- Email: [email protected]
The Yellow Brick Road towards HIV Eradication
Trends in Immunology 1 2 3
*Correspondence: [email protected] (A. Iwasaki). https://doi.org/10.1016/j.it.2019.04.004 © 2019 Elsevier Ltd. All rights reserved. References 1. Louveau, A. et al. (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 2. Aspelund, A. et al. (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 3. Jordao, M.J.C. et al. (2019) Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, eaat7554 4. Da Mesquita, S. et al. (2018) The meningeal lymphatic system: a new player in neurophysiology. Neuron 100, 375–388 5. Russo, M.V. et al. (2018) Distinct myeloid cell subsets promote meningeal remodeling and vascular repair after mild traumatic brain injury. Nat. Immunol. 19, 442–452 6. Hashimoto, D. et al. (2013) Tissue-resident macrophages selfmaintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 7. Scott, C.L. et al. (2016) Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 8. Rua, R. et al. (2019) Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity. Nat. Immunol. 20, 407–419 9. Pavlov, V.A. and Tracey, K.J. (2012) The vagus nerve and the inflammatory reflex–linking immunity and metabolism. Nat. Rev. Endocrinol. 8, 743–754 10. Readhead, B. et al. (2018) Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 99, 64–82 11. Eimer, W.A. et al. (2018) Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99, 56–63
Spotlight
The Yellow Brick Road towards HIV Eradication Asier Saez-Cirion1 and Michaela Müller-Trutwin
1,
*
A London patient living with HIV-1 has become the second person to achieve remission from HIV-1 infection for N 1 year after receiving a bone marrow stem cell transplant from a donor with cells resistant to CCR5-tropic HIV-1 infection (Gupta et al. Nature 2019;568:244–248). This case provides important clues in the uncertain path towards an HIV cure.
Significant progress has been achieved regarding the treatment and prevention of HIV infection in the past two decades. Combinatory antiretroviral treatment (cART) has transformed a deadly disease into a manageable chronic infection. cART drastically reduces viremia to undetectable titers in the blood through inhibition of new rounds of cellular infections, although it is not capable of eliminating already infected cells. HIV persists in socalled viral reservoirs from where it rebounds as soon as cART is stopped. A therapeutic strategy to target the eradication of HIV has been steadfastly sought but has encountered multiple hurdles. The virus most likely possesses several nonexclusive mechanisms to persist once the infection is established. These mechanisms include escape from immune surveillance, clonal proliferation of infected cells, and residual viral replication in immunoprivileged sites of the body such as B cell follicles [1]. Although HIV persists predominantly in intestinal mucosae and lymph nodes, it can be detected in nearly every tissue of the body during cART.
has remained off cART since the first day of his stem cell transplantation (SCT), in other words for 12 years. However, because of the complexity of the intervention, it is unclear which parameters were ultimately responsible for the elimination of the virus and the optimal resolution of infection. Recently, an HIV-1-infected adult in London underwent allo-HSCT treatment for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor [3]. CCR5-tropic, but not CXCR4-tropic viruses were identified in HIV-1 DNA from CD4+ T cells before transplantation. The host genotype was CCR5 +/+ and full chimerism with CCR5Δ32/Δ32 cells was achieved after transplantation. cART was interrupted 16 months after SCT and no viral rebound has been observed 19 months after treatment interruption. Another patient in Düsseldorf who received allo-HSCT from a CCR5Δ32/Δ32 donor has not shown viral rebound so far, 3 months since cART interruption [4]. Comparison between the Berlin and London patients can help to better understand the mechanisms that have led to successful suppression of the virus. The Berlin patient is himself heterozygous for CCR5Δ32, and has been subjected to total body irradiation and strong conditioning with each HSCT, discontinuing cART immediately during the first HSCT [2]. The case of the London patient indicated that a similar outcome could be achieved in CCR5 +/+ individuals after a single CCR5Δ32/Δ32 alloHSCT and mild conditioning, without total body irradiation or cART discontinuation during HSCT [3]. By contrast, some degree of graft-versus-host reaction and early and sustained full donor chimerism in T cells was observed in both patients, and these may be important events associated with HIV clearing.
