Are T cells the only HIV-1 reservoir?
© The Author(s) 2016
Received: 2 August 2016
Accepted: 29 November 2016
Published: 20 December 2016
Current antiretroviral therapies have improved the duration and quality of life of people living with HIV-1. However, viral reservoirs impede complete eradication of the virus. Although there are many strategies to eliminate infectious virus, the most actively pursued are latency reversing agents in conjunction with immune modulation. This strategy, known as “shock and kill”, has been tested primarily against the most widely recognized HIV-1 latent reservoir found in resting memory CD4+ T cells. This is in part because of the dearth of conclusive evidence about the existence of non-T cell reservoirs. Studies of non-T cell reservoirs have been difficult to interpret because of technical and biological issues that have hampered a better understanding. This review considers the current knowledge of non-T cell reservoirs, the challenges encountered in a better understanding of these populations, and their implications for HIV-1 cure research.
KeywordsHIV-1 Eradication Reservoirs Non-T cells Challenges
In the twenty years since combination antiretroviral therapy (ART) for HIV-1 was first announced, people living with HIV-1 (PLWH) have had marked improvements in mortality and quality of life. However, whereas ART is remarkably effective at preventing new cells from becoming infected, it does not eliminate long-lived cells that are already infected prior to ART initiation. Latent reservoirs have thwarted attempts to eliminate all replication competent forms of the virus from infected individuals [1–6].
There is reason for balanced optimism in the HIV-1 cure field. The ‘Berlin’ and ‘Boston’ patients who underwent bone marrow transplants from donors lacking one or both copies of full-length CCR5, a key HIV-1 entry co-receptor, had prolonged remissions without evidence of HIV-1; in the case of the ‘Berlin’ patient, there is still no evidence of HIV-1 since his transplant [7, 8]. The ‘Mississippi Baby’ and results of the VISCONTI study highlight the possibility of long drug-free remission periods if ART is initiated during primary infection [1, 2, 7, 9–11]. Central to each case of a potential cure or ART-free remission has been a reduction in the size of the HIV-1 reservoir. Therefore, it is critical for cure strategies to target all potential reservoirs.
Many cells are susceptible to HIV-1 in vitro, but not all potential reservoirs have been studied in vivo during ART with the same rigor. Resting memory CD4+ T cells are the most widely recognized and best-described HIV-1 reservoir in research that has been extensively reviewed elsewhere [12, 13]. For cells to constitute an HIV-1 reservoir, they have to harbor replication competent forms of the virus that persist for years despite long-term ART suppression of viremia . Against the standard of the T cell reservoir, in this review we consider evidence suggesting the possible long-term persistence of non-T cell reservoirs in individuals on ART, and the current challenges involved in their identification.
Usual and unusual suspects
Summary data on HIV-1 reservoirs and assays in various cell populations
Memory CD4+ T cells
Yes (gold standard) 
Has VOA been applied to PLWH taking long-term ART?
Yes (gold standard) 
Has HIV-1 been demonstrated in the indicated cell type in PLWH taking long-term ART?
Yes (gold standard) 
Is HIV in this reservoir replication competent?
Yes (gold standard) 
Available animal models?
Have animal models been studied during long-term ART?
Do animal models with suppressed viremia contain replication competent HIV-1?
Longevity or T½ of uninfected cells
2–3 days 
≥24–36 months b
Longevity or T½ of reservoir in this cell type
44 months a
9 months c
Macrophages and myeloid cells
Found primarily in tissues, macrophages are mononuclear leukocytes that are key components of innate immunity. For decades, the origin of tissue resident macrophages (TRM) was explained by the concept of the mononuclear-phagocyte system: monocytes were thought to continually replenish TRM that died in tissues [34, 35]. Consistent with this early concept, the death of HIV-1 infected macrophages was thought to be responsible for the second phase of HIV-1 viral kinetic decline during ART. However, recent findings based on murine models suggest that the principal origin of TRM in steady state is from embryonic haematopoietic precursors, while monocytes only contribute in the setting of inflammation and injury . Similarly, detection of TRM even in individuals with monocytopenia suggests monocyte-independent maintenance, a long half-life of embryonically derived macrophages, or likely a combination of both . Studies in patients who received lung transplantation have also shown long-term persistence of donor alveolar macrophages . In parallel, the rapid second phase decline of HIV-1 was found not to be attributable to macrophages . Taken together, these findings have led to a marked revision in our understanding of the maintenance and longevity of TRM.
It is well established in animal models and in vitro that macrophages can be productively infected by lab strains of HIV-1 [39, 40], although there may be anatomical variation in their susceptibility to HIV-1 infection. For example, there are reports of HIV-1 and SIV in brain macrophages such as microglia [41, 42]. Vaginal macrophages have been shown to support HIV-1 replication better than intestinal macrophages, which may be explained by differential expression of entry co-receptors . Comparative in situ fluorescence also suggests higher HIV-1 susceptibility of rectal macrophages compared to colonic macrophages . Cai et al. have shown that SIV infection of lung macrophages leads to preferential destruction of interstitial macrophages, in comparison to alveolar macrophages that experience minimal cell death and low turnover .
Several reports in the pre-ART era demonstrated HIV-1 infection in TRM [46–50]. More recently alveolar macrophages from individuals on ART have been shown to harbor HIV-1 nucleic acids (both proviral DNA and RNA) . Our lab has extended earlier studies of liver macrophages (Kupffer cells), the largest population of TRM in the body, to show that these cells can harbor virus from individuals on ART for as long as 11 years, although their functional significance is still unclear . Other tissue macrophages that have also been implicated as harboring HIV-1 include those in the seminal vesicle, duodenum, urethra, adipose tissue, and liver [25, 46, 52–55].
The study of HIV-1 infection of macrophages is not without controversy. Recent in vivo data from an SIV macaque model has demonstrated the presence of both proviral DNA and T cell receptors (TCR) in myeloid cells: the authors concluded that the presence of viral DNA in macrophages was due to phagocytosis of infected dying cell rather than de novo infection of myeloid cells . However, a subsequent report by Baxter et al. showed that primary monocyte-derived macrophages could selectively capture HIV-1 infected CD4+ T cells, leading to macrophage infection along with efficient HIV-1 cell-to-cell spread . Indeed, others and we have confirmed the exclusion of T cells and TCRs in ex vivo studies of TRM reservoirs [25, 58]. Thus it is important to differentiate between phagocytosis and actual infection of macrophages following detection of nucleic acids in macrophages. In addition, it is clear from in vitro studies that HIV-1 replication dynamics differ in myeloid cells compared to CD4+ T cells: virions can be found dwelling for prolonged periods in long cytoplasmic channels in macrophages and are not immediately released, in contrast to the typical burst that has been described in CD4+ T cells .
