science pharmaceutical expo biotech jobs
Originally published online as doi:10.1189/jlb.0606376 on August 24, 2006

Published online before print August 24, 2006
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.0606376v1
80/5/1103    most recent
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 Aquaro, S.
Right arrow Articles by Perno, C. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aquaro, S.
Right arrow Articles by Perno, C. F.
(Journal of Leukocyte Biology. 2006;80:1103-1110.)
© 2006 by Society for Leukocyte Biology

Mechanisms underlying activity of antiretroviral drugs in HIV-1-infected macrophages: new therapeutic strategies

Stefano Aquaro*,{dagger},1, Valentina Svicher*, Dominique Schols{ddagger}, Michela Pollicita*, Andrea Antinori§, Jan Balzarini{ddagger} and Carlo Federico Perno*

* Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," Rome, Italy;
{dagger} Department of Pharmaco-Biology, University of Calabria, Rende (CS), Italy;
{ddagger} Rega Institute for Medical Research, Catholic University of Leuven, Leuven, Belgium; and
§ National Institute for Infectious Diseases "L. Spallanzani," Rome, Italy

1 Correspondence: University of Rome Tor Vergata, Experimental Medicine and Biochemical Sciences, via Montpellier 1, Roma 00133, Italy. E-mail: aquaro{at}uniroma2.it


arrow
ABSTRACT
 
Monocyte-derived macrophages (M/M) are considered the second cellular target of HIV-1 and a crucial virus reservoir. M/M are widely distributed in all tissues and organs, including the CNS, where they represent the most common HIV-infected cells. Differently from activated CD4+ T lymphocytes, M/M are resistant to the cytopathic effect of HIV and survive HIV infection for a long time. Moreover, HIV-1 replication in M/M is a key pathogenetic event during the course of HIV-1 infection. Overall findings strongly support the clinical relevance of anti-HIV drugs in M/M. Nucleoside RT inhibitors (NRTIs) are more active against HIV in M/M than in CD4+ T lymphocytes. Their activity is further boosted by the presence of an additional monophosphate group (i.e., a phosphonate group, as in the case of Tenofovir), thus overcoming the bottleneck of the low phosphorylation ability of M/M. In contrast, the antiviral activity of non-NRTIs (not affecting the DNA chain elongation) in M/M is similar to that in CD4+ T lymphocytes. Protease inhibitors are the only clinically approved drugs acting at a late stage of the HIV lifecycle. They are able to interfere with HIV replication in HIV-1 chronically infected M/M, even if at concentrations greater than those observed in HIV-1 chronically infected CD4+ T lymphocytes. Finally, several new drugs have been shown to interfere efficiently with HIV replication in M/M, including entry inhibitors. A better understanding of the activity of the anti-HIV drugs in M/M may represent a key element for the design of effective anti-HIV chemotherapy.

Key Words: anti-HIV drugs • protease • reverse transcriptase • gp41 • CCR5 coreceptor


arrow
INTRODUCTION
 
Introduction of the highly active antiretroviral therapy has provided an extraordinary clinical benefit in HIV-infected patients by lowering morbidity and mortality [1 2 3 ]. Despite this success, the eradication of HIV from the body is not achievable, and the main reason is the presence of virus reservoirs. Monocyte-derived macrophages (M/M) are one of the major cellular targets for HIV-1 infection and an important virus reservoir. M/M contribute to the transmission and the pathogenesis of HIV-1 infection throughout the progression of HIV-1 infection, especially at late stages when CD4+ T lymphocytes have been depleted extensively [4 5 6 ]. In fact, productively infected M/M can fuse with uninfected CD4+ T lymphocytes and transfer the virus to these cells, thus further contributing to depletion of CD4+ T lymphocytes [7 ]; in addition, HIV-1 infected M/M may induce the apoptosis on bystander uninfected cells, such as CD4+ and CD8+ T lymphocytes, neurons, and astrocytes by releasing cytotoxic factors [8 9 10 11 12 ]. Consistent with these results, it has been demonstrated that few HIV-infected M/M may completely deplete millions of autologous CD4+ T lymphocytes in a SCID mouse model [13 ].

HIV-infected M/M are commonly found in the blood and widely distributed in all tissues, organ and compartments [14 15 16 ]. In the CNS, M/M and microglia cells represent the most common cell lineages that support virus replication, thus being responsible for the onset of HIV-associated dementia and the neuropathological features of HIV encephalitis [17 18 19 ].

The dynamics of HIV-1 infection in M/M are substantially different from that in CD4+ T lymphocytes. In contrast to HIV-infected CD4+ T lymphocytes, which are rapidly killed by HIV-1 [20 ], M/M may survive to the cytopathic effect of HIV-1 and support long-term production of HIV-1 particles without a significant alteration of their homeostasis [21 22 23 24 ].

All these findings underline the relevance of identifying therapeutic strategies able to prevent HIV-1 replication in M/M. Thus, in this review, we reported the state of the art of the anti-HIV-1 drug activity in M/M, focusing also the attention on new and innovative compounds. As a result of their different cellular characteristics, the efficacy of the anti-HIV-1 drugs in M/M has been described in comparison with that observed in CD4+ T lymphocytes.


arrow
RT INHIBITORS (RTIs)
 
As HIV-1 RT has a pivotal role in the HIV-1 replication cycle, it has become a central target for the development of anti-HIV drugs. In particular, to date, seven nucleoside RTIs (NRTIs: AZT-zidovudine, d4T-stavudine, 3TC-lamivudine, ddI-didanosine, ABC-abacavir, ddC-zalcitabine, FTC-emtricitabine), one acyclic nucleoside phosphonate (NtRTI: TDF-tenofovir), and three non-NRTIs (NNRTIs: nevirapine, efavirenz, and delavirdine) have been approved in clinical practice [25 26 27 28 ].

Analog NRTIs
All the NRTIs clinically available have been demonstrated to be more active in M/M than in CD4+ T lymphocytes in in vitro biological models [29 30 31 32 33 34 35 ]. This is a result of the fact that M/M are resting cells characterized by a poor deoxynucleotide metabolism and low endogenous nucleotides pool, which results in a competition by deoxy-unspecified nucleoside 5'-triphosphates (dNTPs) lower in M/M than in CD4+ T lymphocytes [36 , 37 ]. The strong activity of NRTIs in M/M may have important clinical implications. In fact, despite the low concentration of NRTIs (such as AZT, d4T, 3TC, and ddI) in the cerebrospinal fluid, as a result of their low penetration in this compartment [38 , 39 ] coupled with the high expression of p170 glycoprotein in M/M able to excrete NRTIs outside the cell [38 ], NRTIs have been shown to reduce the onset of HIV-associated dementia and the neuropathological features of HIV encephalitis in the CNS, where M/M represent the majority of cells infected by HIV [39 40 41 ].