Despite these multiple mechanisms of viral persistence, one patient has been reportedly cured from HIV-1 infection [2]. Timothy Brown, also known as the 'Berlin patient', was diagnosed with HIV-1 infection in 1995. After controlling viremia for several years via cART, he was diagnosed with acute myeloid leukemia and, in 2007 and 2008, received two allogeneic hematopoietic stem-cell transplants (allo-HSCT) from a human leukocyte antigen (HLA)matched donor carrying a homozygous 32 nt deletion (Δ32) in the CCR5 gene that encodes a coreceptor for HIV-1 viral entry. In later stages of infection, HIV-1 variants using other coreceptors, in particular CXCR4, can emerge. However, CCR5 is essential for HIV-1 to establish a persistent infection in vivo. The CCR5Δ32 mutation, which is relatively frequent in Northern The International Collaborative ConsorEurope, renders cells resistant to CCR5- tium to Guide and Investigate the Potential tropic HIV-1 infection. The Berlin patient for HIV Cure by Stem Cell Transplantation Trends in Immunology, June 2019, Vol. 40, No. 6
465
Trends in Immunology
Remission from HIV infection
Kill
Allo-HSCT Graft vs HIV reservoir
Block Target cells: CCR5Δ 32
?
Gene therapy?
Immune responses? Immunotherapies? (e.g., bNAbs, CAR T cells) Trends in Immunology
Figure 1. ‘Kill and Block’ Strategy for Attaining Full Remission of HIV Infection. Allogenic hematopoietic stem cell transplantation (allo-HSCT) that replenishes host cells in HIV-1-infected individuals with donor cells is associated with a dramatic decrease of HIV reservoirs relative to before allo-HSCT, probably favored through graftversus-HIV reservoir-like mechanisms (the ‘kill’ axis) [5]. However, some infected cells may remain, and, to achieve durable remission of HIV infection, additional barriers to block the virus may be needed (‘block’ axis). One way to counteract infection has so far been bone marrow engraftment of recipients with HIV-resistant (CRR5Δ32/ Δ32) donor cells, as demonstrated by the Berlin and London patients [2,3]. If no suitable donors are identified, alternative additional interventions could include modification of target cells through gene therapy or boosting immune responses to control the remaining infected cells. Immunotherapies might be based on vaccines, on broadly neutralizing antibodies (bNAbs) against HIV, T cells with an improved capacity to target and destroy infected cells (e.g., expressing chimeric antigen receptors, CAR T cells), or on other strategies to eliminate infected cells and/or block the re-emergence of HIV.
undetectable viremia for 3–9 months following cART discontinuation before the virus reappeared [6,7]. Another HIV-1 infected adult (the 'Essen patient'), with anaplastic large-cell lymphoma, underwent SCT from a CCR5Δ32/Δ32 donor [8]. The virus rebounded 3 weeks after transplantation, and genotypic analyses of HIV-1 variants in this patient showed a shift from a dominantly CCR5-tropic HIV-1 before SCT towards variants that were independent of CCR5 usage (CXCR4-tropic HIV-1). These reports indicate that, despite the dramatic reduction of the HIV reservoir associated with allo-HSCT, the effect is not absolute, and very few remaining infected cells might result in (possibly delayed) but However, allo-HSCT is not a scalable ther- vigorous rebound of viremia, if no additional apy for HIV infection and also does not sys- barrier exists to contain infection. The Berlin tematically lead to remission from infection, and London cases convincingly endorse even when full donor chimerism is achieved. the idea that full engraftment with Recently, three individuals who had under- CCR5Δ32/Δ32 cells constitutes an effecgone allo-HSCT with cells from CCR5 wild- tive block that favors remission from HIV intype donors were reported to maintain fection upon allo-HSCT. Thus, a ‘kill and
(ICISTEM, www.icistem.org) has assembled a large international cohort of HIVpositive individuals who have undergone allo-HSCT to treat diverse hematologic disorders. So far, 39 participants having received HSCT from matched CCR5Δ32 or wildtype donors have been included in the cohort. This study has shown that allo-HSCT is unambiguously associated with a drastic reduction in the HIV reservoir, independently of engraftment with CCR5Δ32 or wild-type cells (Figure 1). In most cases, allo-HSCT in the presence of cART was followed by reduction of all virological markers to below detectable limits, possibly related to graftversus-HIV reservoir-like effects [5].