Monocytes, closely related myeloid cells, were initially reported as being infected in vivo; however, it has now been shown that monocytes are not susceptible to HIV-1, and largely lack proviral HIV-1 DNA in both viremic and ART suppressed individuals [24, 60].
Dendritic cells (DCs) are a heterogeneous group of antigen-presenting cells that play vital roles in orchestrating immune responses . DCs can be broadly divided into those of myeloid or lymphoid origin , and further categorized as plasmacytoid (pDCs), myeloid (mDCs), Langerhans cells (found in the epidermis), and interstitial .
Although DCs comprise a small proportion of cells in various anatomical sites , their role as immunologic sentries makes them among the first cells that encounter invading pathogens like HIV-1. Indeed, analyses of transmitted/founder viruses have shown that they have enhanced binding to mDCs compared to viruses isolated from chronic infection, a feature that may facilitate virus transport across the mucosa [65, 66].
pDCs and mDCs have been noted to have differential susceptibility to HIV-1 infection, although this has largely been ascertained in vitro [67–69]. In vivo, the presence of HIV-1 DNA in DCs has been noted to occur at lower frequency compared to CD4+ T cells [70, 71]. There have been several reports of productive HIV-1 infection of DCs in vitro for as long as 45 days [72–75], but limited data in vivo. Langerhans cells have been considered as a potential reservoir, but largely based on data in the pre-ART era [76, 77].
To fulfill their role as a reservoir, DCs have been posited to transfer infection to T cells, in particular to antigen specific CD4+ T cells, following their encounter with HIV-1, whether or not they themselves are infected [78–80]. This infection in trans is mediated by the formation of an infectious/virological synapse . During trans infection, compartmentalized HIV-1 has been observed to emerge from DCs and fuse with the T cell membrane . Envelope specific inhibitors maintain their potency against these compartmentalized virions . These are tantalizing hypotheses that have been difficult to find evidence for in vivo.
Follicular dendritic cells
Follicular dendritic cells (FDCs) that are found in B cell follicles in secondary lymphoid organs are not typical DCs, although they are similarly named: FDCs develop from perivascular precursors of stromal cell origin and are not known to present antigens using MHC-restricted pathways [26, 64].
FDCs can potentially serve as viral reservoirs by maintaining a stable pool of HIV-1 on their surface without being infected [82, 83]. In vitro studies have revealed that HIV-1 virions adhere on the surface of FDCs through interactions with complement receptors mediated via a C3-dependent mechanism . The binding of C3 fragments to the virus allows its adherence to complement receptors CR1 and CR2, present on FDCs . In addition, the presence of non-neutralizing antibodies specific for HIV-1 in patients may enhance binding to FDCs via FcR-mediated binding .
HIV-1 has been known to persist on these cells even in the presence of neutralizing antibodies, with reports suggesting that FDCs can restore the infectivity of neutralized viruses [85, 86]. FDCs transfer antigens in the B cell follicles of all secondary lymphoid tissues, and in the process may transfer HIV-1 to T follicular helper cells that are also present in the B cell follicles .
In mice, FDCs have been shown to trap HIV-1 following a single exposure, and these virions remained infectious for at least 9 months . A recent study reported visualization of HIV-1 in cycling endosomes in FDCs isolated from individuals on prolonged ART (median = 8 years) . Mathematical models have suggested that FDCs are the major contributor to the low-level viremia detected during the third phase of viral decay, and have been estimated to have a half-life of 39 months .
There have been reports suggesting the possible infection and transmission of infection by epithelial cells even though they do not express CD4 and have undetectable or low expression of the co-receptors CCR5and CXCR4 [88, 89]. Renal epithelial cells have been reported to be susceptible to HIV-1 in vitro . Cultures of renal tubule epithelial cells were productively infected by HIV-1 following co-culture with infected T cells . Transmission of infection was observed to occur by formation of virological synapses . HIV-1 mRNA and DNA have also been detected in renal tubular epithelial cells using in situ hybridization done on biopsies obtained from individuals with HIV-1 associated nephropathy . Phylogenetic analyses of sequences obtained from renal epithelial cells were found to cluster together within the radiation of sequences obtained from peripheral blood mononuclear cells . These cells could play a role in persistence of HIV-1 infection in individuals on ART based on indirect evidence [94, 95].
Mammary epithelial cells have been conjectured to harbor a separate compartment of HIV-1: phlyogenetic analyses of HIV-1 DNA from paired breast-milk and peripheral blood samples from HIV-1 infected women have shown the existence of genetically distinct compartments [96, 97]. Studies of breast-milk from HIV-1 infected women on treatment have shown negligible impact of ART on cell-associated or HIV-1 proviral DNA levels, in contrast with a rapid decline in cell-free HIV-1 RNA [98, 99].
Similar to DCs, oral keratinocytes have been shown to support transmission of virus to susceptible cells without supporting replication [100, 101]. However there is no evidence that these cells serve as HIV-1 reservoirs, and there are no published data on the half-life of epithelial cells in vivo in this context.
Kong et al. have reported detection of integrated HIV-1 DNA and release of infectious virus in liver epithelium following in vitro infection of hepatocyte cell lines and primary hepatocytes . In addition, hepatic stellate cells have also been shown to release infectious virus following infection in vitro . However, the translation of this research to studies of in vivo reservoirs has been more challenging, and data are lacking.
There have been isolated reports of other cells that can possibly be infected with HIV-1. Fibrocytes, defined as CD34+CD45+ collagen I+, have recently been reported to have characteristics of cells that can be persistently infected . In vitro, infected fibrocytes resisted HIV-1 induced cell death and stably expressed low levels of HIV-1 mRNA for >60 days. However, there are no data on whether fibrocytes are HIV-1 infected in vivo .
Other cell types that could be explored as HIV-1 reservoirs in individuals on ART include astrocytes in the CNS and CD56+/CD3− NK cells [105–107]. Hematopoietic progenitor cells (HPCs) that were initially reported to harbor infectious virus are now not considered to fulfill the criteria to be a reservoir following development of enhanced techniques to purify HSCs from bone marrow [108, 109].
Challenges in studying non-T cell reservoirs
In ART-suppressed individuals the number of latently infected T cell varies from 1 to 10 infectious units per million (IUPM) . Estimation of these numbers in ART-suppressed individuals requires isolation of millions of cells from large volume blood draws . Similar studies on cells from HIV-1 infected people that have low or absent numbers in circulation, or that are principally found in tissues, have been technically challenging or unethical [25, 51].
