ß-chemokine concentrations on R5 strains, and the reduced immune surveillance in late-stage disease and the higher intrinsic replication rate and cytopathic effect of CXCR4-utilizng HIV (X4) isolate for T lymphocytes in late-stage disease [1 ]. This strongly suggests that there are opposing selective forces favoring entry of HIV into T lymphocytes and macrophages via CCR5 at all stages of disease. Furthermore, X4 envelopes are able to induce T lymphocyte activation or apoptosis, which would have opposing effects with an unpredictable net outcome on X4 strain replication [6 ]. In our studies, several isolates were able to utilize CXCR4 to enter macrophages and replicate productively also [2 ]. The ability of these X4 strains to induce apoptosis or cell signaling in macrophages needs to be clarified.

The V3 and/or V1-V2 regions of gp120 interact with CCR5 or CXCR4 and therefore are responsible for tropism and entry into macrophages and T lymphocytes [7 ]. As perhaps expected from isolates obtained by mononuclear cell coculture, the strains "replicating at low levels in macrophages" from asymptomatic patients still replicated well in T lymphocytes. No consistent V1-V2 or V3 sequence motifs or phylogenetic clustering were observed in the low- or high-replicating isolates. The envelope sequences of isolates pre- and post-passage in macrophages and T lymphocytes were also compared. The sequences differed by several nucleotide substitutions after a single passage in macrophages vs. T lymphocytes [1 ].

Most studies of primary HIV strains have used blood isolates. Therefore, it was interesting to determine whether there were any biological differences between blood isolates from advanced stages of disease, when blood CD4 lymphocytes were depleted, and tissue isolates from brain, cerebrospinal fluid, lung, and spleen. There was little difference between the ability of these primary blood and tissue strains to replicate in MDM. All used CCR5 for entry. However, tissue strains showed much greater ability to productively infect monocytes than blood strains, similar to M-tropic laboratory-adapted strains such as BaL, which indeed are derived from tissue (see next section). The tissue isolates also showed greater envelope-gene diversity by HMA than late-stage blood isolates. Because most of the tissue isolates were derived from brain or colony-stimulating factor (CSF), these data suggest biological differences from M-tropic strains retained within these tissues compared with those released into blood, probably mostly from lymph nodes, even in late-stage disease. This biological "compartmentalization" is similar to the genetic compartmentalization demonstrated in brain by several groups including our own [8 ].


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HOST MACROPHAGE EFFECTS
 
Relatively few host-cell proteins have been defined that are critical for infection with all HIV strains. These include the binding receptor, CD4, the chemokine (co) receptors, the {alpha} and ß importins, and cyclin T1, which interacts with Tat [9 10 11 ]. Monocytes and macrophages express a variety of chemokine receptors documented to allow fusion of HIV envelopes or entry into transfected cells (such as Hos. CD4). These include CCR2b, CCR3, CCR5, CCR8, CXCR4, BONZO/STRL33, and Bob/GPR15 [12 13 14 ]. Many studies, especially those in patients who lack CCR5 expression (CCR5{triangleup}32 homozygotes), have demonstrated now that only CCR5 of these potential coreceptors and, to a lesser degree, CXCR4 are important for HIV entry into blood-derived and most tissue macrophages. CCR3 may also be important for entry of some HIV strains into brain microglial cells and neonatal macrophages [15 ].

The differentiation of blood monocytes to macrophages was accompanied by the appearance and upregulation of expression of the HIV coreceptor, CCR5, an initial decrease and then slow increase in CD4 expression, and coincident partial and variable downregulation of CXCR4 and CCR2b expression [16 , 17 ]. In neonatal monocytes, CCR5 expression appeared more slowly during macrophage maturation. However, mature, differentiated, placental macrophages expressed negligible levels of CCR5 at the cell surface (despite expression of moderate levels of CCR5 RNA) [18 ]. The ability of R5 primary isolates to infect differentiating neonatal or adult monocytes correlated closely with CCR5 expression and these isolates were unable to infect placental macrophages [16 , 18 ]. Conversely, at similar multiplicity of infection (MOI), laboratory-adapted (LA) strains such as BaL were able to infect monocytes consistently and at early stages of maturation and could even infect placental macrophages, because they were able to utilize lower levels of CD4 and CCR5 than primary strains. Tissue R5 isolates, but not blood R5 isolates, even from patients with terminal AIDS were able to infect monocytes with similar ability (see above) [18 , 19 ].