It is interesting that the poor nucleoside/nucleotide metabolism in M/M may also slow down the activity of the RT and consequently the development of drug resistance. Indeed, a recent study shows that in vitro mutations conferring resistance to lamivudine (one of the most commonly used NRTI) do not emerge during treatment with lamivudine in HIV-infected M/M, even at time-points far longer than those sufficient to induce full-blown resistance in CD4+ T lymphocytes [42 ]. As a confirmation of these data, several studies show that the number of mutations present in HIV-1 from cerebrospinal fluid of NRTI-treated patients is lower than that detected in the corresponding plasma samples [43 44 45 46 47 ]. Under these conditions, recruitment of newly infected cells, transfer of the virus to lymphocytes, induction of apoptosis of bystander lymphocytes, and production of factors triggering virus replication and cell death (all phenomena attributed to M/M in the pathogenesis of HIV infection) may be slowed down under NRTI treatment, which is apparently no longer effective. This can in part contribute to the discordant results often seen in patients, where CD4+ T cell counts continue to increase, and general conditions improve (including enhancement of responses to opportunistic antigens), despite a rebound of viremia.

However, the same study showed that viruses carrying a M184V mutation in the RT enzyme are full-resistant to lamivudine (Fig. 1 ) and have a replicative capacity in M/M, sixfold lower than that observed in CD4+ T lymphocytes. Conversely, the wild-type viruses have a replication capacity threefold lower in M/M than CD4+ T lymphocytes. Again, this difference may be attributed to the resting status of M/M. In fact, it has been demonstrated that the M184V mutation, located in the conserved YMDD region near the polymerase active site, causes a reduced RT processivity in vitro compared with wild-type enzyme in primary cells and cell-free virions [48 49 50 ]. Such defects in RT processivity, likely as a result of an altered interaction of the enzyme with the primer/template duplex [53 ], are correlated with reduced replication capacity, which is more pronounced in primary cells containing a low amount of dNTP levels (such as M/M) [51 ].


Figure 1
View larger version (10K):
[in this window]
[in a new window]
  		Figure 1. Replication capacity of the wild-type 81A virus and its M184V RT virus variant in macrophages (M/M) under lamivudine treatment. The replication capacity of the wild-type HIV-1 81A (open columns) and its M184V RT virus variant (solid columns) was assessed in M/M, in the absence and presence of increasing concentration of lamivudine by measuring p24-antigen concentration in the culture supernatants 14 days post-infection when M/M release the highest amount of viral particles. The results shown are the means from at least four independent experiments. 3TC, Lamivudine. Data from ref. [42 ].

Further studies are necessary to clarify the development of resistance to the other drugs in M/M compared with CD4+ T lymphocytes.

NtRTIs
The majority of NRTIs is characterized by a low affinity for the cellular kinases, responsible of their activation. Thus, several attempts have been undertaken to deliver activated (phosphorylated) NRTIs directly into the virus-infected target cells. One of these approaches is represented by the NtRTIs, in which a phosphonate group is linked to the alkyl side-chain of purines or pyrimidines [52 , 53 ].

Tenofovir disoproxil fumarate (TDF), the first NtRTI approved for clinical use, has a potent anti-HIV-1 activity in M/M, greater than that observed in CD4+ T lymphocytes (Table 1 ). The higher efficacy may be explained by the ability of TDF to overcome the first phosphorylation step coupled with the low dATP levels (poorly competing with phosphorylated TDF) in M/M [61 , 62 ]. It has also been demonstrated that TDF may be converted more efficiently to its active diphosphate metabolite 9-[2-(phosphonomethoxy)propyl]adenine-pp in dendritic cells (DC) and Langherans cells than zidovudine and lamivudine. As Langerhans cells and interstitial DC are the earliest targets for HIV infection through sexual transmission of HIV, TDF has been proposed as a candidate drug for application in postexposure prophylactic treatment [63 ].


View this table:
[in this window]
[in a new window]
  		Table 1. Activity of Anti-HIV Drugs in Acutely Infected T Lymphocytes (PBL), Acutely Infected Macrophages (M/M), and Chronically Infected Macrophages (M/M)

It is conceivable that the antiviral effect of TDF in M/M contributes to its excellent clinical efficacy, making it one of the most effective anti-HIV drugs currently available.

Taken together, these findings suggest that the DNA chain termination is the major mechanism able to impair HIV-1 replication in M/M.

NNRTIs
As the NNRTI activity is not affected by the intracellular dNTP pools, the anti-HIV-1 activity of the currently available NNRTI showed no substantial differences between M/M and CD4+ T lymphocytes (Table 1) . It is interesting that TMC125, a second generation NNRTI, efficiently inhibits HIV replication in M/M, even if at a concentration similar to those observed in CD4+ T lymphocytes [64 ]. In particular, it has been shown that the EC50 of TMC125 against the laboratory strain HIVBal is in the lower nanomolar range [2.0 (0.8–4.0)] nm and highly similar to that observed for efavirenz {2.0 (0.9–3.0) nm [64 ]}. The HIVBal replication in M/M is also inhibited efficiently by the pyrrolobenzoxazepinones, a new class of NNRTIs designed to target the highly conserved primer grip within the {alpha}12-{alpha}13 hairpin. It is interesting that 15c, the most promising pyrrolobenzoxazepine investigated, inhibits HIV-1 replication at a concentration that is 40-fold lower than that necessary to inhibit HIV-1 replication in CD4+ T lymphocytes [55 ]. Similarly, 15f inhibits HIV-1 replication in M/M at a concentration sixfold lower than that required in CD4+ T lymphocytes.


arrow
PROTEASE INHIBITORS
 
The dynamics of the HIV-1 lifecycle in M/M underline the importance of drugs able to interfere with HIV replication at a post-integrational level. Indeed, once the proviral DNA is integrated into the host genome, the production of viral particles is independent of the RT enzyme and thus, is not affected by the RTIs. For these reasons, the activity of several drugs acting at a late stage of HIV replication (anti-rev, anti-tat, transcription inhibitors, IFN-{alpha}, IFN-{gamma}, ampligen) has been tested in chronically infected M/M [64 ]. However, results were not encouraging, as all these drugs failed to suppress HIV replication. Protease inhibitors (PIs) represented the only exception. All clinically available PIs and also the next generation TMC114 are able to inhibit HIV replication in chronically infected M/M, although at EC50 values greater than those required in chronically infected CD4+ T lymphocytes [56 , 65 66 67 68 ]. It should be noted that such data derived from primary M/M cell culture and from the CD4+ T cell line chronically infected with HIV-1LAI. This is a result of the fact that in vivo, HIV-1 chronically and productively infected CD4+ T lymphocytes are not present. Thus, it is not possible to establish in vitro a culture of primary CD4+ T lymphocytes chronically infected by HIV-1.

The difference in the anti-HIV-1 activity of PIs in HIV-1 chronically infected M/M and CD4+ T lymphocytes may be explained by the high and sustained RNA metabolism in M/M, which affords a great production of virus particles, even from a limited amount of proviral DNA in these cells. Consistent with this hypothesis, HIV-RNA production from chronically infected M/M is not at all affected by PIs, even when protein maturation and release of infectious virus particles are inhibited significantly [69 ].