The gold standard for quantifying the amount of replication competent HIV-1 in a purified population of cells during ART has been the quantitative viral outgrowth assay (QVOA), which was initially developed to measure the amount of latent HIV-1 infection in resting memory CD4+ T cells [23, 112]. The potency of the QVOA is that it hinges on the recovery of infectious, replication competent HIV-1 that propagates exponentially, plausibly explaining the virological rebound seen in patients who discontinue ART. The QVOA is a highly consistent assay, but nonetheless poses a number of technical challenges, including that it is expensive, time-consuming, requires large amounts of starting materials, has a limited dynamic range, and underestimates the size of the latent reservoir [111–113]. Several groups have employed PCR-based approaches as alternative tools . PCR-based assays sensitively detect viral nucleic acid over a large dynamic range, and can differentiate between total, integrated, and LTR HIV-1 DNA [114, 115]. Although easier, PCR-based approaches do not differentiate between replication competent and defective viruses, of which the latter constitute the majority of viral forms, and do not correlate well with the number of cells with replication competent virus . PCR-based approaches typically yield infected cell frequencies that are 100–1000 times higher than what is resulted from the QVOA . More recently, an approach called the TILDA (Tat/rev Induced Limiting Dilution Assay) that measures multiply spliced HIV-1 RNA was developed as an alternative . This assay has a quick turnaround time and requires fewer than a million cells of starting material. However, the TILDA does not measure virus production and does not address whether measured RNAs derive from replication competent viruses [116, 117]. Moreover, the TILDA correlates poorly with the QVOA when performed on the same samples .
Therefore, as of now the most accurate measurement of the replication competent viral reservoir requires the QVOA, limiting the quantification of HIV-1 reservoirs in tissues that are poorly accessible. However, an overlooked challenge of using the QVOA is that it has been specifically “tuned” to CD4+ T cells, and may not be sensitive for detecting infection in cells that bear different HIV-1 replication dynamics than CD4+ T cells. Recent advances in adapting the QVOA to macrophages are steps in the right direction for quantifying these HIV-1 reservoirs .
To address the challenges posed in isolating a large number of these cells to study latency, the field has resorted to the use of alternate models that complement each other—in vitro, animal, and mathematical models [22, 58, 118, 119]. Although more feasible, these approaches have their drawbacks. In vitro models are used frequently because of their convenience, but do not fully mimic in vivo infections. [64, 120]. Similarly, heterogeneous cell phenotypes can be observed in in vitro models, such as in monocyte-derived macrophages (MDMs) subpopulations [121–123]. Fundamentally, HIV-1 susceptibility and longevity in vitro may be quite different than in the immunological context of natural infection. Hence, in vitro modeling can only be used to complement findings in vivo.
Non-human primates (NHP) and humanized mice models have been invaluable for understanding HIV-1 pathogenesis [24, 27, 58]. NHP are typically infected either with simian immunodeficiency virus (SIV) or SIV/HIV-1 chimeric viruses (SHIV) [27, 124]. However, SIV and HIV-1 have notable distinctions, sharing only approximately 53% sequence homology and differing in the organization of their overlapping ORFs . For instance, sooty mangabey SIV (SIVsmm) and macaque SIV (SIVmac) lack the HIV-1 accessory gene vpu. Instead, they encode for vpx, which may be a critical difference: vpx degrades SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1), a key retroviral restriction factor in macrophages and DCs [125, 126]. Nevertheless, SIV infection of NHP remains a key experimental tool, especially for in vivo and ex vivo studies of tissues that are inaccessible in humans, such as the brain.
Recent advances in humanized mouse technology have facilitated their infection with HIV-1 [127–129]. A recent humanized model referred to as myeloid-only-mice (MoM), developed from NOD/SCID mice, has been very useful to study infection and persistence in non-T cells [24, 130]. These mice lack T cells, and are developed by adoptive transfer of human CD34+ stem cells, enabling reconstitution of the mouse with human monocytes, macrophages, B cells, and dendritic cells [24, 130]. However, a major hurdle impeding more widespread use of humanized mice is that each experiment requires the surgical engraftment of human tissue, since this aspect cannot be bred . A promising and creative use of humanized mice is in the development of a murine viral outgrowth assay where HIV-1 latency is estimated by adoptive transfer of human cells into humanized mice .
Whereas promising improvements to antiretroviral therapy have improved the quality of life of PLWH, they have not bridged the gap toward an HIV-1 cure . Although it has been debated whether resources for HIV-1 research should be focused on a cure when there are other challenges facing PLWH, we argue that latent reservoirs harbor the potential for high-level virologic rebound in each of the 37 million HIV-1 infected people worldwide, which bears both individual and public harm. Indeed, we further argue that without exploring the true extent of HIV-1 reservoirs with the same rigor as has been used to study peripheral resting memory CD4+ T cells, we risk developing incomplete cure strategies [18, 110]. The current “shock and kill” strategy hinges on the drugs known as latency reversing agents (LRAs) that induce viral production in latently-infected cells [13, 133–135]. Presently, however, latency reversal has been developed to be specific for CD4+ T cell biology, and does not account for the possibility of persistent reservoirs in cells other than T cells [136, 137], reflecting lacunae in our understanding of non-T cell reservoirs . Therefore, a dedicated strategy to eliminate HIV-1 reservoirs requires a better understanding of the role of non-T cell reservoirs using in vivo and ex vivo experimentation.
people living with HIV-1
tissue resident macrophages
T cell receptors
plasmacytoid dendritic cells
myeloid dendritic cells
follicular dendritic cells
hematopoietic progenitor cells
infectious units per million
quantitative viral outgrowth assay
Tat/rev Induced Limiting Dilution Assay
simian immunodeficiency virus
SIV/HIV-1 chimeric viruses
sooty mangabey SIV
SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1
latency reversing agents
AJK prepared the figures and wrote the manuscript. SS assisted with writing of the manuscript. AB wrote and supervised preparation of the manuscript. All the authors read and approved the final manuscript.
We would like to thank David L. Thomas for helpful discussions and critical review of our manuscript.
The authors declare that they have no competing interests.
AB and SS was supported by NIH/NIAID Grants R56 AI118445, NIH/NIDA Grant R01 DA016078, and The Johns Hopkins Center for AIDS Research (JHU CFAR) P30AI094189-01A1.
