PeproTech Inc.

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhu, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhu, T.
(Journal of Leukocyte Biology. 2000;68:338-344.)
© 2000 by Society for Leukocyte Biology

HIV-1 genotypes in peripheral blood monocytes

Tuofu Zhu

Department of Laboratory Medicine, University of Washington, Seattle, Washington

Correspondence: Tuofu Zhu, Department of Laboratory Medicine, University of Washington, PO Box 357110, 1959 NE Pacific Street, Seattle, WA 98195. E-mail: tzhu{at}u.washington.edu


arrow
ABSTRACT
 
CD4+ T cells and tissue macrophages are well defined as the major targets for human immunodeficiency virus type 1 (HIV-1) infection and replication, and their infection accounts for many aspects of HIV-1 pathogenesis in vivo. HIV-1 genotype and phenotype in monocytes and their potential roles in pathogenicity in vivo remain unknown. Herein is an overview of our initial work on HIV-1 genotype in purified CD14+ monocytes isolated longitudinally during the course of infection starting from the time of infection. Our data provide evidence for HIV-1 evolution in monocytes and their role as a reservoir of HIV-1 in vivo. A better understanding of HIV-1 in monocytes may greatly help the development of new therapeutic strategies for HIV-1 infection.

Key Words: HIV-1 • genotype • CD14+ monocytes


arrow
INTRODUCTION
 
CD4+ T cells and tissue macrophages are the major target cells for human immunodeficiency virus type 1 (HIV-1) infection and replication [1 2 3 4 5 6 7 8 ]. Virus replication in CD4+ T lymphocytes accounts for the major pathogenicity in vivo. The role that cells of monocyte-macrophage lineage play in AIDS pathogenesis is less well understood. Monocytes in peripheral blood are rarely infected during primary infection [9 , 10 ]. In fact, HIV-1 replication is blocked before reverse transcription and integration in freshly isolated peripheral blood monocytes [4 ]. Monocytes in culture must undergo differentiation to monocyte-derived macrophages (MDM) to become susceptible to productive infection with HIV-1 [11 12 13 ]. It is likely that differentiation of monocytes to macrophages in tissues such as peripheral lymph nodes, brain, lung, and gut-associated lymphoid tissue can result in susceptibility to infection with HIV-1 [1 2 3 4 5 6 7 8 ]. Although macrophages are susceptible to infection with HIV-1, they are relatively resistant to its cytopathic effects [1 ]. In vitro cultures have shown that MDM are not killed by HIV-1 infection but produce virus for as long as several weeks [4 ]. In contrast, CD4+ T cells are highly sensitive to the cytopathic effects of HIV-1. Tissue macrophages may serve a pathogenetic role by producing virus that can infect other target cells, although they are responsible for the production of only a small percentage of the viral load present in the infected host [6 7 8 ]. Therefore, monocyte-macrophages have the potential to act as a long-term reservoir for HIV-1 and disseminate the virus to other tissues [3 4 5 6 7 8 ].

Several studies suggest that cells of macrophage lineage may be important for the pathogenesis of HIV-1 replication. The selective transmission of monocytotropic viruses [14 15 16 17 ] indicates that macrophage tropism may facilitate establishment of the virus in the newly infected host. The chemokine receptor CCR5 serves as the principal co-receptor for macrophage-tropic (M-tropic) HIV-1 entry into CD4-expressing T cells and macrophages [18 19 20 21 ]. Individuals with homozygous deletions in the CCR5 gene and peripheral blood mononuclear cells (PBMC) of these subjects show high levels of resistance to HIV-1 infection [22 23 24 25 26 ]. Although most retroviruses only infect dividing cells [27 , 28 ], several viral proteins render HIV-1 efficient infection of nondividing macrophages [29 , 30 ]. Simian immunodeficiency virus (SIV) SM variants barely infect macrophages in vitro and are considerably impaired in pathogenicity in vivo [31 ]. After infection with HIV-1, macrophages release several immunoregulatory and inflammatory factors, including TNF-{alpha}, IL-1, and IL-7, which in turn influence viral proliferation and disease associated with HIV-1 infection [32 ].

The heterogeneity of HIV-1 strains is studied mostly by molecular characterization of genomic sequences. This involves sequencing fragments amplified by the PCR or the use of the heteroduplex mobility assay (HMA) [33 , 34 ]. Genetic analyses have demonstrated the homogeneity of envelope sequences immediately after homosexual transmission as well as after mother–infant and parenteral transmission [14 15 16 17 ]. There are a number of reports on the genotypes of M-tropic HIV-1 strains that are characterized by their ability to replicate in primary macrophages but not in T cells such as MT-2 cell line. All of these M-tropic HIV-1 strains were isolated from whole PBMC rather than purified macrophages. This report is a review of our unpublished work on the envelope sequences of HIV-1 in freshly purified peripheral blood monocytes (CD14+) and the comparison with HIV-1 sequences in CD4+ T cells.