This may have important clinical implications. In fact, the high concentration of PIs required to suppress HIV-1 replication in chronically infected M/M is often higher than through the PI concentration in plasma of treated patients. This situation is even more pronounced in patients with a poor compliance to therapy or an altered drug absorption or metabolism. This limitation may be overcome by boosting PIs with ritonavir, which enhances PI concentration in plasma to levels able to maintain full suppression of virus replication, thus creating conditions for consistent and long-lasting HIV inhibition. At the same time, PIs do not affect proviral DNA in chronically infected cells. Therefore, it is conceivable that virus replication resumes after drug removal. This phenomenon, clearly demonstrated in in vitro experiments [70 , 71 ], may explain (at least in part) the rapid reappearance of virus replication after therapeutic interruptions, thus further supporting the role of macrophages as a key target of antiviral interventions.

Despite their antiretroviral activity, treatment of HIV-1-infected patients with PIs is unfortunately associated with a number of clinically significant, metabolic abnormalities and an increased risk of premature atherosclerosis and myocardial infarction. It has been shown that M/M are the most prominent cell types present in atherosclerotic lesions and play an essential role in early lesion development and late lesion complications [70 ]. In particular, a major role in atherosclerotic lesion development in vivo seems to be played by the M/M scavenger receptor CD36 [57 ].


arrow
TOWARD NEW THERAPEUTIC STRATEGY
 
Fusion inhibitors
T-20 (Fuzeon/Enfuvirtide) is the prototype of a new drug class: the entry inhibitors. In particular, T-20 is a fusion inhibitor recently approved for clinical practice. This drug targets the HIV-1 glycoprotein gp41, thus preventing the fusion between the viral and the host cell membrane. It has been demonstrated by using different lab-adapted HIV-1 strains, that T-20 may efficiently prevent the entry of HIV-1 into PBMC, M/M, and immature DC [73 ]. It is interesting that a recent study showed, by using T-20 naïve, primary isolates, that the T-20 susceptibility may be modulated by coreceptor specificity [74 ]. In particular, it has been demonstrated that CCR5-using strains are characterized by an intrinsic resistance to T-20, and thus, their replication is suppressed at concentrations of T-20, higher than those required for CXCR4-using strains [74 ]. Moreover, the clinical efficacy of T-20 is also strengthened by the fact that the development of drug resistance [58 , 75 76 77 78 ] may be associated with immunological success, despite virological failure [79 ]. Thus far, data about the activity of T-20 in M/M are limited (Table 1) . Studies are ongoing to define this point of obvious clinical relevance.

CCR5 chemokine inhibitors
CCR5 (belonging to the G protein-coupled receptor) is a ß-chemokine receptor, mainly expressed by activated CD4+ T cells and M/M and involved in chemotaxis. During the entry of HIV in the target cell, CCR5 is the main coreceptor, which allows HIV to enter M/M. CCR5 also plays a crucial role in the transmission of HIV strains, which establish initial infection, remain the dominant form in 50% of late stage HIV-1-infected patients, and predominate in the brain, where HIV causes HIV-associated dementia complex [80 81 82 83 ]. The natural CCR5{Delta}32 omozigosity confers high protection against HIV infection [83 ], and this concept may not be applied to other pathologies such as West Nile and Hepatitis C [84 , 85 ]. Thus, the rate of disease progression associated with different viral infections may vary according to the genetic of the host. Based on these assumptions, CCR5 have represented an attractive target for anti-HIV-1 chemotherapy. However, the use of CCR5 inhibitors may render HIV-1-infected patients vulnerable to West Nile or Hepatitis C infection.

To date, various CCR5 ligands with antiviral properties have been described including modified chemokines, small-molecule inhibitors with potential for oral administration, and mAb. However, none of them is in clinical practice. The CCR5 inhibitors vicriviroc (SCH-D, Schering-Plough, Kenilworth, NJ), maraviroc (UK-427,857, Pfizer, Groton, CT), and aplaviroc (873140, GlaxoSmithKline, UK) showed an excellent potency in vitro (Table 1) [59 , 86 , 87 ] and a good pharmacokinetic profile [60 , 87 , 88 ] in vivo. Unfortunately, Aplaviroc has been withdrawn from further clinical development as a result of liver toxicity in clinical trials, and Vicriviroc has been associated with high rates of drug failure. Despite this, the antiviral activity of other CCR5 inhibitors is ongoing in investigation [89 ]. It is interesting that novel, small molecules derived from the UK-427,857 discovery program showed no cross-reactivity against alternative HIV coreceptors and have good efficacy against a diverse range of R5 and R5X4 HIV-1 isolates as well as HIV-2 and SIV strains. Inhibition was also observed in cell lines as well as primary PBMCs and M/M, even if the extent of inhibition is dependent on cell type and on cell surface CCR5 concentration.

Recently, the antiviral activity of a number of synthetic peptides mimicking the short region of the V2 or V3 loop of gp120 has been investigated [90 91 92 93 ]. Among them, Peptide T is a synthetic peptide corresponding to eight amino acids (185–192) of the gp120 V2 region, which binds CCR5. This compound has been shown to block HIV-1 entry in M/M and microglia and to prevent the M/M-mediated apoptosis of neuronal cells at nanomolar/subnanomolar concentrations [91 92 93 ].

Another antiviral approach targeting CCR5 selectively is represented by mAb. To date the mAb Pro-140 (Progenics, Tarrytown, NY), directed against CCR5, have been shown to inhibit HIV replication efficiently in CD4+ T lymphocytes and M/M [94 ]. The antiviral activity of other types of molecules directed against the CCR5 is in current investigation. Among them, shikonin, a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with various biological activities, has been shown to inhibit HIV replication in M/M by down-regulating the expression of the CCR5 [95 ].

Plant lectins as potential anti-HIV compounds with microbicidal action
Recently, plant-derived carbohydrate-binding lectins have been proposed as potential anti-HIV microbicide drugs, which target the glycans present on the surface of the HIV-1 gp120. These compounds may inhibit HIV infection and also efficiently prevent HIV transmission from virus-infected cells to uninfected CD4+ T lymphocytes [96 97 98 ]. It is interesting that these compounds were found active against CCR5-using HIV-1 strains in M/M [97 ].


arrow
INTEGRASE INHIBITORS
 
To date, a number of new drugs belonging to the class of aril diketo acids have been demonstrated to inhibit HIV-1 replication by inhibiting the activity of the integrase enzyme.

Despite this, there are no data regarding the efficacy of such inhibitors in interfering with HIV-1 replication in M/M. This is a gap that should be filled rapidly, as some of them are in advanced clinical investigation.


arrow
DRUGS AGAINST NONCLASSICAL TARGET
 
In the last years, a number of new molecules have been proposed to become lead compounds for the development of new drug classes. Some of them are directed against the accessory proteins. In particular, fumagillin was shown to have a potent anti-HIV activity in M/M by a direct interaction with Vpr and a consequent down-regulation of Vpr-dependent genes expression [99 ]. The identification of drugs able to interfere with HIV-1 replication in M/M by targeting Vpr selectively is crucial, as this accessory protein is essential for HIV-1 productive infection in resting cells, which represent the major obstacle for viral eradication.

It is different that the amiloride analogs (5-[N,N-hexamethylene] amiloride and 5-[N,N-dimethyl] amiloride), whose target is HIV-1 accessory protein Vpu, were shown to inhibit the replication of HIV in M/M at micromolar concentration [100 ].