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- Luzuriaga K, Gay H, Ziemniak C, Sanborn KB, Somasundaran M, Rainwater-Lovett K, Mellors JW, Rosenbloom D, Persaud D. Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med. 2015;372:786–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, Robles YP, Davis BT, Li JZ, Heisey A, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014;161:319–27.PubMedPubMed CentralView ArticleGoogle Scholar
- Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278:1295–300.PubMedView ArticleGoogle Scholar
- Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5:512–7.PubMedView ArticleGoogle Scholar
- Montaner JS, Lima VD, Harrigan PR, Lourenco L, Yip B, Nosyk B, Wood E, Kerr T, Shannon K, Moore D, et al. Expansion of HAART coverage is associated with sustained decreases in HIV/AIDS morbidity, mortality and HIV transmission: the “HIV Treatment as Prevention” experience in a Canadian setting. PLoS ONE. 2014;9:e87872.PubMedPubMed CentralView ArticleGoogle Scholar
- Panos G, Samonis G, Alexiou VG, Kavarnou GA, Charatsis G, Falagas ME. Mortality and morbidity of HIV infected patients receiving HAART: a cohort study. Curr HIV Res. 2008;6:257–60.PubMedView ArticleGoogle Scholar
- Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, Schneider T, Hofmann J, Kucherer C, Blau O, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360:692–8.PubMedView ArticleGoogle Scholar
- Brown TR. I am the Berlin patient: a personal reflection. AIDS Res Hum Retrovir. 2015;31:2–3.PubMedPubMed CentralView ArticleGoogle Scholar
- Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, Potard V, Versmisse P, Melard A, Prazuck T, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9:e1003211.PubMedPubMed CentralView ArticleGoogle Scholar
- Cillo AR, Mellors JW. Which therapeutic strategy will achieve a cure for HIV-1? Curr Opin Virol. 2016;18:14–9.PubMedView ArticleGoogle Scholar
- Martin AR, Siliciano RF. Progress toward HIV eradication: case reports, current efforts, and the challenges associated with cure. Annu Rev Med. 2016;67:215–28.PubMedView ArticleGoogle Scholar
- Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, Lloyd AL, Nowak MA, Fauci AS. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA. 1997;94:13193–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Churchill MJ, Deeks SG, Margolis DM, Siliciano RF, Swanstrom R. HIV reservoirs: what, where and how to target them. Nat Rev Microbiol. 2016;14:55–60.PubMedView ArticleGoogle Scholar
- Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity. 2012;37:377–88.PubMedPubMed CentralView ArticleGoogle Scholar
- Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med. 2011;1:a007096.PubMedPubMed CentralView ArticleGoogle Scholar
- Blankson JN, Persaud D, Siliciano RF. The challenge of viral reservoirs in HIV-1 infection. Annu Rev Med. 2002;53:557–93.PubMedView ArticleGoogle Scholar
- Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med. 1995;1:1284–90.PubMedView ArticleGoogle Scholar
- Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, Kovacs C, Gange SJ, Siliciano RF. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003;9:727–8.PubMedView ArticleGoogle Scholar
- Soriano-Sarabia N, Archin NM, Bateson R, Dahl NP, Crooks AM, Kuruc JD, Garrido C, Margolis DM. Peripheral Vγ9Vδ2 T cells are a novel reservoir of latent HIV infection. PLoS Pathog. 2015;11:e1005201.PubMedPubMed CentralView ArticleGoogle Scholar
- Buzon MJ, Sun H, Li C, Shaw A, Seiss K, Ouyang Z, Martin-Gayo E, Leng J, Henrich TJ, Li JZ, et al. HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat Med. 2014;20:139–42.PubMedPubMed CentralView ArticleGoogle Scholar
- Miles B, Connick E. TFH in HIV latency and as sources of replication-competent virus. Trends Microbiol. 2016;24:338–44.PubMedView ArticleGoogle Scholar
- Zhang J, Perelson AS. Contribution of follicular dendritic cells to persistent HIV viremia. J Virol. 2013;87:7893–901.PubMedPubMed CentralView ArticleGoogle Scholar
- Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES, Bosch RJ, Lai J, Chioma S, Emad F, et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog. 2013;9:e1003174.PubMedPubMed CentralView ArticleGoogle Scholar
- Honeycutt JB, Wahl A, Baker C, Spagnuolo RA, Foster J, Zakharova O, Wietgrefe S, Caro-Vegas C, Madden V, Sharpe G, et al. Macrophages sustain HIV replication in vivo independently of T cells. J Clin Invest. 2016;126:1353–66.PubMedPubMed CentralView ArticleGoogle Scholar
- Kandathil AJ, Durand CM, Quinn J, Cameron A, Thomas DL, Balagopal A. Liver macrophages and HIV-1 persistence. In: CROI. Seattle; 2015.
- Heesters BA, Myers RC, Carroll MC. Follicular dendritic cells: dynamic antigen libraries. Nat Rev Immunol. 2014;14:495–504.PubMedView ArticleGoogle Scholar
- Denton PW, Sogaard OS, Tolstrup M. Using animal models to overcome temporal, spatial and combinatorial challenges in HIV persistence research. J Transl Med. 2016;14:44.PubMedPubMed CentralView ArticleGoogle Scholar
- Sacha JB, Ndhlovu LC. Strategies to target non-T-cell HIV reservoirs. Curr Opin HIV AIDS. 2016;11:376–82.PubMedView ArticleGoogle Scholar
- Farber DL, Yudanin NA, Restifo NP. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol. 2014;14:24–35.PubMedView ArticleGoogle Scholar
- De Boer RJ, Perelson AS. Quantifying T lymphocyte turnover. J Theor Biol. 2013;327:45–87.PubMedPubMed CentralView ArticleGoogle Scholar
- Ziegler-Heitbrock HW. Definition of human blood monocytes. J Leukoc Biol. 2000;67:603–6.PubMedGoogle Scholar
- Nayak DK, Zhou F, Xu M, Huang J, Tsuji M, Hachem R, Mohanakumar T. Long-term persistence of donor alveolar macrophages in human lung transplant recipients that influences donor specific immune responses. Am J Transpl. 2016;16:2300–11.View ArticleGoogle Scholar
- McDonald D, Wu L, Bohks SM, KewalRamani VN, Unutmaz D, Hope TJ. Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science. 2003;300:1295–7.PubMedView ArticleGoogle Scholar