arrow
HIV-1 GENOTYPES IN MONOCYTES DURING ACUTE INFECTION
 
Previous studies have shown that HIV-1 sequences in newly infected individuals are relatively homogeneous, even though the transmitters harbor heterogeneous genotypes [14 15 16 17 , 35 ]. There is also evidence that the pressure to conserve sequences is stronger for HIV-1 envelope gp120 than for gp41, nef, and p17 of gag during sexual transmission [14 , 16 ]. In a further study of sexual transmission, we found evidence for HIV-1 selection and compartmentalization in both chronically infected transmitters and newly infected individuals [36 ]. These results enable us to propose a multiple-step process for the selection of HIV-1 during sexual transmission, that is, compartmentalization from blood to semen in the transmitter, as well as the selection of HIV-1 in the new host, either at the level of penetration or amplification or both. It is likely that because of the multiple steps of selection of the virus during transmission, HIV-1 in most of the newly infected individuals is relatively homogeneous. Moreover, HIV-1 isolates obtained from newly infected individuals are largely M-tropic and nonsyncytium inducing (NSI) [14 , 37 ], although those from some of the corresponding donors are both syncytium inducing (SI) and NSI [14 , 16 , 17 , 37 ]. We further observed that a few of multiple NSI variants found in the transmitters were detected in the newly infected recipient [36 ]. Other studies have also provided evidence that the transmitted virus was one of the multiple NSI variants found in the corresponding transmitter [17 , 35 ]. Taken together, these findings suggest that, in sexual transmission, some, but not all, NSI virus are selected to establish new infection.

However, the so-called M-tropic HIV-1 strains were actually isolated from PBMC and not from purified monocytes-macrophages. These viruses were designated as M-tropic HIV-1 strains because they could replicate in primary macrophages but not in transformed T cell lines. There is little information about the genotypes of HIV-1 existing in macrophages, and almost no data of HIV-1 genotypes in monocytes, probably because of the fact that monocytes do not support HIV-1 replication [4 ]. Several studies have clearly shown altered susceptibility to HIV-1 infection depending on the state of maturation of monocytes into macrophages [38 , 39 ]. For most previous studies, monocytes were isolated by plastic adherence only, allowing the differentiation of monocytes into MDM in a few hours as a result of adherence, and thus these cells became susceptible to HIV-1 infection [39 ]. Recently, we have used a 2-step strategy to isolate highly purified monocytes from peripheral blood without adherence in vitro by combining a negative selection assay [40 41 42 43 44 ] with monoclonal antibodies against molecules CD8, CD19, CD16, and CD3, and a positive selection by cell-sorting with antibodies against CD14 that is exclusively expressed on monocyte-macrophages. These freshly isolated CD14+ monocytes, representing about 80% populations of monocytes existing in vivo [45 ], were used for DNA extraction, PCR, and sequence analyses. Ten acutely infected patients who initiated highly active antiretroviral therapy (HAART) within 121 days of onset of symptoms of primary HIV-1 infection were studied. The plasma viral RNA of all 10 subjects declined to below the detection level of 50 HIV-1 copies per milliliter of plasma within 4 months of therapy. Of them, 9 remained on HAART with undetectable levels of plasma virus for the 2–4 years of follow-up, whereas 1 patient chose to discontinue therapy after his plasma virus had been remained undetectable for 1 year, and his plasma virus rebounded in 2 weeks after the interruption of therapy. None of individuals had advanced infection. Initial studies were focused on the samples obtained at the time of acute infection, before seroconversion and the initiation of therapy. HIV-1 in CD14+ monocytes was genetically homogeneous near the time of seroconversion in 8 individuals. Figure 1 is a typical example of the sequences of the first and second variable region (V1–V2) of HIV-1 envelope gene found in CD14+ monocytes freshly isolated from a newly infected individual. Extremely homogeneous sequences were found in this patient despite the fact that V1–V2 regions are believed to be the most variable regions in the HIV-1 genome. Similar homogeneity of sequences was also observed in the V3–V5 regions of HIV-1 from this individual. However, significant HIV-1 sequence heterogeneity was identified in CD14+ monocytes of 2 out of the 10 newly infected individuals that we studied (Zhu et al., unpublished results). These findings, consistent with previous observations in PBMC and plasma from us and others, suggest that HIV-1 genotypes in CD14+ monocytes during primary infection are homogeneous in most newly infected individuals but heterogeneous in ~20% of patients with primary infection.



View larger version (13K):
[in this window]
[in a new window]
  		Figure 1. Deduced amino acid sequence alignment of the V1–V2 region of gp120 from CD14+ monocytes purified before seroconversion from an individual with primary infection. The consensus sequence is indicated at the top, with the V1 and V2 loop underlined. Dots indicate sequence identical to the consensus sequence. Each sequence represents a sequence from 1 clone.


arrow
HIV-1 SEQUENCE EVOLUTION IN MONOCYTES DURING THE COURSE OF HIV-1 INFECTION
 
HIV-1 genetic evolution during the course of infection was studied either by cross-sectional analysis of samples from individuals at various stages of disease [34 , 46 ] or longitudinal studies within some infected individuals [34 , 47 48 49 50 ]. Distinct proviral sequence variants in PBMC compared with blood plasma and other tissues were observed during the infection course of patients [36 , 51 52 53 54 ]. It is believed that this high level of genetic variation is the result of rapid and mutation-prone replication of large viral populations. A large amount of information attests to the adaptable nature of HIV-1 quasispecies replicating in vivo. Studies of HIV-1 and SIV evolution in vivo have shown a high ratio of nonsynonymous to synonymous site mutations (dN/dS ratio), likely reflecting a selection for phenotypic changes [56 , 57 ]. The selective forces driving such evolution may include strong and changing immune responses [58 59 60 61 ] as well as viral adaptation to growth in different cell types [62 63 64 ].