Another promising compound is Ozadiasol, targeting the process of nuclear translocation of the HIV preintegration complex. This compound shows potent anti-HIV activity in cultures of CD4+ T lymphocytes and M/M and also inhibited HIV-1 replication in ex vivo-cultured lymphoid tissue by inhibiting the nuclear import of viral DNA [101 ]. The development of these compounds is still in preclinical stages; thus, further studies are required to assess whether these interesting characteristics have implications in clinical practice.


arrow
CONCLUSIONS
 
As a consequence of the peculiar characteristics of the HIV lifecycle, the RTIs and the protease inhibitors are able to inhibit HIV replication in M/M, even if at concentrations different than those required in actively replicating CD4+ T lymphocytes. The limited development of drug resistance suggests that these drugs may efficiently suppress HIV replication in M/M (the main cellular reservoir of HIV infection) for a long time.

Moreover, the crucial role of M/M in the pathogenesis of HIV infection, especially in the CNS, underlines the importance of testing in M/M the antiviral efficacy of new drugs designed to target different stages of the HIV lifecycle. Particular attention has been dedicated to drugs able to target the CCR5 coreceptor selectively, the main coreceptor used by HIV to enter M/M. The CCR5 antagonists also represent a promising approach for their ability to synergize with T-20, the first fusion inhibitor in clinical use.

Taken together, overall findings support the clinical relevance of interfering with HIV replication in M/M. In particular, the inherent properties of HIV infection of M/M should be taken into account in designing therapeutic strategies aimed at achieving an optimal, therapeutic effect in all tissue compartments where the virus hides and replicates.


arrow
ACKNOWLEDGEMENTS
 
This work was supported by grants from Project AIDS of the Italian National Institute of Health (I. S. S.), European Community (Gene/Chemotherapy, HIV Resistance; Renè Descartes Prize 2001), National Research Council (CNR), MIUR (FIRB project), and Ricerca Corrente and Finalizzata of the Ministry of Health. The authors thank Emanuela Balestra, Fabiola Di Santo, Sara Giannella, Fabio Marcuccilli, and Patrizia Saccomandi for excellent technical assistance.

Received June 7, 2006; revised July 21, 2006; accepted July 26, 2006.