However, 1-day-old monocytes demonstrated other pre- and also post-reverse transcription (RT) blocks to infection more often than in mature macrophages (30% vs. 10% of donors, respectively, for post-RT blocks). With advancing maturation, monocytes become more permissive to HIV infection at most stages of the replication cycle [16 , 18 ].

The level of surface-CCR5 expression varied between macrophages and T lymphocytes of different donors [1 , 20 ]. Studies with identical twins, compared with pairs of unrelated donors, showed a highly significant correlation of these levels within twin pairs only, indicating genetic control of expression (Fig. 3 ). This was independent of the heterozygous state for the CCR5{triangleup}32 deletion. Heterozygotes showed a lower median level of expression, but the range was wide (18–32%) and overlapped with the similar wide range of expression in those with the wild-type gene (<1–67%).



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  		Figure 3. This scattergram shows the correlation of the proportions of 3-day-old macrophages expressing CCR5 within unrelated donor pairs (A) and within identical twin pairs (B). There was a significant correlation only between identical twin pairs (r=0.81, p<0.01). Membrane CCR5 expression by macrophages was examined by staining with anti-CCR5 monoclonal antibody (2D7) and flow cytometry (from ref. 1 ).

A series of mutations have been described in the promoter region of CCR5 (P1–P6), and the PI mutation was associated with accelerated progression of disease [21 ]. However, no correlation between any of these mutations and the level of CCR5 expression on CD4 lymphocyte has been demonstrated [21 , 22 ]. Thus, the precise nature of genetic control over cellular CCR5 expression, whether in macrophages or T lymphocytes, remains unclear.

The role of CXCR4 as a coreceptor for entry of X4-HIV strains into macrophages via CXCR4 is being clarified (see Collman, JLB, this issue). Several groups, including our own, showed that primary, but not laboratory-adapted, X4-HIV strains could infect macrophages [2 , 23 24 25 ].

These studies refine the earlier observations that primary- or laboratory-adapted strains, which induce syncytia in T cell lines [syncytium-inducing (or SI) isolates], are usually unable to infect macrophages [26 ]. The key question is why laboratory-adapted X4 strains potently infect T cells but not macrophages when both express CXCR4. Furthermore, why can many primary but not LA X4 strains infect macrophages? The answer may be because of the quaternary structure of CXCR4 on macrophages compared with T lymphocytes or differences in its interactions with CD4. CXCR4 has been shown to exist as two forms, a 55-kDa monomer and 90-kDa oligomer, in macrophages and as a 47-kDa monomer in T lymphocytes [27 ]. Binding of CD4 is stronger to CCR5 than CXCR4 [28 , 29 ]. Membrane CD4 has been shown to exist partially as a dimer on lymphoid and monocytoid cells also. Some cell activators, such as phorbol 12-myristate 13-acetate (PMA) enhance dimerization [30 , 31 ]. CD4 in T lymphocytes interacts with lck, but the interacting partner(s) in macrophages are unknown and could alter quaternary structure. Furthermore, the importance of the quaternary structure of CD4, CCR5, and CXCR4 and their interactions in modulating HIV entry is likely but not yet established.


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HOST MACROPHAGE-VIRUS INTERACTIONS
 