- van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med. 1968;128:415–35.PubMedPubMed CentralView ArticleGoogle Scholar
- van Furth R, Cohn ZA, Hirsch JG, Humphrey JH, Spector WG, Langevoort HL. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull World Health Organ. 1972;46:845–52.PubMedPubMed CentralGoogle Scholar
- Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14:392–404.PubMedView ArticleGoogle Scholar
- Bigley V, Haniffa M, Doulatov S, Wang XN, Dickinson R, McGovern N, Jardine L, Pagan S, Dimmick I, Chua I, et al. The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency. J Exp Med. 2011;208:227–34.PubMedPubMed CentralView ArticleGoogle Scholar
- Spivak AM, Rabi SA, McMahon MA, Shan L, Sedaghat AR, Wilke CO, Siliciano RF. Short communication: dynamic constraints on the second phase compartment of HIV-infected cells. AIDS Res Hum Retrovir. 2011;27:759–61.PubMedPubMed CentralView ArticleGoogle Scholar
- Gartner S, Markovits P, Markovitz DM, Kaplan MH, Gallo RC, Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986;233:215–9.PubMedView ArticleGoogle Scholar
- Igarashi T, Brown CR, Endo Y, Buckler-White A, Plishka R, Bischofberger N, Hirsch V, Martin MA. Macrophage are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4+ T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): implications for HIV-1 infections of humans. Proc Natl Acad Sci USA. 2001;98:658–63.PubMedPubMed CentralView ArticleGoogle Scholar
- Churchill MJ, Gorry PR, Cowley D, Lal L, Sonza S, Purcell DF, Thompson KA, Gabuzda D, McArthur JC, Pardo CA, Wesselingh SL. Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues. J Neurovirol. 2006;12:146–52.PubMedView ArticleGoogle Scholar
- Thompson KA, Cherry CL, Bell JE, McLean CA. Brain cell reservoirs of latent virus in presymptomatic HIV-infected individuals. Am J Pathol. 2011;179:1623–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Shen R, Richter HE, Clements RH, Novak L, Huff K, Bimczok D, Sankaran-Walters S, Dandekar S, Clapham PR, Smythies LE, Smith PD. Macrophages in vaginal but not intestinal mucosa are monocyte-like and permissive to human immunodeficiency virus type 1 infection. J Virol. 2009;83:3258–67.PubMedPubMed CentralView ArticleGoogle Scholar
- McElrath MJ, Smythe K, Randolph-Habecker J, Melton KR, Goodpaster TA, Hughes SM, Mack M, Sato A, Diaz G, Steinbach G, et al. Comprehensive assessment of HIV target cells in the distal human gut suggests increasing HIV susceptibility toward the anus. J Acquir Immune Defic Syndr. 2013;63:263–71.PubMedPubMed CentralView ArticleGoogle Scholar
- Cai Y, Sugimoto C, Arainga M, Midkiff CC, Liu DX, Alvarez X, Lackner AA, Kim WK, Didier ES, Kuroda MJ. Preferential destruction of interstitial macrophages over alveolar macrophages as a cause of pulmonary disease in simian immunodeficiency virus-infected rhesus macaques. J Immunol. 2015;195:4884–91.PubMedPubMed CentralView ArticleGoogle Scholar
- Cao YZ, Dieterich D, Thomas PA, Huang YX, Mirabile M, Ho DD. Identification and quantitation of HIV-1 in the liver of patients with AIDS. AIDS. 1992;6:65–70.PubMedView ArticleGoogle Scholar
- Kure K, Lyman WD, Weidenheim KM, Dickson DW. Cellular localization of an HIV-1 antigen in subacute AIDS encephalitis using an improved double-labeling immunohistochemical method. Am J Pathol. 1990;136:1085–92.PubMedPubMed CentralGoogle Scholar
- Lebargy F, Branellec A, Deforges L, Bignon J, Bernaudin JF. HIV-1 in human alveolar macrophages from infected patients is latent in vivo but replicates after in vitro stimulation. Am J Respir Cell Mol Biol. 1994;10:72–8.PubMedView ArticleGoogle Scholar
- Hufert FT, Schmitz J, Schreiber M, Schmitz H, Racz P, von Laer DD. Human Kupffer cells infected with HIV-1 in vivo. J Acquir Immune Defic Syndr. 1993;6:772–7.PubMedGoogle Scholar
- Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, Hermankova M, Chadwick K, Margolick J, Quinn TC, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997;387:183–8.PubMedView ArticleGoogle Scholar
- Cribbs SK, Lennox J, Caliendo AM, Brown LA, Guidot DM. Healthy HIV-1-infected individuals on highly active antiretroviral therapy harbor HIV-1 in their alveolar macrophages. AIDS Res Hum Retrovir. 2015;31:64–70.PubMedPubMed CentralView ArticleGoogle Scholar
- Deleage C, Moreau M, Rioux-Leclercq N, Ruffault A, Jegou B, Dejucq-Rainsford N. Human immunodeficiency virus infects human seminal vesicles in vitro and in vivo. Am J Pathol. 2011;179:2397–408.PubMedPubMed CentralView ArticleGoogle Scholar
- Zalar A, Figueroa MI, Ruibal-Ares B, Bare P, Cahn P, de Bracco MM, Belmonte L. Macrophage HIV-1 infection in duodenal tissue of patients on long term HAART. Antiviral Res. 2010;87:269–71.PubMedView ArticleGoogle Scholar
- Ganor Y, Zhou Z, Bodo J, Tudor D, Leibowitch J, Mathez D, Schmitt A, Vacher-Lavenu MC, Revol M, Bomsel M. The adult penile urethra is a novel entry site for HIV-1 that preferentially targets resident urethral macrophages. Mucosal Immunol. 2013;6:776–86.PubMedView ArticleGoogle Scholar
- Damouche A, Lazure T, Avettand-Fenoel V, Huot N, Dejucq-Rainsford N, Satie AP, Melard A, David L, Gommet C, Ghosn J, et al. Adipose tissue is a neglected viral reservoir and an inflammatory site during chronic HIV and SIV infection. PLoS Pathog. 2015;11:e1005153.PubMedPubMed CentralView ArticleGoogle Scholar
- Calantone N, Wu F, Klase Z, Deleage C, Perkins M, Matsuda K, Thompson EA, Ortiz AM, Vinton CL, Ourmanov I, et al. Tissue myeloid cells in SIV-infected primates acquire viral DNA through phagocytosis of infected T cells. Immunity. 2014;41:493–502.PubMedPubMed CentralView ArticleGoogle Scholar
- Baxter AE, Russell RA, Duncan CJ, Moore MD, Willberg CB, Pablos JL, Finzi A, Kaufmann DE, Ochsenbauer C, Kappes JC, et al. Macrophage infection via selective capture of HIV-1-infected CD4+ T cells. Cell Host Microbe. 2014;16:711–21.PubMedPubMed CentralView ArticleGoogle Scholar