466
Trends in Immunology, June 2019, Vol. 40, No. 6
block’ approach to HIV infection seems to be required (Figure 1). More than 22 000 CCR5Δ32 homozygous donors have been identified so far in the context of the ICISTEM initiative, and these may help in the selection of suitable donors for HIVinfected individuals in need of allo-HSCT. Gene therapy approaches aimed at knocking out CCR5 are also under study (Figure 1). However, this raises the question of how best to prevent the risk of emergence of subdominant CXCR4 viruses (as was the case in the Essen patient). The role of immune responses may be crucial to durably control infection. Although it is still unclear how immune responses against HIV evolve following alloHSCT, HIV-1 Gag-specific CD4+ and CD8+ T cell responses and HIV-1-specific antibodies seem to decrease following transplantation [3,5]. If some level of exposure to antigen occurred after transplantation, this appears to be insufficient to confer protection in allo-HCST recipients,
Trends in Immunology
and complementary immunotherapies may be needed in these individuals to achieve remission.
patients experience a progressive decline in cell-associated HIV-1 DNA and virusproducing cells, ultimately reaching undetectable blood titers in standard assays [10,11]. Therefore, defining which individuals are cured or in remission remains a difficult task, and the road ahead towards finally attaining a scalable HIV cure remains uncertain.
The cases of the Berlin and London patients also highlight our limits to defining an HIV cure. No signs of the virus have been found in numerous assays with multiple samples from diverse tissues that Timothy Brown has generously conAcknowledgments tributed to advance research over the A.S-C. is an investigator in the ICISTEM consortium, past 12 years. In the case of the London which is supported by amfAR. A.S-C. and M.M-T. repatient, HIV-1 RNA has been undetectable ceive grants from the French Agency of HIV/AIDS Reat less than 1 copy per milliliter of plasma, search (ANRS), Sidaction, and MSDAVENIR. and HIV-1 DNA was undetectable in blood CD4+ T cells. Quantitative viral out1 growth assays using a total of 24 million Institut Pasteur, HIV Inflammation and Persistence Unit, 75015 Paris, France + resting CD4 T cells were negative. However, the presence of the virus in tissues from this patient remains unexplored. One *Correspondence: HIV-infected child, deceased from graft- [email protected] (M. Müller-Trutwin). versus-host disease after transplantation https://doi.org/10.1016/j.it.2019.04.006 with cells from a CCR5Δ32/Δ32 donor, © 2019 Elsevier Ltd. All rights reserved. showed undetectable virus posttransplantation in the blood although the References 1. Huot, N. et al. (2018) Lymph node cellular and viral dynamics virus was readily detected in multiple tisin natural hosts and impact for HIV cure strategies. Front. Immunol. 9, 780 sues [9]. In most cases, tests similar to 2. Hutter, G. et al. (2009) Long-term control of HIV by CCR5 those used to characterize the Berlin and delta32/delta32 stem-cell transplantation. N. Engl. J. Med. 360, 692–698 London patients have failed to detect the 3. Gupta, R.K. et al. (2019) HIV-1 remission following virus during cART treatment, and even for CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 568, 244–248 several months after cART discontinuation 4. Jensen, B.O. et al. (2019) Analytic treatment interruption in allo-HSCT patients with viral relapse [6]. after allogeneic CCR-Δ32 HSCT for AML in 2013. Conference on Retroviruses and Opportunistic Infections. Ultimately, only treatment interruption may A394. CROI Foundation/IAS–USA reveal whether remission is achieved or 5. Salgado, M. et al. (2018) Mechanisms that contribute to a profound reduction of the HIV-1 reservoir after allogeneic not. Because only 19 months have passed stem cell transplant. Ann. Intern. Med. 169, 674–683 after cART interruption in