Infection of the same cell type from different human donors by the same HIV isolate may not result in similar levels of replication necessarily. Indeed, variability of replication of any given HIV strain in T lymphocytes or macrophages from different donors has been well known for many years [32 33 34 35 ]. As mentioned above, the best-defined, host-genetic effect is the CCR5{triangleup}32 homozygous state, which results in complete absence of CCR5 at the surface of T lymphocytes and macrophages, resulting in refractoriness to infection by R5-HIV strains [36 37 38 ]. However, our twin studies have demonstrated more subtle host-genetic effects. For example, two HIV strains may behave in opposite ways in macrophages from two different unrelated donors (Fig. 1) . Strain 1 may be high-replicating in donor A’s macrophages but low-replicating in donor B’s macrophages. The converse may occur with another HIV strain. This was apparent when macrophages from 10 pairs of unrelated donors were infected with primary HIV strains (variable strains; see Table 1 in Fig. 4 ) [1 ]. However, within eight twin pairs, the kinetics and level of productive infection were very similar (Fig. 4) . The patterns in nonidentical twins were similar or dissimilar but, on average, were intermediate in their differences between identical twins and unrelated donors. This indicates a complex polygenic host-cell effect on HIV replication, reflecting the many proteins involved in the various stages of HIV replication [1 ].



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  		Figure 4. This scattergram shows the correlation between levels of HIV replication in 3-day-old macrophages within identical twin pairs (twin 1 vs. twin 2) measured as intracellular HIV DNA by semiquantitative PCR (a total of 24 donor macrophage HIV combinations). HIV DNA levels in 105 macrophages were classified as 0 (undetectable), + (low copy number <102), ++ (intermediate copy number 102–103), +++ (high copy number >103). There was a high concordance (r=0.96, P=0.0001). (B) Correlation between levels of HIV replication within unrelated donor pairs (URD1 vs. URD2) measured as intracellular DNA (a total of 35 host MDM-HIV combinations). There was a very low concordance (r=0.11, P=0.3; from ref. 1 ).

The predominant stage of these host-cell genetic effects was then dissected by quantifying the early and late products of RT (HIV DNA) using different sets of primers and the extracellular p24 antigen levels and comparing these with the level of CCR5 expression on these cells. The main host-cell genetic effect was exerted prereverse transcription in 90% of cases. However, this pre-RT restriction did not correlate with the level of CCR5 expression on the surface of macrophages. Indeed, CCR5 was found to be a restricting factor for HIV entry only at a very low level (as also found with maturing monocytes; Fig. 5 ). This strongly suggests that there are other stage(s) in viral entry or uncoating that occur prior to RT, which may act as bottlenecks beyond binding to the chemokine receptor. Efforts are now being made to identify these stages via a gene-screening approach [1 ].



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  		Figure 5. Correlation between the proportions of 3-day-old macrophages expressing CCCR5 and HIV-DNA levels (measured as for Fig. 4 ) in macrophages infected with HIV for 7 days. Note that in general, there is no correlation between CCR5 and HIV-DNA levels and that only very low levels of CCR5 expression (<1%) affect HIV-DNA levels.

The selective effect of the various bottlenecks or critical protein-protein interactions at the various stages pre- or post-RT is also shown by the selective effect on the predominant strains emerging from the infected macrophages. Interestingly, if the same strain were used to infect the macrophages or two pairs of identical twins and two pairs of unrelated donors, the envelope sequences of the predominant HIV strains emerging from these macrophages were found to show less variation within the pairs of identical twins than between the pairs of unrelated donors. This indicated the similarity of the selective mechanisms within the macrophages of identical twins. These effects were surprisingly strong given the inherent biological variability of culturing cells, indicating the importance of certain key protein-protein interactions at critical stages in the virus-replication cycle. It is likely that there are different bottlenecks—i.e., different proteins at the same or different stages exerting effects on the various HIV strains depending on the nature of the protein-protein interactions and therefore on the sequence of host-cell proteins and of viral proteins (Figs. 1 and 2) . Nevertheless, it is important to note that the predominant restrictive effects were defined as those occurring between viral entry and RT.


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CONCLUSIONS
 
The capacity of primary strains to infect macrophages in vitro was determined by the following: 1) state of maturation of the monocytes/macrophages (The host genetic effect is more pronounced at earlier stages of maturation, especially days 1 and 2.); 2) the stage of HIV disease at which the primary isolate has harvested (At later stages of disease, where there is a greater diversity of the quasispecies within primary isolates, there is a greater ability to produce higher levels of productive infection.); 3) viral genotype; and 4) host-cell genotype.