- Avalos CR, Price SL, Forsyth ER, Pin JN, Shirk EN, Bullock BT, Queen SE, Li M, Gellerup D, O’Connor SL, et al. Quantitation of productively infected monocytes and macrophages of SIV-infected macaques. J Virol. 2016;90:5643–56.PubMedPubMed CentralView ArticleGoogle Scholar
- Bennett AE, Narayan K, Shi D, Hartnell LM, Gousset K, He H, Lowekamp BC, Yoo TS, Bliss D, Freed EO, Subramaniam S. Ion-abrasion scanning electron microscopy reveals surface-connected tubular conduits in HIV-infected macrophages. PLoS Pathog. 2009;5:e1000591.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhu T, Muthui D, Holte S, Nickle D, Feng F, Brodie S, Hwangbo Y, Mullins JI, Corey L. Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy. J Virol. 2002;76:707–16.PubMedPubMed CentralView ArticleGoogle Scholar
- Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52.PubMedView ArticleGoogle Scholar
- Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811.PubMedView ArticleGoogle Scholar
- Lambotin M, Raghuraman S, Stoll-Keller F, Baumert TF, Barth H. A look behind closed doors: interaction of persistent viruses with dendritic cells. Nat Rev Microbiol. 2010;8:350–60.PubMedPubMed CentralView ArticleGoogle Scholar
- Wu L, KewalRamani VN. Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol. 2006;6:859–68.PubMedPubMed CentralView ArticleGoogle Scholar
- Shen R, Kappes JC, Smythies LE, Richter HE, Novak L, Smith PD. Vaginal myeloid dendritic cells transmit founder HIV-1. J Virol. 2014;88:7683–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Parrish NF, Gao F, Li H, Giorgi EE, Barbian HJ, Parrish EH, Zajic L, Iyer SS, Decker JM, Kumar A, et al. Phenotypic properties of transmitted founder HIV-1. Proc Natl Acad Sci USA. 2013;110:6626–33.PubMedPubMed CentralView ArticleGoogle Scholar
- Smed-Sorensen A, Lore K, Vasudevan J, Louder MK, Andersson J, Mascola JR, Spetz AL, Koup RA. Differential susceptibility to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells. J Virol. 2005;79:8861–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Groot F, van Capel TM, Kapsenberg ML, Berkhout B, de Jong EC. Opposing roles of blood myeloid and plasmacytoid dendritic cells in HIV-1 infection of T cells: transmission facilitation versus replication inhibition. Blood. 2006;108:1957–64.PubMedView ArticleGoogle Scholar
- Patterson S, Rae A, Hockey N, Gilmour J, Gotch F. Plasmacytoid dendritic cells are highly susceptible to human immunodeficiency virus type 1 infection and release infectious virus. J Virol. 2001;75:6710–3.PubMedPubMed CentralView ArticleGoogle Scholar
- Pope M, Gezelter S, Gallo N, Hoffman L, Steinman RM. Low levels of HIV-1 infection in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells. J Exp Med. 1995;182:2045–56.PubMedView ArticleGoogle Scholar
- McIlroy D, Autran B, Cheynier R, Wain-Hobson S, Clauvel JP, Oksenhendler E, Debre P, Hosmalin A. Infection frequency of dendritic cells and CD4+ T lymphocytes in spleens of human immunodeficiency virus-positive patients. J Virol. 1995;69:4737–45.PubMedPubMed CentralGoogle Scholar
- Kawamura T, Gulden FO, Sugaya M, McNamara DT, Borris DL, Lederman MM, Orenstein JM, Zimmerman PA, Blauvelt A. R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms. Proc Natl Acad Sci USA. 2003;100:8401–6.PubMedPubMed CentralView ArticleGoogle Scholar
- Burleigh L, Lozach PY, Schiffer C, Staropoli I, Pezo V, Porrot F, Canque B, Virelizier JL, Arenzana-Seisdedos F, Amara A. Infection of dendritic cells (DCs), not DC-SIGN-mediated internalization of human immunodeficiency virus, is required for long-term transfer of virus to T cells. J Virol. 2006;80:2949–57.PubMedPubMed CentralView ArticleGoogle Scholar
- Nobile C, Petit C, Moris A, Skrabal K, Abastado JP, Mammano F, Schwartz O. Covert human immunodeficiency virus replication in dendritic cells and in DC-SIGN-expressing cells promotes long-term transmission to lymphocytes. J Virol. 2005;79:5386–99.PubMedPubMed CentralView ArticleGoogle Scholar
- Popov S, Chenine AL, Gruber A, Li PL, Ruprecht RM. Long-term productive human immunodeficiency virus infection of CD1a-sorted myeloid dendritic cells. J Virol. 2005;79:602–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Giannetti A, Zambruno G, Cimarelli A, Marconi A, Negroni M, Girolomoni G, Bertazzoni U. Direct detection of HIV-1 RNA in epidermal Langerhans cells of HIV-infected patients. J Acquir Immune Defic Syndr. 1993;6:329–33.PubMedGoogle Scholar
- Bhoopat L, Eiangleng L, Rugpao S, Frankel SS, Weissman D, Lekawanvijit S, Petchjom S, Thorner P, Bhoopat T. In vivo identification of Langerhans and related dendritic cells infected with HIV-1 subtype E in vaginal mucosa of asymptomatic patients. Mod Pathol. 2001;14:1263–9.PubMedView ArticleGoogle Scholar
- Cameron PU, Freudenthal PS, Barker JM, Gezelter S, Inaba K, Steinman RM. Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. Science. 1992;257:383–7.PubMedView ArticleGoogle Scholar
- Pope M, Betjes MG, Romani N, Hirmand H, Cameron PU, Hoffman L, Gezelter S, Schuler G, Steinman RM. Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell. 1994;78:389–98.PubMedView ArticleGoogle Scholar
- Lore K, Smed-Sorensen A, Vasudevan J, Mascola JR, Koup RA. Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells. J Exp Med. 2005;201:2023–33.PubMedPubMed CentralView ArticleGoogle Scholar
- Yu HJ, Reuter MA, McDonald D. HIV traffics through a specialized, surface-accessible intracellular compartment during trans-infection of T cells by mature dendritic cells. PLoS Pathog. 2008;4:e1000134.PubMedPubMed CentralView ArticleGoogle Scholar
- van Nierop K, de Groot C. Human follicular dendritic cells: function, origin and development. Semin Immunol. 2002;14:251–7.PubMedView ArticleGoogle Scholar
- Spiegel H, Herbst H, Niedobitek G, Foss HD, Stein H. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol. 1992;140:15–22.PubMedPubMed CentralGoogle Scholar
- Joling P, Bakker LJ, Van Strijp JA, Meerloo T, de Graaf L, Dekker ME, Goudsmit J, Verhoef J, Schuurman HJ. Binding of human immunodeficiency virus type-1 to follicular dendritic cells in vitro is complement dependent. J Immunol. 1993;150:1065–73.PubMedGoogle Scholar