the London pa- 6. Henrich, T.J. et al. (2014) Antiretroviral-free HIV-1 remission and viral rebound following allogeneic stem cell tient, it is premature to conclude that this transplantation: a report of two cases. Ann. Intern. patient has been cured. Moreover, will the Med. 161, 319–327 duration of the off-treatment period be suf- 7. Cummins, N.W. et al. (2017) Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic ficient to cross the gap between remission stem cell transplant and analytic cessation of antiretroviral therapy: a case study. PLoS Med. 14, e1002461 and cure? Some individuals – natural con8. Kordelas, L. et al. (2014) Shift of HIV tropism in stem-cell trollers and post-treatment controllers – transplantation with CCR5 delta32 mutation. N. Engl. J. Med. 371, 880–882 are able to maintain undetectable viremia 9. Rothenberger, M. et al. (2018) Transplantation of CCR5Δ32 for decades [10]. Although in most of homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired HIV these controllers viral DNA is still readily deinfection. Open Forum Infect. Dis. 5, ofy090 tectable in the blood, in some cases the 10. Saez-Cirion, A. et al. (2013) Post-treatment HIV-1 controllers with a long-term virological remission after the interrupcontrol is very stringent (with undetectable tion of early initiated antiretroviral therapy ANRS VISCONTI viremia at the single-copy level); they can study. PLoS Pathog. 9, e1003211 display weakly reactive or negative western 11. Mendoza, D. et al. (2012) Comprehensive analysis of unique cases with extraordinary control over HIV replication. Blood blots for anti-HIV antibodies, and some 119, 4645–4655
Spotlight
Dengue and Zika: The Complexities of Being Related Florian Krammer1,@ and Jean K. Lim1,*,@ Following the recent Zika virus (ZIKV) outbreak in the Americas, a major question that has arisen is how dengue virus (DENV) immunity impacts Zika virus infection and disease. A recent study (Rodriguez-Barraquer, I. et al. Science 2019;363:607–610) shows that DENV immunity is, for the most part, protective against ZIKV, but exceptions may exist. Zika virus (ZIKV) is a mosquito-transmitted flavivirus that is closely related to dengue virus (DENV). Since its discovery in 1947, ZIKV remained relatively unnoticed, causing small, local outbreaks primarily in parts of Africa and Asia, and was associated with minor symptoms, such as mild fever. However, in the past decade, ZIKV started to spread geographically across the Pacific Islands, eventually reaching South America, where it caused an explosive outbreak that started in Brazil in 2015 and rapidly spread to other South and Central American countries. This has been accompanied by a startling link between ZIKV infection during pregnancy and the development of birth defects among fetuses and babies, including microcephaly [1]. It is unclear what factors may have led to the massive ZIKV outbreak or the severe disease manifestations in the Americas, but one potential variable is that much of the at-risk population in the Americas have pre-existing immunity to DENV. It is well documented that preexisting immunity to one serotype of DENV can alter the disease pathogenesis of a subsequent infection with a different DENV
Trends in Immunology, June 2019, Vol. 40, No. 6
467
*Correspondence: [email protected] (A. Iwasaki). https://doi.org/10.1016/j.it.2019.04.004 © 2019 Elsevier Ltd. All rights reserved. References 1. Louveau, A. et al. (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 2. Aspelund, A. et al. (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 3. Jordao, M.J.C. et al. (2019) Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, eaat7554 4. Da Mesquita, S. et al. (2018) The meningeal lymphatic system: a new player in neurophysiology. Neuron 100, 375–388 5. Russo, M.V. et al. (2018) Distinct myeloid cell subsets promote meningeal remodeling and vascular repair after mild traumatic brain injury. Nat. Immunol. 