We were particularly interested in the evolution of HIV-1 in monocytes and the comparison with variants in other cell compartments such as resting CD4+ T cells and activated CD4+ T cells. We have thus examined the proviral sequences in CD14+ monocytes isolated longitudinally from the time of infection to present. There was no evidence of sequence variation during the 2–4 year period of study in 7 of 10 studied individuals, whereas significant sequence variation was seen in 3 patients (2 with continuous HAART, 1 off therapy). Figure 2 , as an example, depicts the sequence evolution of HIV-1 V3–V5 regions during a period of 2 years within the individual who initiated HAART at the day of seroconversion and discontinued therapy 1 year later. We were able to obtain an early sample at 5 days before the patient was diagnosed with HIV-1 infection with detectable HIV antibodies (seroconversion), and another time point sample at 735 days after seroconversion and at 300 days after the interruption of HAART. In early infection, HIV-1 in CD14+ monocytes was homogeneous and was the same as the strain in resting and activated CD4+ T cells. However, 2 years later, distinct variant populations (designated as subgroups 1–6 in Fig. 2 ) were seen in monocytes as well as in other cells. HIV-1 variants in monocytes were neither identical to those in activated CD4+ T cells nor resting CD4+ T cells. There were 3 viral populations (subgroups 1–3) of sequences in monocytes, 4 populations (subgroups 2, 4–6) in activated CD4+ T cells, and only 2 in resting CD4+ T cells. Although subgroup 2 was found in all 3 cell compartments, distinct mutations were seen within subgroup 2 in each cell type. More sequence populations found in activated CD4+ T cells may reflect higher levels of viral replication and viral turnover in activated CD4+ T cells in patients after the interruption of therapy. In contrast, in patients receiving continuous HAART, we observed in some individuals relatively higher viral replication and sequence variation in CD14+ monocytes compared with both activated and resting CD4+ T cells (Zhu et al., unpublished results). The difference may be explained by the finding that inhibition of viral replication by protease inhibitors, which are often a major potent component of HAART, is much less efficient in monocyte-macrophages than in CD4+ T cells [65 , 66 ].



View larger version (36K):
[in this window]
[in a new window]
  		Figure 2. Deduced amino acid sequence alignment of the V3–V5 region of gp120 from CD14+ monocytes, resting and activated CD4+ T cells isolated during the course of HIV-1 infection from 1 individual. The consensus sequence is indicated at the top with V3, V4, and V5 loop underlined. Dots indicate sequence identical to the consensus sequence, dashes indicate deletions, and asterisks indicate stop codons. Clone numbers with identical sequence are shown at right.


arrow
MONOCYTES AS A POTENTIAL RESERVOIR OF HIV-1
 
Chronically infected macrophages could provide a reservoir of HIV-1 that persists in patients whose CD4+ T cell viral burdens have been drastically reduced by HAART [67 ]. Our studies of patients taking HAART suggest that HIV-1 may replicate in monocytes in vivo and that monocytes can serve as reservoirs of HIV-1 (Zhu et al., unpublished results). This hypothesis is also supported by data presented in Figure 2 . Early in infection, there was only 1 variant population (subgroup 1) in all cell types. This initial virus was still detected in monocytes but not in CD4+ T cells 2 years later. We also used HMA to check if there was a trace of subgroup 1 virus in CD4+ T cells but failed to detect it. These findings suggest that monocytes can carry HIV-1 for relatively longer periods than CD4+ T cells. The role of CD14+ monocytes as a source of virus during HIV-1 disease has not been considered, or as few if any productively infected cells expressing monocyte markers have been documented. Our data suggest that monocytes, unlike CD4+ T cells, are capable of producing HIV-1 without necessarily succumbing to the lethal effects of productive viral infection and, therefore, can serve as a long-term source of HIV-1.


arrow
PATTERNS OF LINEAL SEQUENCES OF HIV-1 ENVELOPE GP120 IN MONOCYTES
 
HIV-1 proviral sequences can be nonuniformly distributed throughout the body. Distinct proviral sequence variants have been reported in PBMC and brain tissue [62 , 68 , 69 ] or cerebrospinal fluid [52 , 53 ], spleen [62 ], lymph node [50 , 51 ], lung [63 ], and semen [36 , 70 ]. Furthermore, quasispecies of HIV-1 can differ between virion RNA and integrated proviral DNA in both blood and semen [36 ].