Overall, taking a random group of HIV isolates, the viral genotype was dominant in two-thirds, and the host-genetic effect was prominent in one-third of isolates; macrophages were infected after three days of maturation. However, the importance of the genetic effect was further enhanced when isolates were obtained from nonimmunosuppressed patients and tested in 1-day-old monocytes [39 ].


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IMPLICATIONS
 
These data suggest that inhibitors acting at these critical stages might be found and could contribute to new strategies for antiviral therapy, at least in macrophages. They could be synergistic with chemokine-receptor inhibitors. This type of work needs to be expanded to determine whether such critical bottlenecks occur during HIV replication in CD4 lymphocytes [34 ]. Our experience so far suggests that these will be more difficult to define.

An example of the importance of these bottlenecks is shown by the very low expression of CCR5 on placental macrophages and the inability of over 20 primary R5 strains to infect them. This provides one layer of protection of the fetal circulation from maternal blood-borne HIV infection.

These studies also suggest that genetic factors other than those affecting immune control of HIV infection and CCR5 might have a critical role in controlling the productivity of HIV from macrophages and therefore influence the viral load in vivo in certain tissues [40 ]. These include the late stages of disease in lymph nodes where CD4 lymphocytes have been depleted, but macrophages are still plentiful, and in brain and bone marrow where microglial cells and macrophages, respectively, are the predominant targets for infection [40 41 42 ]. Evolution (and usually increasing diversity) of the HIV quasispecies toward enhanced tropism and productivity in macrophages in the late stages of disease probably contributes to enhanced total-body viral load. Exogenous factors, including stimulatory cytokines (e.g., TNF-{alpha}) and chemokines [43 , 44 ], or the products of opportunistic infections, including lipoarabinomannan [41 , 45 ] present in the late stages of HIV disease, can alter the intracellular environment of macrophages and relieve the bottlenecks to enhance productive HIV infection by macrophages. Foci of such HIV-producing macrophages have been demonstrated in lymph nodes, and macrophage-derived HIV was demonstrated in the plasma of patients with active tuberculosis in vivo [41 , 45 ]. Hence, the role of macrophage production of HIV in vivo in the late stages of HIV disease should be more precisely quantified in a larger patient sample.


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ACKNOWLEDGEMENTS
 
This work was supported by the Australian National Council on AIDS and Related Diseases. Ms. Claire Wolczak typed the manuscript.