arrow
REFERENCES
 
    1
  1. Palella, F. J., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Aschman, D. J., Holmberg, S. D. (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators N. Engl. J. Med. 338,853-860[Abstract/Free Full Text]
    2. 2
  2. Valenti, W. M. (2001) HAART is cost-effective and improves outcomes AIDS Read 11,260-262[Medline]
    3. 3
  3. King, J. T., Justice, A. C., Roberts, M. S., Chang, C. C., Fusco, J. S., . Collaboration in HIV Outcomes Research-US Program Team (2003) Long-term HIV/AIDS survival estimation in the highly active antiretroviral therapy era Med. Decis. Making 23,9-20[Abstract/Free Full Text]
    4. 4
  4. Williams, K. C., Hickey, W. F. (2002) Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS Annu. Rev. Neurosci. 25,537-562[CrossRef][Medline]
    5. 5
  5. Tomkowicz, B., Lee, C., Ravyn, V., Cheung, R., Ptasznik, A., Collman, R. (2006) The Src kinase Lyn is required for CCR5 signaling in response to MIP-1{ß} and R5 HIV-1 gp120 in human macrophages Blood 108,1145-1150[Abstract/Free Full Text]
    6. 6
  6. Herbein, G., Coaquette, A., Perez-Bercoff, D., Pancino, G. (2002) Macrophage activation and HIV infection: can the Trojan horse turn into a fortress? Curr. Mol. Med. 2,723-738[CrossRef][Medline]
    7. 7
  7. Crowe, S. M., Mills, J., Kirihara, J., Boothman, J., Marshall, J. A., McGrath, M. S. (1990) Full-length recombinant CD4 and recombinant gp120 inhibit fusion between HIV infected macrophages and uninfected CD4-expressing T-lymphoblastoid cells AIDS Res. Hum. Retroviruses 6,1031-1037[Medline]
    8. 8
  8. Badley, A. D., Dockrell, D., Simpson, M., Schut, R., Lynch, D. H., Leibson, P., Paya, C. V. (1997) Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor J. Exp. Med. 185,55-64[Abstract/Free Full Text]
    9. 9
  9. Herbein, G., Mahlknecht, U., Batliwalla, F., Gregersen, P., Pappas, T., Butler, J., O’Brien, W. A., Verdin, E. (1998) Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4 Nature 395,189-194[CrossRef][Medline]
    10. 10
  10. Shi, B., De Girolami, U., He, J., Wang, S., Lorenzo, A., Busciglio, J., Gabuzda, D. (1996) Apoptosis induced by HIV-1 infection of the central nervous system J. Clin. Invest. 98,1979-1990[Medline]
    11. 11
  11. Aquaro, S., Panti, S., Caroleo, M. C., Balestra, E., Cenci, A., Forbici, F., Ippolito, G., Mastino, A., Testi, R., Mollace, V., Calio, R., Perno, C. F. (2000) Primary macrophages infected by human immunodeficiency virus trigger CD95-mediated apoptosis of uninfected astrocytes J. Leukoc. Biol. 68,429-435[Abstract/Free Full Text]
    12. 12
  12. Mollace, V., Salvemini, D., Riley, D. P., Muscoli, C., Iannone, M., Granato, T., Masuelli, L., Modesti, A., Rotiroti, D., Nistico, R., Bertoli, A., Perno, C. F., Aquaro, S. (2002) The contribution of oxidative stress in apoptosis of human-cultured astroglial cells induced by supernatants of HIV-1-infected macrophages J. Leukoc. Biol. 71,65-72[Abstract/Free Full Text]
    13. 13
  13. Garaci, E., Aquaro, S., Lapenta, C., Amendola, A., Spada, M., Covaceuszach, S., Perno, C. F., Belardelli, F. (2003) Anti-nerve growth factor Ab abrogates macrophage-mediated HIV-1 infection and depletion of CD4+ T lymphocytes in hu-SCID mice Proc. Natl. Acad. Sci. USA 100,8927-8932[Abstract/Free Full Text]
    14. 14
  14. Koenig, S., Gendelman, H. E., Orenstein, J. M., Dal Canto, M. C., Pezeshkpour, G. H., Yungbluth, M., Janotta, F., Aksamit, A., Martin, M. A., Fauci, A. S. (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy Science 233,1089-1093[Abstract/Free Full Text]
    15. 15
  15. Tschachler, E., Groh, V., Popovic, M., Mann, D. L., Konrad, K., Safai, B., Eron, L., Di Marzo Veronese, F., Wolff, K., Stingl, G. (1987) Epidermal Langerhans cells a target for HTLV-III/LAV infection J. Invest. Dermatol. 88,233-237[CrossRef][Medline]
    16. 16
  16. 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]
    17. 17
  17. Gabuzda, D. H., Ho, D. D., de la Monte, S. M., Hirsch, M. S., Rota, T. R., Sobel, R. A. (1986) Immunohistochemical identification of HTLV-III antigen in brains of patients with AIDS Ann. Neurol. 20,289-295[CrossRef][Medline]
    18. 18
  18. Giulian, D., Vaca, K., Noonan, C. A. (1990) Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1 Science 250,1593-1596[Abstract/Free Full Text]
    19. 19
  19. Tyor, W. R., Power, C., Gendelman, H. E., Markham, R. B. (1993) A model of human immunodeficiency virus encephalitis in SCID mice Proc. Natl. Acad. Sci. USA 90,8658-8662[Abstract/Free Full Text]
    20. 20
  20. Bagnarelli, P., Valenza, A., Menzo, S., Sampaolesi, R., Varaldo, P. E., Butini, L., Montoni, M., Perno, C. F., Aquaro, S., Mathez, D., Leibowitch, J., Balotta, C., Clementi, M. (1996) Dynamics and modulation of human immunodeficiency virus type 1 transcripts in vitro and in vivo J. Virol. 70,7603-7613[Abstract]
    21. 21
  21. Gendelman, H. E., Orenstein, J. M., Martin, M. A., Ferrua, C., Mitra, R., Phipps, T., Wahl, L. A., Lane, H. C., Fauci, A. S., Burke, D. S. (1988) Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes J. Exp. Med. 167,1428-1441[Abstract/Free Full Text]
    22. 22
  22. Orenstein, J. M., Meltzer, M. S., Phipps, T., Gendelman, H. E. (1988) Cytoplasmic assembly and accumulation of human immunodeficiency virus types 1 and 2 in recombinant human colony-stimulating factor-1-treated human monocytes: an ultrastructural study J. Virol. 62,2578-2586[Abstract/Free Full Text]
    23. 23
  23. Aquaro, S., Bagnarelli, P., Guenci, T., De Luca, A., Clementi, M., Balestra, E., Caliò, R., Perno, C. F. (2002) Long-term survival and virus production in human primary macrophages infected by human immunodeficiency virus J. Med. Virol. 68,479-488[CrossRef][Medline]
    24. 24
  24. Garaci, E., Caroleo, M. C., Aloe, L., Aquaro, S., Piacentini, M., Costa, N., Amendola, A., Micera, A., Caliò, R., Perno, C. F., Levi- Montalcini, R. (1999) Nerve growth factor is an autocrine factor essential for the survival of macrophages infected with HIV Proc. Natl. Acad. Sci. USA 96,14013-10418[Abstract/Free Full Text]
    25. 25
  25. De Clercq, E. (2004) Antivirals and antiviral strategies Nat. Rev. Microbiol. 2,704-720[CrossRef][Medline]
    26. 26
  26. Parniak, M. A., Sluis-Cremer, N. (2000) Inhibitors of HIV-1 reverse transcriptase Adv. Pharmacol. 49,67-109[Medline]
    27. 27
  27. Clavel, F., Hance, A. J. (2004) HIV drug resistance N. Engl. J. Med. 350,1023-1035[Free Full Text]
    28. 28
  28. Balzarini, J. (2004) Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1 Curr. Top. Med. Chem. 4,921-944[CrossRef][Medline]
    29. 29
  29. Perno, C. F., Yarchoan, R., Cooney, D. A., Hartman, N. R., Webb, D. S., Hao, Z., Mitsuya, H., Johns, D. G., Broder, S. (1988) Inhibition of human immunodeficiency virus (HIV-1/HTLV-IIIBa-L) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2',3'-dideoxynucleosides J. Exp. Med. 168,1111-1125[Abstract/Free Full Text]
    30. 30