If particular characteristics are required for replication and production of virus in monocytes, they may be detected as signature sequences found across various individuals as monocyte-specific. We have not detected a monocyte-specific signature sequence of HIV-1 V3–V5 region by using a signature pattern analysis assay [71 ]. However, recognition of distinctions between viruses in monocytes and those in CD4+ T cells indicates that further analyses should be conducted.

The NSI and SI phenotypes of HIV-1 are well predicted by variants at positions 11 and 25 of the amino acids in the V3 loop (Fig. 3 ). Amino acids with positive charge (R and K) at one or two of these positions predict the SI and T-tropic phenotype. It is interesting that the deduced amino acid sequences of the V3 loop of each virus in monocytes of our patients suggested an NSI and M-tropic phenotype. Further studies are needed to determine if SI virus is present in CD4+ T cells of these patients at transmission, although transmission of SI virus is rare [14 15 16 17 , 35 36 37 ]. These studies may provide evidence for a restriction of SI variants in CD14+ monocytes.



View larger version (34K):
[in this window]
[in a new window]
  		Figure 3. Amino acid sequence comparison of the V3 region of gp120 in CD14+ monocytes of our patients with published M-tropic and T-tropic HIV-1 strains. All sequences were aligned with HIV-1BAL strain that is shown at the top. Sequences derived from purified monocytes of the patient in the present study are 1M–8M. The other symbols are the same as in Figure 2 . Amino acids with positive charge (R or K) at positions 11 and 25 (downward-pointing arrow) predict SI and T-tropic phenotype, and other amino acids in these two positions predict NSI and M-tropic phenotype.


arrow
CONCLUSIONS
 
The results of our studies indicate that CD14+ monocytes were infected at an early stage of the course of HIV-1 infection and that HIV-1 persisted in CD14+ monocytes during the course of infection. HIV-1 in monocytes was largely homogeneous during primary infection. The distinct viral variants found in CD14+ monocytes compared with CD4+ T cells in some individuals at a later stage of HIV-1 infection suggest that HIV-1 may replicate and evolve in CD14+ monocytes independently from CD4+ T cells. There is also evidence that monocytes can be a potentially important reservoir of HIV-1. Consistent with previous findings from other laboratories regarding HIV-1 V3 genotypes, all viruses in CD14+ monocytes are predicted to be NSI and M-tropic HIV-1 strains. Further studies would be needed to investigate HIV-1 replication in purified CD14+ monocytes, which may provide important information for the role of monocytes in HIV-1 pathogenesis and for the development of new therapeutic strategies for HIV-1 infection.


arrow
ACKNOWLEDGEMENTS
 
This work was supported by NIH grants AI41535, AI45206, AI35605, and AI45402 and the University of Washington Center for AIDS Research Young Investigator Award (NIH AI27757).

I thank my colleagues Yon Hwangbo Chang, Feng Feng, and David Muthui for their work, and Lawrence Corey and James Mullins for helpful discussions.