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REFERENCES
 
    1
  1. Naif, H. M., Li, S., Alali, M., Chang, J., Mayne, C., Sullivan, J., Cunningham, A. L. (1999) Definition of the stage of host cell genetic restriction of replication of human immunodeficiency virus type 1 in monocytes and monocyte-derived macrophages using twins J. Virol. 73,4866-4881[Abstract/Free Full Text]
    2. 2
  2. Li, S., Juarez, J., Alali, M., Dwyer, D., Collman, R., Cunningham, A. L., Naif, H. M. (1999) Persistent CCR5 utilisation and enhanced macrophage tropism by primary blood human immunodeficiency virus type 1 isolates from advanced stages of disease and comparison to tissue-derived isolates J. Virol. 73,9741-9755[Abstract/Free Full Text]
    3. 3
  3. Wain-Hobson, S. (1992) Human immunodefiency virus type 1 quasispecies in vivo and ex vivo Curr. Top. Microbiol. Immunol. 176,181-193[Medline]
    4. 4
  4. Connor, R. I., Sheridan, K. E., Ceradini, D., Choe, S., Landau, N. R. (1997) Change in coreceptor use correlates with disease progression in HIV-1-infected individuals J. Exp. Med. 185,621-628[Abstract/Free Full Text]
    5. 5
  5. Scarlatti, G., Tresold, E., Bjorndal, S., Fredriksson, R., Colognesi, C., Deng, H. K., Malnati, M. S., Plebani, A., Siccardi, A. G., Littman, D. R., Fenyo, E. M. (1997) In vivo evolution of HIV-1 coreceptor usage and sensitivity to chemokine-mediated suppression Nat. Med. 3,1259-1265[Medline]
    6. 6
  6. Glushakova, S., Yi, Y., Grivel, J. C., Singh, A., Schols, D., De Clerq, E., Collman, R. G., Margolis, L. (1999) Preferential coreceptors utilization and cytopathicity by dual-tropic HIV-1 in human lymphoid tissue ex vivo J. Clin. Invest. 104,R7-R11[Medline]
    7. 7
  7. Hwang, S. S., Boyle, T. J., Lyerly, H. K., Cullen, B. R. (1991) Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1 Science (Wash. DC) 253,71-73[Abstract/Free Full Text]
    8. 8
  8. Chang, J., Jozwiak, R., Wang, B., Ng, T., Ge, Y. C., Bolton, W., Dwyer, D. E., Randle, C., Osborn, R., Cunningham, A. L., Saksena, N. K. (1998) Unique HIV type 1 V3 region sequences derived from six different regions of brain: region-specific evolution within host-determined quasispecies AIDS Res. Hum. Retrovir. 14,25-30[Medline]
    9. 9
  9. Wei, P., Garber, M. E., Fang, S. M., Fischer, W. H., Jones, K. A. (1998) A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA Cell 92,451-462[Medline]
    10. 10
  10. Gallay, P., Stitt, V., Mundy, C., Oettinger, M., Trono, D. (1996) Role of the Karyopherin pathway in human immunodefiency virus type 1 nuclear import J. Virol. 70,1027-1032[Abstract]
    11. 11
  11. Jenkins, Y., McEntee, M., Weis, K., Greene, W. C. (1998) Characterization of HIV-1 vpr nuclear import: analysis of signals and pathways J. Cell Biol. 143,875-885[Abstract/Free Full Text]
    12. 12
  12. Deng, H. D., Unutmaz, D., Kewal-Armai, V. N., Littman, D. R. (1997) Expression, cloning of new receptors used by simian and human immunodeficiency viruses Nature 388,296-300[Medline]
    13. 13
  13. Doranz, B. J., Rucker, J., Yi, Y., Smyth, R. J., Samson, M., Peiper, S. C., Parmentier, M., Collman, R. G., Doms, R. W. (1996) A dual tropic isolate that uses fusin and the beta chemokine receptors CKR-5, CKR-3 and CKR-2b as fusion cofactors Cell 85,1149-1158[Medline]
    14. 14
  14. Liao, F., Alkhatib, G., Peden, K. W. C., Sharma, G., Berger, E. A., Farber, J. M. (1997) STRL33, a novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1 J. Exp. Med. 185,2015-2023[Abstract/Free Full Text]
    15. 15
  15. He, J., Chen, Y., Farzan, M., Choe, H., Ohagen, A., Gartner, S., Busciglio, J., Yang, X., Hofmann, W., Neuman, W., Mackay, C. R., Sodroski, J., Gabuzda, D. (1997) CCR3 and CCR5 are coreceptors for HIV-1 infection of microglia Nature 385,645-649[Medline]
    16. 16