19, 442–452 6. Hashimoto, D. et al. (2013) Tissue-resident macrophages selfmaintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 7. Scott, C.L. et al. (2016) Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 8. Rua, R. et al. (2019) Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity. Nat. Immunol. 20, 407–419 9. Pavlov, V.A. and Tracey, K.J. (2012) The vagus nerve and the inflammatory reflex–linking immunity and metabolism. Nat. Rev. Endocrinol. 8, 743–754 10. Readhead, B. et al. (2018) Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 99, 64–82 11. Eimer, W.A. et al. (2018) Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99, 56–63
Spotlight
The Yellow Brick Road towards HIV Eradication Asier Saez-Cirion1 and Michaela Müller-Trutwin
1,
*
A London patient living with HIV-1 has become the second person to achieve remission from HIV-1 infection for N 1 year after receiving a bone marrow stem cell transplant from a donor with cells resistant to CCR5-tropic HIV-1 infection (Gupta et al. Nature 2019;568:244–248). This case provides important clues in the uncertain path towards an HIV cure.
Significant progress has been achieved regarding the treatment and prevention of HIV infection in the past two decades. Combinatory antiretroviral treatment (cART) has transformed a deadly disease into a manageable chronic infection. cART drastically reduces viremia to undetectable titers in the blood through inhibition of new rounds of cellular infections, although it is not capable of eliminating already infected cells. HIV persists in socalled viral reservoirs from where it rebounds as soon as cART is stopped. A therapeutic strategy to target the eradication of HIV has been steadfastly sought but has encountered multiple hurdles. The virus most likely possesses several nonexclusive mechanisms to persist once the infection is established. These mechanisms include escape from immune surveillance, clonal proliferation of infected cells, and residual viral replication in immunoprivileged sites of the body such as B cell follicles [1]. Although HIV persists predominantly in intestinal mucosae and lymph nodes, it can be detected in nearly every tissue of the body during cART.
has remained off cART since the first day of his stem cell transplantation (SCT), in other words for 12 years. However, because of the complexity of the intervention, it is unclear which parameters were ultimately responsible for the elimination of the virus and the optimal resolution of infection. Recently, an HIV-1-infected adult in London underwent allo-HSCT treatment for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor [3]. CCR5-tropic, but not CXCR4-tropic viruses were identified in HIV-1 DNA from CD4+ T cells before transplantation. The host genotype was CCR5 +/+ and full chimerism with CCR5Δ32/Δ32 cells was achieved after transplantation. cART was interrupted 16 months after SCT and no viral rebound has been observed 19 months after treatment interruption. Another patient in Düsseldorf who received allo-HSCT from a CCR5Δ32/Δ32 donor has not shown viral rebound so far, 3 months since cART interruption [4]. Comparison between the Berlin and London patients can help to better understand the mechanisms that have led to successful suppression of the virus. The Berlin patient is himself heterozygous for CCR5Δ32, and has been subjected to total body irradiation and strong conditioning with each HSCT, discontinuing cART immediately during the first HSCT [2]. The case of the London patient indicated that a similar outcome could be achieved in CCR5 +/+ individuals after a single CCR5Δ32/Δ32 alloHSCT and mild conditioning, without total body irradiation or cART discontinuation during HSCT [3]. By contrast, some degree of graft-versus-host reaction and early and sustained full donor chimerism in T cells was observed in both patients, and these may be important events associated with HIV clearing.