arrow
REFERENCES
 
    1
  1. Gartner, S., Markovits, P., Markovitz, M., Kapla, M., Gallo, R., Popovic, M. (1986) The role of mononuclear phagocytes in HTLV-III/LAV infection Science 233,215-219[Abstract/Free Full Text]
    2. 2
  2. Wiley, C. A., Schrier, R. D., Nelson, J. A., Lampert, P. W., Oldstone, M. B. A. (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients Proc. Natl. Acad. Sci. USA 83,7089-7093[Abstract/Free Full Text]
    3. 3
  3. Veazey, R., DeMaria, M., Chalifoux, L., Shvetz, D., Pauley, D., Knight, H., Rosenzweig, M., Johnson, R., Desrosiers, R., Lacker, A. (1998) Gastrointestinal tract as a major site of CD4+ T cells depletion and viral replication in SIV infection Science 280,427-429[Abstract/Free Full Text]
    4. 4
  4. Sonza, S., Maerz, A., Deacon, N., Meanger, J., Mills, J., Crowe, S. (1996) Human immunodeficiency virus type 1 replication is blocked prior to reverse transcription and integration in freshly isolated peripheral blood monocytes J. Virol. 70,3863-3869[Abstract]
    5. 5
  5. Orenstein, J. M., Cecil, F., Wahl, S. M. (1997) Macrophages as a source of HIV during opportunistic infection 276,1857-1861
    6. 6
  6. Schnittman, S. M., Lane, H. C., Greenhouse, J., Justement, J. S., Baseler, M., Fauci, A. S. (1990) Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals Proc. Natl. Acad. Sci. USA 87,6058-6062[Abstract/Free Full Text]
    7. 7
  7. Meltzer, M., Skillman, D., Gomatos, P., Kalter, D., Gendelman, H. (1990) Role of mononuclear phagocytes in the pathogenesis of human immunodeficiency virus infection Amu. Rev. Immunol. 8,169-173
    8. 8
  8. Finzi, D., Silicano, R. F. (1998) Viral dynamics in HIV-1 infection Cell 93,665[Medline]
    9. 9
  9. Schuitemaker, H., Kootstra, N. A., Koppelman, M., Bruisten, M., Huisman, H. G., Tersmette, M., Miedema, F. (1992) Proliferation-dependent HIV-1 infection of monocytes occurs during differentiation into macrophages J. Clin. Invest. 89,1154-1160
    10. 10
  10. McElrath, M. J., Pruett, J. E., Cohn, Z. A. (1989) Mononuclear phagocytes of blood and bone marrow: comparative roles as viral reservoirs in human immunodeficiency virus type 1 infections Proc. Natl. Acad. Sci. USA 86,675-679[Abstract/Free Full Text]
    11. 11
  11. Rich, E. A., Chen, I., Zack, J. A., Leonard, M. L., O’Brien, W. A. (1992) Increased susceptibility of differentiated mononuclear phagocytes to productive infection with human immunodeficiency virus-1 (HIV-1) J. Clin. Invest. 89,176-183
    12. 12
  12. Schmidtmayerova, H., Sherry, B., Burkinsky, M. (1996) Chemokines and HIV replication Nature 382,767[Medline]
    13. 13
  13. Tuttle, D. L., Jeffrey, K., Harrison, J. K., Anders, C., Sleasman, J. W., Goodenow, M. M. (1998) Expression of CCR5 Increases during monocyte differentiation and directly mediates macrophage susceptibility to infection by human immunodeficiency virus type 1 J. Virol. 72,4962-4969[Abstract/Free Full Text]
    14. 14
  14. Zhu, T., Mo, H., Wang, N., Nam, D.S., Cao, Y., Koup, R. A., Ho, D. D. (1993) Genotypic and phenotypic characterization of HIV-1 patients with primary infection Science 261,1179-1181
    15. 15
  15. Fouchier, R. A., Groenink, M. M., Kootstra, A., Termette, M., Huisman, H. G., Miedema, F., Schuitemaker, H. (1992) Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule J. Virol. 66,3183-3187[Abstract/Free Full Text]
    16. 16
  16. Zhang, L., MacKenzie, P., Cleland, A., Homes, E. C., Leigh-Brown, A. J., Simmonds, P. (1993) Selection for specific sequences in the external envelope protein of HIV-1 upon primary infection J. Virol. 67,3345-3356[Abstract/Free Full Text]
    17. 17
  17. Van’t Wout, A. B., Kootstra, N. A., Mulder-Kampinga, G. A., Albrecht-van Lent, N., Scherpbier, H. J., Veenstra, J., Boer, K., Coutinho, R. A., Miedma, F., Schuitemaker, H. (1994) Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission J. Clin. Invest. 94,2060-2067
    18. 18
  18. Alkhatib, G., Combadiere, C., Broder, C. C., Feng, F., Kennedy, P. E., Murphy, P. M., Berger, E. A. (1996) CC CKR5: a RANTES, MIP-1(, MIP-1( receptor as a fusion cofactor for macrophage-tropic HIV-1 Science 272,1955-1958[Abstract]
    19. 19
  19. Choe, H., Farzan, M., Sun, Y., Sullivan, N, Rollins, B., Ponath, P. D., Wu, L., Mackay, C. R., LaRosa, G., Newman, W., Gerard, N., Gerard, C., Sodroski, J. (1996) The (-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates Cell 85,1135-1148[Medline]
    20. 20
  20. Deng, H., Liu, R., Ellmeier, W., Choe, S., Unutmaz, D., Burkhart, M., Di Marzio, P., Marmon, S., Sutton, R. E., Hill, C. M., Davis, C. B., Peiper, S. C., Schall, T. J., Littman, D., Landau, N. R. (1996) Identification of a major co-receptor for primary isolates of HIV-1 Nature 381,661-666[Medline]
    21. 21
  21. Dragic, T., Litwin, V., Allaway, G. P., Martin, S. R., Huang, Y., Nagashima, K. A., Cayanan, C., Maddon, P. J., Koup, R. A., Moore, J. P., Paxton, W. A. (1996) HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5 Nature 381,667-673[Medline]
    22. 22
  22. Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., MacDonald, M. E., Stuhlman, 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]
    23. 23
  23. Dean, M., Carrington, M., Winkler, C., Huttley, G. A., Smith, M. W., Allikmets, R., Goedert, J. J., Buchbinder, S. P., Vittinghof, E., Gomperts, E., Donfield, S., Vlahov, D., Kaslow, R., Saah, A., Rinaldo, C., Detels, R., O’Brien, S. J. (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene Science 273,1856-1862[Abstract/Free Full Text]
    24. 24
  24. Huang, Y., Paxton, W. A., Wolinsky, S. M., Neumann, A. U., Zhang, L., He, T., Kang, S., Ceradini, D., Jin, Z., Yazdanbakhsh, K., Kunstman, K., Erickson, D., Dragon, E., Landau, N. R., Phair, J., Ho, D. D., Koup, R. A. (1996) The role of a mutant CCR5 allele in HIV-1 transmission and disease progression Nat. Med. 2,1240-1243[Medline]
    25. 25