  30. Ahluwalia, G., Cooney, D. A., Mitsuya, H., Fridland, A., Flora, K. P., Hao, Z., Dalal, M., Broder, S., Johns, D. G. (1987) Initial studies on the cellular pharmacology of 2',3'-dideoxyinosine, an inhibitor of HIV infectivity Biochem. Pharmacol. 36,3797-3801[CrossRef][Medline]
    31. 31
  31. Balzarini, J., Kang, G. J., Dalal, M., Herdewijn, P., De Clercq, E., Broder, S., Johns, D. G. (1987) The anti-HTLV-III (anti-HIV) and cytotoxic activity of 2',3'-didehydro-2',3'-dideoxyribonucleosides: a comparison with their parental 2',3'-dideoxyribonucleosides Mol. Pharmacol. 32,162-167[Abstract]
    32. 32
  32. Balzarini, J., Baba, M., Pauwels, R., Herdewijn, P., De Clercq, E. (1988) Anti-retrovirus activity of 3'-fluoro- and 3'-azidosubstituted pyrimidine 2',3'-dideoxynucleoside analogues Biochem. Pharmacol. 37,2847-2856[CrossRef][Medline]
    33. 33
  33. Balzarini, J., Herdewijn, P., De Clercq, E. (1989) Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-humanimmunodeficiency virus compounds J. Biol. Chem. 264,6127-6133[Abstract/Free Full Text]
    34. 34
  34. Johnson, M. A., Fridland, A. (1989) Phosphorylation of 2',3'-dideoxyinosine by cytosolic 5'-nucleotidase of humanlymphoid cells Mol. Pharmacol. 36,291-295[Abstract]
    35. 35
  35. Hao, Z., Cooney, D. A., Farquhar, D., Perno, C. F., Zhang, K., Masood, R., Wilson, Y., Hartman, N. R., Balzarini, J., Johns, D. G. (1990) Potent DNA chain termination activity and selective inhibition of human immunodeficiency virus reverse transcriptase by 2',3'-dideoxyuridine-5'-triphosphate Mol. Pharmacol. 37,157-163[Abstract]
    36. 36
  36. Aquaro, S., Perno, C. F., Balestra, E., Balzarini, J., Cenci, A., Francesconi, M., Panti, S., Serra, F., Villani, N., Caliò, 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]
    37. 37
  37. Aquaro, S., Caliò, R., Balestra, E., Bagnarelli, P., Cenci, A., Bertoli, A., Tavazzi, B., Di Pierro, D., Francesconi, M., Abdelahad, D., Perno, C. F. (1998) Clinical implications of HIV dynamics and drug resistance in macrophages J. Biol. Regul. Homeost. Agents 12,23-27[Medline]
    38. 38
  38. Malorni, W., Lucia, M. B., Rainaldi, G., Cauda, R., Cianfriglia, M., Donelli, G., Ortona, L. (1998) Intracellular expression of p170 glycoprotein in peripheral blood mononuclear cell subsets from healthy donors and HIV-infected patients Haematologica 83,13-20[Abstract/Free Full Text]
    39. 39
  39. Haworth, S. J., Christofalo, B., Anderson, R. D., Dunkle, L. M. (1998) A single-dose study to assess the penetration of stavudine into human cerebrospinal fluid in adults J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 17,235-238[Medline]
    40. 40
  40. Lewis, L. L., Venzon, D., Church, J., Farley, M., Wheeler, S., Keller, A., Rubin, M., Yuen, G., Mueller, B., Sloas, M., Wood, L., Balis, F., Shearer, G. M., Brouwers, P., Goldsmith, J., Pizzo, P. A. (1996) Lamivudine in children with human immunodeficiency virus infection: a phase I–II study. The National Cancer Institute Pediatric Branch-Human Immunodeficiency Virus Working Group J. Infect. Dis. 174,16-25[Medline]
    41. 41
  41. Limoges, J., Persidsky, Y., Poluektova, L., Rasmussen, J., Ratanasuwan, W., Zelivyanskaya, M., McClernon, D. R., Lanier, E. R., Gendelman, H. E. (2000) Evaluation of antiretroviral drug efficacy for HIV-1 encephalitis in SCID mice Neurology 54,379-389[Abstract/Free Full Text]
    42. 42
  42. Aquaro, S., Svicher, V., Cenci, A., Ceccherini-Silberstein, F., Marcuccilli, F., Giannella, S., Marcon, L., Caliò, R., Balzarini, J., Perno, C. F. (2005) Limited development and progression of resistance to the nucleoside analogue reverse transcriptase inhibitor 3TC in human primary macrophages J. Antimicrob. Chemother. 55,872-878[Abstract/Free Full Text]
    43. 43
  43. Cunningham, P. H., Smith, D. G., Satchell, C., Cooper, D. A., Brew, B. (2000) Evidence for independent development of resistance to HIV-1 reverse transcriptase inhibitors in the cerebrospinal fluid AIDS 14,1949-1954[CrossRef][Medline]
    44. 44
  44. Tang, Y. W., Huong, J. T., Lloyd, R. M., Spearman, P., Haas, D. W. (2000) Comparison of human immunodeficiency virus type 1 RNA sequence heterogeneity in cerebrospinal fluid and plasma J. Clin. Microbiol. 38,4637-4639[Abstract/Free Full Text]
    45. 45
  45. Venturi, G., Catucci, M., Romano, L., Corsi, P., Leoncini, F., Valensin, P. E., Zazzi, M. (2000) Antiretroviral resistance mutations in human immunodeficiency virus type 1 reverse transcriptase and protease from paired cerebrospinal fluid and plasma samples J. Infect. Dis. 181,740-745[CrossRef][Medline]
    46. 46
  46. Price, R. W., Palmatier, R., Wring, S., Lu, J., Baker, B., Sailstad, J., Lollo, N., Spudich, S., Hoh, R., Liegler, T., Miralles, D., Kuritzkes, D., Deeks, S. (2005) Enfuvirtide cerebrospinal fluid pharmacokinetics: a potiential tool to analyze CSF HIV origin and the therapeutic role of local drug penetration 12th Conf. Retrovir. Opportunisitic Infect. ,a402
    47. 47
  47. Bestetti, A., Presi, S., Pierotti, C., Bossolasco, S., Sala, S., Racca, S., Carrera, P., Lazzarin, A., Cinque, P. (2004) Long-term virological effect of highly active antiretroviral therapy on cerebrospinal fluid and relationship with genotypic resistance J. Neurovirol. 10(Suppl. 1),52-57[Medline]
    48. 48
  48. Boyer, P. L., Hughes, S. H. (1995) Analysis of mutations at position 184 in reverse transcriptase of human immunodeficiency virus type 1 Antimicrob. Agents Chemother. 39,1624-1628[Abstract]
    49. 49
  49. Back, N. K., Nijhuis, M., Keulen, W., Boucher, C. A., Oude Essink, B. O., Van Kuilenburg, A. B., Van Gennip, A. H., Berkhout, B. (1996) Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme EMBO J. 15,4040-4049[Medline]
    50. 50
  50. Sharma, P. L., Crumpacker, C. S. (1999) Decreased processivity of human immunodeficiency virus type 1 reverse transcriptase (RT) containing didanosine-selected mutation Leu74Val: a comparative analysis of RT variants Leu74Val and lamivudine-selected Met184Val J. Virol. 73,8448-8456[Abstract/Free Full Text]
    51. 51
  51. Huang, H., Chopra, R., Verdine, G. L., Harrison, S. C. (1998) Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance Science 282,1669-1675[Abstract/Free Full Text]
    52. 52
  52. De Clercq, E., Sakuma, T., Baba, M., Pauwels, R., Balzarini, J., Rasemberg, I., Holy, A. (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines Antiviral Res. 8,261-272[CrossRef][Medline]
    53. 53
  53. Balzarini, J., Aquaro, S., Perno, C. F., Witvrouw, M., Holy, A., De Clercq, E. (1996) Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)adenine and 9-(2-phosphonylmethoxypropyl)-2-6-diaminopurine against human immunodeficiency virus in different human cell systems Biochem. Biophys. Res. Commun. 219,337-341[CrossRef][Medline]
    54. 54
  54. Perno, C. F., Svicher, V., Schols, D., Pollicita, M., Balzarini, J., Aquaro, S. (2006) Therapeutic strategies towards HIV-1 infection in macrophages Antiviral Res. 71,293-300[CrossRef][Medline]