- Smith BA, Gartner S, Liu Y, Perelson AS, Stilianakis NI, Keele BF, Kerkering TM, Ferreira-Gonzalez A, Szakal AK, Tew JG, Burton GF. Persistence of infectious HIV on follicular dendritic cells. J Immunol. 2001;166:690–6.PubMedView ArticleGoogle Scholar
- Heath SL, Tew JG, Tew JG, Szakal AK, Burton GF. Follicular dendritic cells and human immunodeficiency virus infectivity. Nature. 1995;377:740–4.PubMedView ArticleGoogle Scholar
- Heesters BA, Lindqvist M, Vagefi PA, Scully EP, Schildberg FA, Altfeld M, Walker BD, Kaufmann DE, Carroll MC. Follicular dendritic cells retain infectious HIV in cycling endosomes. PLoS Pathog. 2015;11:e1005285.PubMedPubMed CentralView ArticleGoogle Scholar
- Kumar RB, Maher DM, Herzberg MC, Southern PJ. Expression of HIV receptors, alternate receptors and co-receptors on tonsillar epithelium: implications for HIV binding and primary oral infection. Virol J. 2006;3:25.PubMedPubMed CentralView ArticleGoogle Scholar
- Kohli A, Islam A, Moyes DL, Murciano C, Shen C, Challacombe SJ, Naglik JR. Oral and vaginal epithelial cell lines bind and transfer cell-free infectious HIV-1 to permissive cells but are not productively infected. PLoS ONE. 2014;9:e98077.PubMedPubMed CentralView ArticleGoogle Scholar
- Blasi M, Balakumaran B, Chen P, Negri DR, Cara A, Chen BK, Klotman ME. Renal epithelial cells produce and spread HIV-1 via T-cell contact. AIDS. 2014;28:2345–53.PubMedPubMed CentralView ArticleGoogle Scholar
- Chen P, Chen BK, Mosoian A, Hays T, Ross MJ, Klotman PE, Klotman ME. Virological synapses allow HIV-1 uptake and gene expression in renal tubular epithelial cells. J Am Soc Nephrol. 2011;22:496–507.PubMedPubMed CentralView ArticleGoogle Scholar
- Bruggeman LA, Ross MD, Tanji N, Cara A, Dikman S, Gordon RE, Burns GC, D’Agati VD, Winston JA, Klotman ME, Klotman PE. Renal epithelium is a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol. 2000;11:2079–87.PubMedGoogle Scholar
- Marras D, Bruggeman LA, Gao F, Tanji N, Mansukhani MM, Cara A, Ross MD, Gusella GL, Benson G, D’Agati VD, et al. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nat Med. 2002;8:522–6.PubMedView ArticleGoogle Scholar
- Canaud G, Dejucq-Rainsford N, Avettand-Fenoel V, Viard JP, Anglicheau D, Bienaime F, Muorah M, Galmiche L, Gribouval O, Noel LH, et al. The kidney as a reservoir for HIV-1 after renal transplantation. J Am Soc Nephrol. 2014;25:407–19.PubMedView ArticleGoogle Scholar
- Wyatt CM, Klotman PE. HIV-associated nephropathy in the era of antiretroviral therapy. Am J Med. 2007;120:488–92.PubMedView ArticleGoogle Scholar
- Becquart P, Chomont N, Roques P, Ayouba A, Kazatchkine MD, Belec L, Hocini H. Compartmentalization of HIV-1 between breast milk and blood of HIV-infected mothers. Virology. 2002;300:109–17.PubMedView ArticleGoogle Scholar
- Dorosko SM, Connor RI. Primary human mammary epithelial cells endocytose HIV-1 and facilitate viral infection of CD4+ T lymphocytes. J Virol. 2010;84:10533–42.PubMedPubMed CentralView ArticleGoogle Scholar
- Shapiro RL, Ndung’u T, Lockman S, Smeaton LM, Thior I, Wester C, Stevens L, Sebetso G, Gaseitsiwe S, Peter T, Essex M. Highly active antiretroviral therapy started during pregnancy or postpartum suppresses HIV-1 RNA, but not DNA, in breast milk. J Infect Dis. 2005;192:713–9.PubMedView ArticleGoogle Scholar
- Lehman DA, Chung MH, John-Stewart GC, Richardson BA, Kiarie J, Kinuthia J, Overbaugh J. HIV-1 persists in breast milk cells despite antiretroviral treatment to prevent mother-to-child transmission. AIDS. 2008;22:1475–85.PubMedPubMed CentralView ArticleGoogle Scholar
- Vacharaksa A, Asrani AC, Gebhard KH, Fasching CE, Giacaman RA, Janoff EN, Ross KF, Herzberg MC. Oral keratinocytes support non-replicative infection and transfer of harbored HIV-1 to permissive cells. Retrovirology. 2008;5:66.PubMedPubMed CentralView ArticleGoogle Scholar
- Liu X, Zha J, Chen H, Nishitani J, Camargo P, Cole SW, Zack JA. Human immunodeficiency virus type 1 infection and replication in normal human oral keratinocytes. J Virol. 2003;77:3470–6.PubMedPubMed CentralView ArticleGoogle Scholar
- Kong L, Cardona Maya W, Moreno-Fernandez ME, Ma G, Shata MT, Sherman KE, Chougnet C, Blackard JT. Low-level HIV infection of hepatocytes. Virol J. 2012;9:157.PubMedPubMed CentralView ArticleGoogle Scholar
- Tuyama AC, Hong F, Saiman Y, Wang C, Ozkok D, Mosoian A, Chen P, Chen BK, Klotman ME, Bansal MB. Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis. Hepatology. 2010;52:612–22.PubMedPubMed CentralView ArticleGoogle Scholar
- Hashimoto M, Nasser H, Bhuyan F, Kuse N, Satou Y, Harada S, Yoshimura K, Sakuragi J, Monde K, Maeda Y, et al. Fibrocytes differ from macrophages but can be infected with HIV-1. J Immunol. 2015;195:4341–50.PubMedView ArticleGoogle Scholar
- Valentin A, Rosati M, Patenaude DJ, Hatzakis A, Kostrikis LG, Lazanas M, Wyvill KM, Yarchoan R, Pavlakis GN. Persistent HIV-1 infection of natural killer cells in patients receiving highly active antiretroviral therapy. Proc Natl Acad Sci USA. 2002;99:7015–20.PubMedPubMed CentralView ArticleGoogle Scholar
- Gray LR, Turville SG, Hitchen TL, Cheng WJ, Ellett AM, Salimi H, Roche MJ, Wesselingh SL, Gorry PR, Churchill MJ. HIV-1 entry and trans-infection of astrocytes involves CD81 vesicles. PLoS ONE. 2014;9:e90620.PubMedPubMed CentralView ArticleGoogle Scholar
- Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MB. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA. 1986;83:7089–93.PubMedPubMed CentralView ArticleGoogle Scholar
- Carter CC, Onafuwa-Nuga A, McNamara LA, Riddell J 4th, Bixby D, Savona MR, Collins KL. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010;16:446–51.PubMedPubMed CentralView ArticleGoogle Scholar