  25. Michael, N. L., Chang, G., Louie, L. G., Mascola, J. R., Dondero, D., Birx, D. L., Sheppard, H. W. (1997) The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression Nat. Med. 3,338-340[Medline]
    26. 26
  26. Samson, M., Libert, F., Doranz, B. J., Rucker, J., Liesnard, C., Farber, C.-M., Saragosti, S., Lapoumeroulie, C., Conaux, J., Foceille, C., Muyldermans, G., Verhostede, C., Burtonboy, G., Georges, M., Imai, T., Rana, S., Yi, Y., Smyth, R. J., Collman, R. G., Doms, R. W., Vassart, G., Parmentier, M. (1996) Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene Nature 382,722-725[Medline]
    27. 27
  27. Lewis, P. F., Emerman, M. (1994) Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus J. Virol. 68,510-516[Abstract/Free Full Text]
    28. 28
  28. Roe, T., Reynolds, T. C., Yu, G., Brown, P. O. (1993) Integration of murine leukemia virus DNA depends on mitosis EMBO I 12,2099-2108
    29. 29
  29. Weinherg, J. B., Mattews, T. J., Cullen, B. R., Malim, M. H. (1991) Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes J. Exp. Med. 174,1477-1482[Abstract/Free Full Text]
    30. 30
  30. Heinzinger, N. K., Bukinsky, M. I., Haggerty, S. A., Ragland, A. M., Kewalramani, V., Lee, M. A., Gendelman, H. E., Ratner, L., Stevenson, M., Emerman, M. (1994) The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells Proc Natl Acad Sci USA 91,7311-7315[Abstract/Free Full Text]
    31. 31
  31. Hirsch, V. M., Sharkey, M.E., Brown, C. R., Brichacek, B., Goldstein, S., Wakefield, J., Byrum, R., Elkins, W. R., Hahn, B. H., Lifson, J. D., Stevenson, M. (1998) Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification Nat Med 4,1401-1408[Medline]
    32. 32
  32. Poli, G., Fauci, A. S. (1995) Role of cytokines in the pathogenesis of human immunodeficiency virus infection Aggarwal, B. B Puri, R. K. eds. Human Cytokines: Their Role in Disease and Therapy ,421 Blackwell Cambridge..
    33. 33
  33. Delwart, E. L., Shpaer, E. G., McCutchan, F. E., Louwagie, J., Grez, M., Rübsamen-Waigmann, H., Mullins, J. I. (1993) Genetic relationships determined by a heteroduplex mobility assay: analysis of HIV env genes Science 262,1257-1261[Abstract/Free Full Text]
    34. 34
  34. Delwart, E. L., Sheppard, H. W., Walker, B. D., Goudsmit, J., Mullins, J. I. (1994) Human immunodeficiency virus type 1 evolution in vivo tracked by DNA heteroduplex mobility assays J. Virol. 68,6672-6683[Abstract/Free Full Text]
    35. 35
  35. Wolinsky, S. M., Wike, C. M., Korber, B., Hutto, C., Parks, W. P., Rosenblum, L. L., Kunstman, K. J., Furtado, M. R., Munoz, J. (1992) Selective transmission of human immunodeficiency virus type 1 variants from mothers to infants Science 255,1134-1137[Abstract/Free Full Text]
    36. 36
  36. Zhu, T., Wang, N., Carr, A., Nam, D. S., Moor-Jankowski, R., Cooper, D. A., Ho, D. D. (1996) Genetic characterization of human immunodeficiency virus type 1 in blood and genital secretions: evidence for viral compartmentalization and selection during sexual transmission J Virol 70,3098-3107[Abstract]
    37. 37
  37. Roos, M. T. L., Lange, J. M. A., de Goede, R. E. Y., Coutinho, R. A., Schellekens, P. T. A., Miedema, F., Tersmette, M. (1992) Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection J. Infect. Dis. 165,427-432[Medline]
    38. 38
  38. 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]
    39. 39
  39. 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 by using twins J Virol 73,4866-4881[Abstract/Free Full Text]
    40. 40
  40. Chun, T.W., Stuyver, L., Mizell, B., Ehler, L., Mican, J. A. M., Baseler, M., Lloyd, A. L., Nowak, M. A., Fauci, A. S. (1997) Presence of an inducible HIV-1 latent reservoirs during highly active antiretroviral therapy Proc. Natl. Acad. Sci. USA 94,13193-13197[Abstract/Free Full Text]
    41. 41
  41. Finzi, D., Hermankova, M., Pierson, T., Carrhth, L. M., Buck, C., Chaisson, R. E., Quin, T. C., Chadwick, K., Marglick, J., Brookmeyer, R., Gallant, J., Markowitz, M., Ho, D. D., Richman, D. D., Siliciano, R. F. (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy Science 278,1295-1300[Abstract/Free Full Text]
    42. 42
  42. Wong, J. K., Hezareh, M., Qunthard, H. F., Halir, D. V., Ignacio, C. C., Spina, C. A., Richman, D. D. (1997) Recovery of replication-competent HIV despite prolonged suppression of plasma viremia Science 278,1291-1295[Abstract/Free Full Text]
    43. 43
  43. Finzi, D., Blankson, J., Siliciano, J. D., Margolick, J. B., Chadwick, K., Pierson, T., Smith, K., Lisziewicz, J., Lori, F., Flexner, C., Quinn, T. C., Chaisson, R. E., Rosenberg, E., Walker, B., Gange, S., Gallant, J., Siliciano, R. F. (1999) Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy Nature Med 5,512-517[Medline]
    44. 44
  44. Chun, T. W., Engel, D., Berry, M. M., Shea, T., Corey, L., Fauci, A. S. (1998) Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection Proc. Natl. Acad. Sci. USA. 95,8869-8873[Abstract/Free Full Text]
    45. 45
  45. Smith, P. D., Janoff, E. N. (1997) Mosteller-Barnum M, Merger M, Orenstein J. M., Kearney JF, Graham MF. Isolation and purification of CD14-negative mucosal macrophages from normal human small intestine J. Immunol. Methods. 202,1-11[Medline]
    46. 46
  46. Donaldson, Y. K., Bell, J. E., Holmes, E. C., Hughes, E. S., Brown, H. K., Simmonds, P. (1994) In vivo distribution and cytopathology of variants of human immunodeficiency virus type 1 showing restricted sequence variability in the V3 loop J. Virol. 68,5991-6005[Abstract/Free Full Text]
    47. 47
  47. Delwart, E. L., Pan, H., Sheppard, H. W, Wolpert, D., Neumann, A. U., Korber, B., Nullins, J. I. (1997) Slower evolution of human immunodeficiency virus type 1 quasispecies during progression to AIDS J. Vriol. 71,7498-7508
    48. 48
  48. McNearney, T., Hornickova, Z., Markham, R., Birdwell, A., Arens, M., Saah, A, Ratner, L. (1992) Relationship of human immunodeficiency virus type 1 sequence heterogeneity to stage of disease Proc. Natl. Acad. Sci. USA 89,10247-10251[Abstract/Free Full Text]
    49. 49