    55. 55
  55. Perno, C. F., Aquaro, S., Rosenwirth, B., Balestra, E., Peichl, P., Billich, A., Villani, N., Caliò, R. (1994) In vitro activity of inhibitors of late stages of the replication of HIV in chronically infected macrophages J. Leukoc. Biol. 56,381-386[Abstract]
    56. 56
  56. Perno, C.F., Newcomb, F.M., Davis, D.A., Aquaro, S., Humphrey, R.W., Caliò, R., Yarchoan, R. (1998) Relative potency of protease inhibitors in monocytes/macrophages acutely and chronically infected with human immunodeficiency virus J. Infect. Dis. 178,413-422[Medline]
    57. 57
  57. Ketas, T. J., Frank, I., Klasse, P. J., Sullivan, B. M., Gardner, J. P., Spenlehauer, C., Nesin, M., Olson, W. C., Moore, J. P., Pope, M. (2003) Human immunodeficiency virus type 1 attachment, coreceptor, and fusion inihibitors are active against both direct and trans infection of primary cells J. Virol. 77,2762-2767[Abstract/Free Full Text]
    58. 58
  58. Wei, X., Decker, J. M., Liu, H., Zhang, Z., Arani, R. B., Kilby, J. M., Saag, M. S., Wu, X., Shaw, G. M., Kappes, J. C. (2002) Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy Antimicrob. Agents Chemother. 46,1896-1905[Abstract/Free Full Text]
    59. 59
  59. Strizki, J. M., Tremblay, C., Xu, S., Wojcik, L., Wagner, N., Gonsiorek, W., Hipkin, R. W., Chou, C. C., Pugliese-Sivo, C., Xiao, Y., Tagat, J. R., Cox, K., Priestley, T., Sorota, S., Huang, W., Hirsch, M., Reyes, G. R., Baroudy, B. M. (2005) Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1 Antimicrob. Agents Chemother. 49,4911-4919[Abstract/Free Full Text]
    60. 60
  60. Walker, D.K., Abel, S., Comby, P., Muirhead, G.J., Nedderman, A.N., Smith, D.A. (2005) Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV Drug Metab. Dispos. 33,587-595[Abstract/Free Full Text]
    61. 61
  61. De Clercq, E., Holy, A., Rosemberg, I., Sakuma, T., Balzarini, J., Maudgal, P. C. (1986) A novel selective broad-spectrumanti-DNA agent Nature 323,464-467[CrossRef][Medline]
    62. 62
  62. Balzarini, J., Van Herrewege, Y., Vanham, G. (2002) Metabolic activation of nucleoside and nucleotide reverse transcriptase inhibitors in dendritic and Langerhans cells AIDS 16,2159-2163[CrossRef][Medline]
    63. 63
  63. Andries, K., Azijn, H., Thielemans, T., Ludovici, D., Kukla, M., Heeres, J., Janssen, P., De Corte, B., Vingerhoets, J., Pauwels, R., de Bethune, M. P. (2004) TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1 Antimicrob. Agents Chemother. 48,4680-4686[Abstract/Free Full Text]
    64. 64
  64. Fattorusso, C., Gemma, S., Butini, S., Huleatt, P., Catalanotti, B., Persico, M., De Angelis, M., Fiorini, I., Nacci, V., Ramunno, A., Rodriquez, M., Greco, G., Novellino, E., Bergamini, A., Marini, S., Coletta, M., Maga, G., Spadari, S., Campiani, G. (2005) Specific targeting highly conserved residues in the HIV-1 reverse transcriptase primer grip region. Design, synthesis, and biological evaluation of novel, potent, and broad spectrum NNRTIs with antiviral activity J. Med. Chem. 48,7153-7165[CrossRef][Medline]
    65. 65
  65. Perno, C.F., Bergamini, A., Pesce, C.D., Milanese, G., Capozzi, M., Aquaro, S., Thaisrivongs, S., Tarpley, W.G., Zon, G., D’Agostini, C., Rocchi, G., Garaci, E., Caliò, R. (1993) Inhibition of the protease of human immunodeficiency virus blocks replication and infectivity of the virus in chronically infected macrophages J. Infect. Dis. 168,1148-1156[Medline]
    66. 66
  66. De Meyer, S., Azijn, H., Surleraux, D., Jochmans, D., Tahri, A., Pauwels, R., Wigerinck, P., de Bethune, M. P. (2005) TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates Antimicrob. Agents Chemother. 49,2314-2321[Abstract/Free Full Text]
    67. 67
  67. Aquaro, S., Guenci, T., Di Santo, F., Francesconi, M., Caliò, R., Perno, C. F. (2004) Potent antiviral activity of amprenavir in primary macrophages infected by human immunodeficiency virus Antiviral Res. 61,133-137[CrossRef][Medline]
    68. 68
  68. Aquaro, S., Bagnarelli, P., Guenci, T., De Luca, A., Clementi, M., Balestra, E., Caliò, R., Perno, C. F. (2002) Long-term survival and virus production in human primary macrophages infected by human immunodeficiency virus J. Med. Virol. 68,479-488[CrossRef][Medline]
    69. 69
  69. Ortiz, G.M., Wellons, M., Brancato, J., Vo, H.T., Zinn, R.L., Clarkson, D.E., Van Loon, K., Bonhoeffer, S., Miralles, G.D., Montefiori, D., Bartlett, J.A., Nixon, D.F. (2001) Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects Proc. Natl. Acad. Sci. USA 98,13288-13293[Abstract/Free Full Text]
    70. 70
  70. Lori, F., Lisziewicz, J. (2001) Structured treatment interruptions for the management of HIV infection JAMA 286,2981-2987[Abstract/Free Full Text]
    71. 71
  71. Zhou, H., Pandak, W. M., Lyall, V., Natarajan, R., Hylemon, P. B. (2005) HIV protease inhibitors activate the unfolded protein response in macrophages: implication for atherosclerosis and cardiovascular disease Mol. Pharmacol. 68,690-700[Abstract/Free Full Text]
    72. 72
  72. Dressman, J., Kincer, J., Matveev, S. V., Guo, L., Greenberg, R. N., Guerin, T., Meade, D., Li, X. A., Zhu, W., Uittenbogaard, A., Wilson, M. E., Smart, E. J. (2003) HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages J. Clin. Invest. 111,389-397[CrossRef][Medline]
    73. 73
  73. Reeves, J. D., Gallo, S. A., Ahmad, N., Miamidian, J., Harvey, P. E., Sharron, M., Pöhlmann, S., Sfakianos, J. N., Derdeyn, C. A., Blumenthal, R., Hunter, E., Doms, R. W. (2002) Sensivity of HIV-1 to entry inihibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics Proc. Natl. Acad. Sci. USA 99,16249-16254[Abstract/Free Full Text]
    74. 74
  74. Mink, M., Greenberg, M. L., Mosier, S. (2002) Impact of HIV-1 gp41 amino acid substitutions (position 36–45) on susceptibility to T20 (Enfuvirtide) in vitro; analysis of primary virus isolates recovered from patients during chronic Enfuvirtide treatment and site-directed mutants in NL4–3 Antivir. Ther. 7,17-18
    75. 75
  75. Greenberg, M., Cammack, N., Salgo, M., Smiley, L. (2004) HIV fusion and its inhibition in antiretroviral therapy Rev. Med. Virol. 14,321-337[CrossRef][Medline]
    76. 76
  76. Miller, M. D., Hazuda, D. J. (2004) HIV resistance to the fusion inhibitor enfuvirtide: mechanisms and clinical implications Drug Resist. Updat. 7,89-95[CrossRef][Medline]
    77. 77
  77. Reeves, J. D., Lee, F. H., Miamidian, J. L., Jabara, C. B., Juntilla, M. M., Doms, R. W. (2005) Enfuvirtide resistance mutations: impact on human immunodeficiency virus envelope function, entry inhibitor sensitivity, and virus neutralization J. Virol. 79,4991-4999[Abstract/Free Full Text]
    78. 78
  78. Aquaro, S., Svicher, V., D’Arrigo, R., Visco-Comandini, U., Antinori, A., Santoro, M., Di Perri, G., Lo Caputo, S., Narciso, P., Perno, C. F. (2006) Characterization of Gp41 evolution in a large cohort of HIV-1-infected patients receiving long-term T-20 treatment as a single active drug. 13th Conference on Retroviruses and Opportunistic Infection, Denver, CO, February 5–8