  16. Naif, H. M., Li, S., Alali, M., Sloane, A., Wu, L., Kelly, M., Lynch, G., Lloyd, A., Cunningham, A. L. (1998) CCR5 expression correlates with susceptibility of maturing monocytes to human immunodeficiency virus type 1 infection J. Virol. 72,830-836[Abstract/Free Full Text]
    17. 17
  17. Di Marzio, P., Tse, J., Landau, N. R. (1998) Chemokine receptor regulation and HIV type 1 tropism in monocyte-macrophages AIDS Res. Hum. Retrovir. 14,129-138[Medline]
    18. 18
  18. Fear, W. R., Kesson, A. M., Naif, H. M., Lynch, G. W., Cunningham, A. L. (1998) Differential tropism and chemokine receptor expression of human immunodeficiency virus type 1 in neonatal monocytes, monocyte-derived macrophages, and placental macrophages J. Virol. 72,1334-1344[Abstract/Free Full Text]
    19. 19
  19. Platt, E. J., Wehrly, K., Kuhnman, S. E., Chesbro, B., Kabat, D. (1998) Effects of CCR5 and CD4 cell surface concentrations on infections by macrophage-tropic isolates of human immunodeficiency virus type 1 J. Virol. 72,2855-2864[Abstract/Free Full Text]
    20. 20
  20. Moore, J. P. (1997) Coreceptors: implications for HIV pathogenesis and therapy Science (Wash. DC) 276,51-52[Free Full Text]
    21. 21
  21. Martin, M. P., Dean, M., Smith, M. W., Winkler, C., Gerrard, B., Michael, N. L., Lee, B., Doms, R. W., Margolick, J., Buchbinder, S., Goedert, J. J., O’Brien, T. R., Hilgartner, M. W., Vlahov, D., O’Brien, S. J., Carrington, M. (1998) Genetic acceleration of AIDS progression by a promoter variant of CCR5 Science (Wash. DC) 282,1907-1911[Abstract/Free Full Text]
    22. 22
  22. Liu, R., Zhao, X., Gurney, T. A., Landau, N. R. (1998) Functional analysis of the proximal CCR5 promoter AIDS Res. Hum. Retrovir. 14,1509-1519[Medline]
    23. 23
  23. Yi, Y., Rana, S., Tyrner, J. D., Gaddis, N., Collman, R. G. (1998) CXCR4 is expressed by primary macrophages and supports CCR5-independent infection by dual-tropic but not T-tropic isolates of human immunodeficiency virus type 1 J. Virol. 72,772-777[Abstract/Free Full Text]
    24. 24
  24. Verani, A., Pesenti, E., Polo, S., Tresoldi, E., Scarlatti, G., Lusso, P., Siccardi, A. G., Vercelli, D. (1998) CXCR4 is a functional coreceptor for infection of human macrophages by CXCR4-dependent primary HIV-1 isolates J. Immunol. 161,2084-2088[Abstract/Free Full Text]
    25. 25
  25. Simmons, G., Reeves, J. D., McKnight, A., Dejucq, N., Hibitts, S., Power, C. A., Aarons, E., Schols, D., De Clercq, E., Proudfoot, A. E., Clapham, P. R. (1998) CXCR4 as a functional coreceptor for human immunodeficiency virus type 1 infection of primary macrophages J. Virol. 72,8453-8457[Abstract/Free Full Text]
    26. 26
  26. Schuitemaker, H., Koot, M., Kootstra, K. N. A., Dercksen, M. W., de Goede, R. E. Y., van Steenwijk, R. P., Lange, T. M. A., Eeftink Schattenkerk, T. K. M., Miedema, F., Tersmette, M. (1992) Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell tropic virus populations J. Virol. 66,1354-1360[Abstract/Free Full Text]
    27. 27
  27. Lapham, C. K., Zaitseva, M. B., Lee, S., Romanstseva, T., Golding, H. (1999) Fusion of monocytes and macrophages with HIV-1 correlates with biochemical properties of CXCR4 and CCR5 Nat. Med. 5,590
    28. 28
  28. Xiao, X., Wu, L., Stantchev, T. S., Feng, Y. R., Ugolini, S., Chen, H., Shen, Z., Riley, J. L., Broder, C. C., Sattentau, Q. J., Dimitrov, D. S. (1999) Constitutive cell surface association between CD4 and CCR5 Proc. Natl. Acad. Sci. USA 96,7496-7501[Abstract/Free Full Text]
    29. 29
  29. Dimitrov, D. S., Norwood, D., Stantchev, T. S., Feng, Y., Xiao, X., Broder, C. C. (1999) A mechanism of resistance to HIV-1 entry: inefficient interactions of CXCR4 with CD4 and gp120 in macrophages Virology 259,1-6[Medline]
    30. 30
  30. Lynch, G., Dearden, M., Sloane, A. J., Humphrey Smith, I., Cunningham, A. L. (1996) Analysis of recombinant and native CD4 by single and two dimensional gel electrophoresis Electrophoresis 17,227-234[Medline]