  49. Wolfs, T. F., de Jong, J. J., Van den Berg, H., Tijnagel, J. M., Krone, W. J., Goudsmit, J. (1990) Evolution of sequences encoding the principal neutralization epitope of human immunodeficiency virus 1 is host dependent, rapid, and continuous Proc. Natl. Acad. Sci. USA 87,9938-9942[Abstract/Free Full Text]
    50. 50
  50. Meyerhans, A., Cheynier, R., Albert, J., Seth, M., Kwok, S., Sninsky, J., Morfeldt-M{varsigma}nson, L., Asjo, B., Wain-Hobson, S. (1989) Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations Cell 58,901-910[Medline]
    51. 51
  51. Ball, J. K., Holmes, E. C., Whitwell, H., H. Desselberger, H. (1994) Genomic variation of human immunodeficiency virus type 1 (HIV-1): molecular analyses of HIV-1 in sequential blood samples and various organs obtained at autopsy J. Gen. Virol. 75,67-69[Medline]
    52. 52
  52. Sheehy, N., Desselberger, U., Whitwell, H., Ball, J. K. (1996) Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 during zidovudine (AZT) therapy J. Gen. Virol. 77,1071-1081[Abstract/Free Full Text]
    53. 53
  53. Kuiken, C. L., Goudsmit, J., Weiller, G. F., Armstrong, J. S., Hartman, S., Portegies, P., Dekker, J., Cornelissen, M. (1995) Differences in human immunodeficiency virus type 1 V3 sequences from patients with and without AIDS dementia complex J. Gen. Virol. 76,175-180[Abstract/Free Full Text]
    54. 54
  54. Steuler, H., Storch-Hagenlocher, B., Wildemann, B. (1992) Distinct populations of human immunodeficiency virus type 1 in blood and cerebrospinal fluid AIDS Res. Hum. Retroviruses 8,53-59[Medline]
    55. 55
  55. Burns, D. P. W., Desrosiers, R. C. (1991) Selection of genetic variants of simian immunodeficiency virus in persistently infected rhesus monkeys J. Virol. 65,1843-1854[Abstract/Free Full Text]
    56. 56
  56. Overbaugh, J., Rudensey, L. M., Papenhausen, M. D., Benveniste, R. E., Morton, W. R. (1991) Variation in simian immunodeficiency virus env is confined to V1 and V4 during progression to simian AIDS J. Virol. 65,7025-7031[Abstract/Free Full Text]
    57. 57
  57. Simmonds, P., Balfe, P., Ludlam, C. A., Bishop, J. O., Leigh Brown, A. J. (1990) Analysis of sequence diversity in hypervariable regions of the external glycoprotein of human immunodeficiency virus type 1 J. Virol. 64,5840-5850[Abstract/Free Full Text]
    58. 58
  58. Burns, D. P., Collignon, W. C., Desrosiers, R. C. (1993) Simian immunodeficiency virus mutants resistant to serum neutralization arise during persistent infection of rhesus monkeys J. Virol. 67,4104-4113[Abstract/Free Full Text]
    59. 59
  59. Koup, R. A., Safrit, J. T., Cao, Y., Andrews, C. A., McLeod, G., Borkowsky, W., Farthing, C., Ho, D. D. (1994) Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome J. Virol. 68,4650-4655[Abstract/Free Full Text]
    60. 60
  60. Phillips, R. E., Rowland-Jones, S., Nixon, D. F., Gotch, F. M., Edwards, J. P., Ogunlesi, A. O., Elvin, J. G., Rothbard, J. A., Bangham, C. R. M., Rizza, C. R., McMichael, A. J. (1991) Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition Nature 354,453-459[Medline]
    61. 61
  61. Wolinsky, S. M., Korber, B. T. M., Neumann, A. U., Daniels, M., Kunstman, K. J., Whetsell, A. J., Furtado, M. R., Cao, Y., Ho, D. D., Safrit, J. T., Koup, R. A. (1996) Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection Science 272,537-542[Abstract]
    62. 62
  62. Epstein, L. G., Kuiken, C., Blumberg, B. M., Hartman, S., Sharer, L. R., Clement, M., Goudsmit, J. (1991) HIV-1 V3 domain variation in brain and spleen of children with AIDS: tissue-specific evolution within host-determined quasispecies Virology 180,583-590[Medline]
    63. 63
  63. Itescu, S., Simonelli, P. F., Winchester, R. J., Ginsberg, H. S. (1994) Human immunodeficiency virus type 1 strains in the lungs of infected individuals evolve independently from those in peripheral blood and are highly conserved in the C-terminal region of the envelope V3 loop Proc. Natl. Acad. Sci. USA 91,11378-11382[Abstract/Free Full Text]
    64. 64
  64. Korber, B. T., Kunstman, K. J., Patterson, B. K., Furtado, M., McEvilly, M. M., Levy, R., Wolinsky, S. M. (1994) Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences J. Virol. 68,7467-7481[Abstract/Free Full Text]
    65. 65
  65. Aquaro, S., Perno, C. F., Balestra, E., Balzarini, J., Cenci, A., Francesconi, M., Panti, S., Serra, F., Villani, N., Calio, R. (1997) Inhibition of replication of HIV in primary monocyte/macrophages by different antiviral drugs and comparative efficacy in lymphocytes J Leukoc Biol 62,138-143[Abstract]
    66. 66
  66. Perno, C. F., Newcomb, F. M., Davis, D. A., Aquaro, S., Humphrey, R. W., Calio, R., Yarchoan, R. (1997) Relative potency of protease inhibitors in monocytes/macrophages acutely and chronically infected with human immunodeficiency virus J Infect Dis 178,413-422
    67. 67
  67. Perelson, A. S., Essunger, P., Cao, Y., Vesanen, M., Hurley, A., Saksela, K., Markowitz, M., Ho, D. D. (1997) Decay characteristics of HIV-1 infected compartments during therapy Nature 387,189-191
    68. 68
  68. Hughes, E. S., Bell, J. E., Simmonds, P. (1997) Investigation of the dynamics of the spread of human immunodeficiency virus to brain and other tissues by evolutionary analysis of sequences from the p17 gag and env genes J. Virol. 71,1272-1280[Abstract]
    69. 69
  69. Wong, J. K., Ignacio, C. C., Torriani, F., Havler, D., Fitch, N. J. S., Richman, D. D. (1997) In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues J. Virol. 71,2059-2071[Abstract]
    70. 70
  70. Delwart, E. L., Mullins, J. I., Gupta, P., Learn, G. H., Jr, Holodniy, M., Katzenstein, D., Walker, B. D., Singh, M. K. (1998) Human immunodeficiency virus type 1 populations in blood and semen J Virol 72,617-623[Abstract/Free Full Text]
    71. 71
  71. Korber, B., Myers, G. (1992) Signature pattern analysis: a method for assessing viral sequence relatedness AIDS Res. Hum. Retroviruses 8,1549-1560[Medline]