- Durand CM, Ghiaur G, Siliciano JD, Rabi SA, Eisele EE, Salgado M, Shan L, Lai JF, Zhang H, Margolick J, et al. HIV-1 DNA is detected in bone marrow populations containing CD4+ T cells but is not found in purified CD34+ hematopoietic progenitor cells in most patients on antiretroviral therapy. J Infect Dis. 2012;205:1014–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Crooks AM, Bateson R, Cope AB, Dahl NP, Griggs MK, Kuruc JD, Gay CL, Eron JJ, Margolis DM, Bosch RJ, Archin NM. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J Infect Dis. 2015;212:1361–5.PubMedPubMed CentralView ArticleGoogle Scholar
- Laird GM, Rosenbloom DI, Lai J, Siliciano RF, Siliciano JD. Measuring the frequency of latent HIV-1 in resting CD4(+) T cells using a limiting dilution coculture assay. Methods Mol Biol. 2016;1354:239–53.PubMedView ArticleGoogle Scholar
- Siliciano JD, Siliciano RF. Enhanced culture assay for detection and quantitation of latently infected, resting CD4+ T-cells carrying replication-competent virus in HIV-1-infected individuals. Methods Mol Biol. 2005;304:3–15.PubMedGoogle Scholar
- Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, Lai J, Blankson JN, Siliciano JD, Siliciano RF. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell. 2013;155:540–51.PubMedPubMed CentralView ArticleGoogle Scholar
- O’Doherty U, Swiggard WJ, Jeyakumar D, McGain D, Malim MH. A sensitive, quantitative assay for human immunodeficiency virus type 1 integration. J Virol. 2002;76:10942–50.PubMedPubMed CentralView ArticleGoogle Scholar
- Vandergeeten C, Fromentin R, Merlini E, Lawani MB, DaFonseca S, Bakeman W, McNulty A, Ramgopal M, Michael N, Kim JH, et al. Cross-clade ultrasensitive PCR-based assays to measure HIV persistence in large-cohort studies. J Virol. 2014;88:12385–96.PubMedPubMed CentralView ArticleGoogle Scholar
- Procopio FA, Fromentin R, Kulpa DA, Brehm JH, Bebin AG, Strain MC, Richman DD, O’Doherty U, Palmer S, Hecht FM, et al. A novel assay to measure the magnitude of the inducible viral reservoir in HIV-infected individuals. EBioMedicine. 2015;2:872–81.View ArticleGoogle Scholar
- Ananworanich J, Mellors JW. How much HIV is alive? The challenge of measuring replication competent HIV for HIV cure research. EBioMedicine. 2015;2:786–7.View ArticleGoogle Scholar
- Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol. 2014;12:750–64.PubMedPubMed CentralView ArticleGoogle Scholar
- Hernandez-Vargas EA, Middleton RH. Modeling the three stages in HIV infection. J Theor Biol. 2013;320:33–40.PubMedView ArticleGoogle Scholar
- Turville SG, Arthos J, Donald KM, Lynch G, Naif H, Clark G, Hart D, Cunningham AL. HIV gp120 receptors on human dendritic cells. Blood. 2001;98:2482–8.PubMedView ArticleGoogle Scholar
- Eligini S, Brioschi M, Fiorelli S, Tremoli E, Banfi C, Colli S. Human monocyte-derived macrophages are heterogenous: proteomic profile of different phenotypes. J Proteom. 2015;124:112–23.View ArticleGoogle Scholar
- Bol SM, van Remmerden Y, Sietzema JG, Kootstra NA, Schuitemaker H, van’t Wout AB. Donor variation in in vitro HIV-1 susceptibility of monocyte-derived macrophages. Virology. 2009;390:205–11.PubMedView ArticleGoogle Scholar
- Cassol E, Alfano M, Biswas P, Poli G. Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence. J Leukoc Biol. 2006;80:1018–30.PubMedView ArticleGoogle Scholar
- Hatziioannou T, Evans DT. Animal models for HIV/AIDS research. Nat Rev Microbiol. 2012;10:852–67.PubMedPubMed CentralView ArticleGoogle Scholar
- Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, Florens L, Washburn MP, Skowronski J. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature. 2011;474:658–61.PubMedPubMed CentralView ArticleGoogle Scholar
- Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Segeral E, Yatim A, Emiliani S, Schwartz O, Benkirane M. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature. 2011;474:654–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Morrow WJ, Wharton M, Lau D, Levy JA. Small animals are not susceptible to human immunodeficiency virus infection. J Gen Virol. 1987;68(Pt 8):2253–7.PubMedView ArticleGoogle Scholar
- Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988;335:256–9.PubMedView ArticleGoogle Scholar
- Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, Wege AK, Haase AT, Garcia JV. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med. 2006;12:1316–22.PubMedView ArticleGoogle Scholar
- Palucka AK, Gatlin J, Blanck JP, Melkus MW, Clayton S, Ueno H, Kraus ET, Cravens P, Bennett L, Padgett-Thomas A, et al. Human dendritic cell subsets in NOD/SCID mice engrafted with CD34+ hematopoietic progenitors. Blood. 2003;102:3302–10.PubMedView ArticleGoogle Scholar
- Metcalf Pate KA, Pohlmeyer CW, Walker-Sperling VE, Foote JB, Najarro KM, Cryer CG, Salgado M, Gama L, Engle EL, Shirk EN, et al. A murine viral outgrowth assay to detect residual HIV Type 1 in patients with undetectable viral loads. J Infect Dis. 2015;212:1387–96.PubMedPubMed CentralView ArticleGoogle Scholar
- Siliciano JM, Siliciano RF. The remarkable stability of the latent reservoir for HIV-1 in resting memory CD4+ T cells. J Infect Dis. 2015;212:1345–7.PubMedView ArticleGoogle Scholar
- Rasmussen TA, Tolstrup M, Sogaard OS. Reversal of latency as part of a cure for HIV-1. Trends Microbiol. 2016;24:90–7.PubMedView ArticleGoogle Scholar
- Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, Zhang H, Margolick JB, Blankson JN, Siliciano RF. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012;36:491–501.PubMedPubMed CentralView ArticleGoogle Scholar
- Denton PW, Long JM, Wietgrefe SW, Sykes C, Spagnuolo RA, Snyder OD, Perkey K, Archin NM, Choudhary SK, Yang K, et al. Targeted cytotoxic therapy kills persisting HIV infected cells during ART. PLoS Pathog. 2014;10:e1003872.PubMedPubMed CentralView ArticleGoogle Scholar
- Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014;20:425–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Laird GM, Bullen CK, Rosenbloom DI, Martin AR, Hill AL, Durand CM, Siliciano JD, Siliciano RF. Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations. J Clin Invest. 2015;125:1901–12.PubMedPubMed CentralView ArticleGoogle Scholar