Despite these multiple mechanisms of viral persistence, one patient has been reportedly cured from HIV-1 infection [2]. Timothy Brown, also known as the 'Berlin patient', was diagnosed with HIV-1 infection in 1995. After controlling viremia for several years via cART, he was diagnosed with acute myeloid leukemia and, in 2007 and 2008, received two allogeneic hematopoietic stem-cell transplants (allo-HSCT) from a human leukocyte antigen (HLA)matched donor carrying a homozygous 32 nt deletion (Δ32) in the CCR5 gene that encodes a coreceptor for HIV-1 viral entry. In later stages of infection, HIV-1 variants using other coreceptors, in particular CXCR4, can emerge. However, CCR5 is essential for HIV-1 to establish a persistent infection in vivo. The CCR5Δ32 mutation, which is relatively frequent in Northern The International Collaborative ConsorEurope, renders cells resistant to CCR5- tium to Guide and Investigate the Potential tropic HIV-1 infection. The Berlin patient for HIV Cure by Stem Cell Transplantation Trends in Immunology, June 2019, Vol. 40, No. 6
465
Trends in Immunology
Remission from HIV infection
Kill
Allo-HSCT Graft vs HIV reservoir
Block Target cells: CCR5Δ 32
?
Gene therapy?
Immune responses? Immunotherapies? (e.g., bNAbs, CAR T cells) Trends in Immunology
Figure 1. ‘Kill and Block’ Strategy for Attaining Full Remission of HIV Infection. Allogenic hematopoietic stem cell transplantation (allo-HSCT) that replenishes host cells in HIV-1-infected individuals with donor cells is associated with a dramatic decrease of HIV reservoirs relative to before allo-HSCT, probably favored through graftversus-HIV reservoir-like mechanisms (the ‘kill’ axis) [5]. However, some infected cells may remain, and, to achieve durable remission of HIV infection, additional barriers to block the virus may be needed (‘block’ axis). One way to counteract infection has so far been bone marrow engraftment of recipients with HIV-resistant (CRR5Δ32/ Δ32) donor cells, as demonstrated by the Berlin and London patients [2,3]. If no suitable donors are identified, alternative additional interventions could include modification of target cells through gene therapy or boosting immune responses to control the remaining infected cells. Immunotherapies might be based on vaccines, on broadly neutralizing antibodies (bNAbs) against HIV, T cells with an improved capacity to target and destroy infected cells (e.g., expressing chimeric antigen receptors, CAR T cells), or on other strategies to eliminate infected cells and/or block the re-emergence of HIV.
undetectable viremia for 3–9 months following cART discontinuation before the virus reappeared [6,7]. Another HIV-1 infected adult (the 'Essen patient'), with anaplastic large-cell lymphoma, underwent SCT from a CCR5Δ32/Δ32 donor [8]. The virus rebounded 3 weeks after transplantation, and genotypic analyses of HIV-1 variants in this patient showed a shift from a dominantly CCR5-tropic HIV-1 before SCT towards variants that were independent of CCR5 usage (CXCR4-tropic HIV-1). These reports indicate that, despite the dramatic reduction of the HIV reservoir associated with allo-HSCT, the effect is not absolute, and very few remaining infected cells might result in (possibly delayed) but However, allo-HSCT is not a scalable ther- vigorous rebound of viremia, if no additional apy for HIV infection and also does not sys- barrier exists to contain infection. The Berlin tematically lead to remission from infection, and London cases convincingly endorse even when full donor chimerism is achieved. the idea that full engraftment with Recently, three individuals who had under- CCR5Δ32/Δ32 cells constitutes an effecgone allo-HSCT with cells from CCR5 wild- tive block that favors remission from HIV intype donors were reported to maintain fection upon allo-HSCT. Thus, a ‘kill and
(ICISTEM, www.icistem.org) has assembled a large international cohort of HIVpositive individuals who have undergone allo-HSCT to treat diverse hematologic disorders. So far, 39 participants having received HSCT from matched CCR5Δ32 or wildtype donors have been included in the cohort. This study has shown that allo-HSCT is unambiguously associated with a drastic reduction in the HIV reservoir, independently of engraftment with CCR5Δ32 or wild-type cells (Figure 1). In most cases, allo-HSCT in the presence of cART was followed by reduction of all virological markers to below detectable limits, possibly related to graftversus-HIV reservoir-like effects [5].