    79. 79
  79. Alkhatib, G., Combadiere, C., Broder, C. C., Feng, Y., Kennedy, P. E., Murphy, P. M., Berger, E. A. (1996) CCCKR5: a RANTES, MIP-1{alpha}, MIP-1ß receptor as a fusion cofactor for macrophage-tropic HIV-1 Science 272,1955-1958[Abstract]
    80. 80
  80. Weissman, D., Rabin, R. L., Arthos, J., Rubbert, A., Dybul, M., Swofford, R., Venkatesan, S., Farber, J. M., Fauci, A. S. (1997) Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor Nature 389,981-985[CrossRef][Medline]
    81. 81
  81. Tuttle, D. L., 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]
    82. 82
  82. Becker, Y. (2005) The molecular mechanism of human resistance to HIV-1 infectionin persistently infected individuals—a review, hypothesis and implications Virus Genes 31,113-119[CrossRef][Medline]
    83. 83
  83. Glass, W. G., McDermott, D. H., Lim, J. K., Lekhong, S., Yu, S. F., Frank, W. A., Pape, J., Cheshier, R. C., Murphy, P. M. (2006) CCR5 deficiency increases risk of symptomatic West Nile virus infection J. Exp. Med. 203,35-40[Abstract/Free Full Text]
    84. 84
  84. Goulding, C., McManus, R., Murphy, A., MacDonald, G., Barrett, S., Crowe, J., Hegarty, J., McKiernan, S., Kelleher, D. (2005) The CCR5-{Delta}32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source Gut 54,1157-1161[Abstract/Free Full Text]
    85. 85
  85. Dorr, P., Westby, M., Dobbs, S., Griffin, P., Irvine, B., Macatney, M., Mori, J., Rickett, G., Smith-Burchnell, C., Napier, C., Webster, R., Armour, D., Price, D., Stammen, B., Wood, A., Perros, M. (2005) Maraviroc (UK-427,857), a potent, orally bioavailable and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity Antimicrob. Agents Chemother. 49,4721-4732[Abstract/Free Full Text]
    86. 86
  86. Reeves, J. D., Piefer, A. J. (2005) Emerging drug targets for antiretroviral therapy Drugs 65,1747-1766[CrossRef][Medline]
    87. 87
  87. Westby, M., Van der Ryst, E. (2005) CCR5 antagonists: host- targeted antivirals fort he treatment of HIV infection Antivir. Chem. Chemother. 16,339-354[Medline]
    88. 88
  88. Willey, S., Peters, P. J., Sullivan, W. M., Dorr, P., Perros, M., Clapham, P. R. (2005) Inhibition of CCR5-mediated infection by diverse R5 and R5X4 HIV and SIV isolates using novel small molecule inhibitors of CCR5: effects of viral diversity, target cell and receptor density Antiviral Res. 68,96-108[CrossRef][Medline]
    89. 89
  89. Westby, M., Lewis, M., Whitcomb, J., Youle, M., Pozniak, A. L., James, I. T., Jenkins, T. M., Perros, M., Van der Ryst, E. (2006) Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir J. Virol. 80,4909-4920[Abstract/Free Full Text]
    90. 90
  90. Baritaki, S., Dittmar, M. T., Spandidos, D. A., Krambovitis, E. (2005) In vitro inhibition of R5 HIV-1 infectivity by X4 V3-derived synthetic peptides Int. J. Mol. Med. 16,333-336[Medline]
    91. 91
  91. Ruff, M.R., Polianova, M., Yang, Q.E., Leoung, G.S., Ruscetti, F.W., Pert, CB (2003) Update on D-ala-peptide T-amide (DAPTA): a viral entry inhibitor that blocks CCR5 chemokine receptors Curr. HIV Res. 1,51-67[CrossRef][Medline]
    92. 92
  92. Ruff, M. R., Melendez-Guerrero, L. M., Yang, Q. E., Ho, W. Z., Mikovits, J. W., Pert, C. B., Ruscetti, F. A. (2001) Peptide T inhibits HIV-1 infection mediated by the chemokine receptor-5 (CCR5) Antiviral Res. 52,63-75[CrossRef][Medline]
    93. 93
  93. Pollicita, M., Ruff, M., Polianova, M., Pert, C., Ranazzi, A., Perno, C. F., Aquaro, S. (2006) Anti-HIV-1 and anti-apoptotic effects of D-ala-peptide T-amide in human macrophages and in a neuronal cell line. 13th Conference on Retroviruses and Opportunistic Infection, Denver, CO, February 5–8
    94. 94
  94. Trkola, A., Ketas, T. J., Nagashima, K. A., Zhao, L., Cilliers, T., Morris, L., Moore, J. P., Maddon, P. J., Olson, W. C. (2001) Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140 J. Virol. 75,579-588[Abstract/Free Full Text]
    95. 95
  95. Chen, X., Yang, L., Zhang, N., Turpin, J. A., Buckheit, R. W., Osterling, C., Oppenheim, J. J., Howard, O. M. (2003) Shikonin, a component of Chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1 Antimicrob. Agents Chemother. 47,2810-2816[Abstract/Free Full Text]
    96. 96
  96. Balzarini, J., Van Laethem, K., Hatse, S., Froeyen, M., Peumans, W., Van Damme, E., Schols, D. (2005) Carbohydrate-binding agents cause deletions of highly conserved glycosylation sites in HIV GP120. A new therapeutic concept to hit the Achilles heel of HIV J. Biol. Chem. 280,41005-41014[Abstract/Free Full Text]
    97. 97
  97. Balzarini, J., Hatse, S., Vermeire, K., Princen, K., Aquaro, S., Perno, C. F., De Clercq, E., Egberink, H., Vanden Mooter, G., Peumans, W., Van Damme, E., Schols, D. (2004) Mannose-specific plant lectins from the Amaryllidaceae family qualify as efficient microbicides for prevention of human immunodeficiency virus infection Antimicrob. Agents Chemother. 48,3858-3870[Abstract/Free Full Text]
    98. 98
  98. Balzarini, J. (2005) Targeting the glycans of gp120: a novel therapeutic approach aimed at the Achilles heel of HIV Lancet Infect. Dis. 5,726-731[CrossRef][Medline]
    99. 99
  99. Watanabe, N., Nishihara, Y., Yamaguchi, T., Koito, A., Miyoshi, H., Kakeya, H., Osada, H. (2006) Fumagillin suppresses HIV-1 infection of macrophages through the inhibition of Vpr activity FEBS Lett. 580,2598-2602[CrossRef][Medline]
    100. 100
  100. Ewart, G. D., Nasr, N., Naif, H., Cox, G. B., Cunningham, A. L., Gage, P. W. (2004) Potential new anti-human immunodeficiency virus type 1 compounds depress virus replication in cultured human macrophages Antimicrob. Agents Chemother. 48,2325-2330[Abstract/Free Full Text]
    101. 101
  101. Haffar, O., Dubrovsky, L., Lowe, R., Berro, R., Kashanchi, F., Godden, J., Vanpouille, C., Bajorath, J., Bukrinsky, M. (2005) Oxadiazols: a new class of rationally designed anti-human immunodeficiency virus compounds targeting the nuclear localization signal of the viral matrix protein J. Virol. 79,13028-13036[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Exp. Biol. Med.Home page
M. Eilers, U. Roy, and D. Mondal
MRP (ABCC) Transporters-Mediated Efflux of Anti-HIV Drugs, Saquinavir and Zidovudine, from Human Endothelial Cells
Experimental Biology and Medicine, September 1, 2008; 233(9): 1149 - 1160.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
L. J. Montaner, S. M. Crowe, S. Aquaro, C.-F. Perno, M. Stevenson, and R. G. Collman
Advances in macrophage and dendritic cell biology in HIV-1 infection stress key understudied areas in infection, pathogenesis, and analysis of viral reservoirs
J. Leukoc. Biol., November 1, 2006; 80(5): 961 - 964.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.0606376v1
80/5/1103    most recent
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 Aquaro, S.
Right arrow Articles by Perno, C. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aquaro, S.
Right arrow Articles by Perno, C. F.