This article has been cited by other articles:


Home page
 BloodHome page
X. Wang, L. Ye, W. Hou, Y. Zhou, Y.-J. Wang, D. S. Metzger, and W.-Z. Ho
Cellular microRNA expression correlates with susceptibility of monocytes/macrophages to HIV-1 infection
Blood, January 15, 2009; 113(3): 671 - 674.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
P. J. Ellery, E. Tippett, Y.-L. Chiu, G. Paukovics, P. U. Cameron, A. Solomon, S. R. Lewin, P. R. Gorry, A. Jaworowski, W. C. Greene, et al.
The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo
J. Immunol., May 15, 2007; 178(10): 6581 - 6589.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
S. Crowe, T. Zhu, and W. A. Muller
The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection
J. Leukoc. Biol., November 1, 2003; 74(5): 635 - 641.
[Abstract] [Full Text] [PDF]

Home page
 J Antimicrob ChemotherHome page
T. Zhu
HIV-1 in peripheral blood monocytes: an underrated viral source
J. Antimicrob. Chemother., September 1, 2002; 50(3): 309 - 311.
[Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
L. J. Montaner, C.-F. Perno, and S. Crowe
Macrophage infection by HIV-1: focus on viral reservoirs and pathogenesis
J. Leukoc. Biol., September 1, 2000; 68(3): 301 - 302.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhu, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhu, T.