    31. 31
  31. Lynch, G., Sloane, A. J., Raso, V., Lai, A., Cunningham, A. L. (1999) Direct evidence for native CD4 oligomers in lymphoid and monocytoid cells Eur. J. Immunol. 29,2590-2602[Medline]
    32. 32
  32. Chang, J., Li, S., Naif, H., Cunningham, A. L. (1994) The magnitude of HIV replication in monocytes and macrophages is influenced by environmental conditions, viral strain and host cells J. Leukoc. Biol. 56,230-235[Abstract]
    33. 33
  33. Evans, L. A., McHugh, T. M., Stites, D. P., Levy, J. A. (1987) Differential ability of human immunodeficiency virus isolates to productively infect human cells J. Immunol. 138,3415-3418[Abstract]
    34. 33
  34. Collman, R. G., Yi, Y., Liu, Q-H., Freedman, B. D. (2000) Chemokine signaling and HIV-1 fusion mediated by macrophage CXCR4: implications for target cell tropism J. Leukoc. Biol. 68,000-000
    35. 34
  35. Williams, L. M., Cloyd, M. W. (1992) Polymorphic human genes determines differential susceptibility of CD4 lymphocytes to infection by certain HIV-1 isolates Virology 184,723-728
    36. 35
  36. Spira, A. I., Ho, D. D. (1995) Effect of different donor cells on human immunodeficiency virus type 1 replication and selection in vitro J. Virol. 69,422-429[Abstract]
    37. 36
  37. Paxton, W. A., Martin, S. R., Tse, D., O’Brien, T. R., Skurnick, J., Van Devanter, N. L., Padian, N., Braun, J. F., Kotler, D. P., Wolinsky, S. M., Koup, R. A. (1996) Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure Nat. Med. 2,412-417[Medline]
    38. 37
  38. Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., MacDonald, M. E., Stuhlmann, H., Koup, R. A., Landau, N. R. (1996) Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection Cell 86,367-377[Medline]
    39. 38
  39. Rana, S., Besson, G., Cook, D. G., Rucker, J., Smyth, R. J., Yi, Y., Turner, J. D., Guo, H-H., Du, J-G., Peiper, S. C., Lavi, E., Samson, M., Libert, F., Liesnard, C., Vassart, G., Doms, R. W., Parmentier, M., Collman, R. (1997) Role of CCR5 in infection of primary macrophages and lymphocytes by macrophage-tropic strains of HIV: resistance to patient-derived and prototype isolates resulting from the CCR5 mutation J. Virol. 71,3219-3227[Abstract]
    40. 39
  40. Chang, J., Naif, H. M., Li, S., Sullivan, J. S., Randle, C. M., Cunningham, A. L. (1996) Twin studies demonstrate a host cell genetic effect on productive human immunodeficiency virus infection of human monocytes and macrophages in vitro J. Virol. 70,7792-7803[Abstract]
    41. 40
  41. Mellors, J. W., Kingsley, L. A., Rinaldo, C. R., Jr, Todd, J. A., Hoo, B. S., Kokka, R. P., Gupta, P. (1995) Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion Ann. Intern. Med. 122,573-579[Abstract/Free Full Text]
    42. 41
  42. Orenstein, J. M., Fox, C., Wahl, S. M. (1997) Macrophages as a source of HIV during opportunistic infections Science (Wash. DC) 276,1857-1860[Abstract/Free Full Text]
    43. 42
  43. Gartner, S. (2000) HIV infection and dementia Science (Wash. DC) 287,602-604[Free Full Text]
    44. 43
  44. Fauci, A. S., Pantaleo, G., Stanley, S., Weissman, D. (1996) Immunopathogenic mechanisms of HIV infection Ann. Intern. Med. 124,654-663[Abstract/Free Full Text]
    45. 44
  45. Kelly, M. D., Naif, H. M., Adams, S. L., Cunningham, A. L., Lloyd, A. R. (1998) Cutting edge: dichotomous effects of ß-chemokines on HIV replication in monocytes and monocyte-derived macrophages J. Immunol. 160,3091-3095[Abstract/Free Full Text]
    46. 45
  46. Lawn, S. D., Roberts, B. D., Griffin, G. E., Folks, T. M., Butera, S. T. (2000) Cellular compartments of human immunodeficiency virus type 1 replication in vivo: determination by presence of virion-associated host proteins and impact of opportunistic infection J. Virol. 74,139-145[Abstract/Free Full Text]



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