466
Trends in Immunology, June 2019, Vol. 40, No. 6
block’ approach to HIV infection seems to be required (Figure 1). More than 22 000 CCR5Δ32 homozygous donors have been identified so far in the context of the ICISTEM initiative, and these may help in the selection of suitable donors for HIVinfected individuals in need of allo-HSCT. Gene therapy approaches aimed at knocking out CCR5 are also under study (Figure 1). However, this raises the question of how best to prevent the risk of emergence of subdominant CXCR4 viruses (as was the case in the Essen patient). The role of immune responses may be crucial to durably control infection. Although it is still unclear how immune responses against HIV evolve following alloHSCT, HIV-1 Gag-specific CD4+ and CD8+ T cell responses and HIV-1-specific antibodies seem to decrease following transplantation [3,5]. If some level of exposure to antigen occurred after transplantation, this appears to be insufficient to confer protection in allo-HCST recipients,
Trends in Immunology
and complementary immunotherapies may be needed in these individuals to achieve remission.
patients experience a progressive decline in cell-associated HIV-1 DNA and virusproducing cells, ultimately reaching undetectable blood titers in standard assays [10,11]. Therefore, defining which individuals are cured or in remission remains a difficult task, and the road ahead towards finally attaining a scalable HIV cure remains uncertain.
The cases of the Berlin and London patients also highlight our limits to defining an HIV cure. No signs of the virus have been found in numerous assays with multiple samples from diverse tissues that Timothy Brown has generously conAcknowledgments tributed to advance research over the A.S-C. is an investigator in the ICISTEM consortium, past 12 years. In the case of the London which is supported by amfAR. A.S-C. and M.M-T. repatient, HIV-1 RNA has been undetectable ceive grants from the French Agency of HIV/AIDS Reat less than 1 copy per milliliter of plasma, search (ANRS), Sidaction, and MSDAVENIR. and HIV-1 DNA was undetectable in blood CD4+ T cells. Quantitative viral out1 growth assays using a total of 24 million Institut Pasteur, HIV Inflammation and Persistence Unit, 75015 Paris, France + resting CD4 T cells were negative. However, the presence of the virus in tissues from this patient remains unexplored. One *Correspondence: HIV-infected child, deceased from graft- [email protected] (M. Müller-Trutwin). versus-host disease after transplantation https://doi.org/10.1016/j.it.2019.04.006 with cells from a CCR5Δ32/Δ32 donor, © 2019 Elsevier Ltd. All rights reserved. showed undetectable virus posttransplantation in the blood although the References 1. Huot, N. et al. (2018) Lymph node cellular and viral dynamics virus was readily detected in multiple tisin natural hosts and impact for HIV cure strategies. Front. Immunol. 9, 780 sues [9]. In most cases, tests similar to 2. Hutter, G. et al. (2009) Long-term control of HIV by CCR5 those used to characterize the Berlin and delta32/delta32 stem-cell transplantation. N. Engl. J. Med. 360, 692–698 London patients have failed to detect the 3. Gupta, R.K. et al. (2019) HIV-1 remission following virus during cART treatment, and even for CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 568, 244–248 several months after cART discontinuation 4. Jensen, B.O. et al. (2019) Analytic treatment interruption in allo-HSCT patients with viral relapse [6]. after allogeneic CCR-Δ32 HSCT for AML in 2013. Conference on Retroviruses and Opportunistic Infections. Ultimately, only treatment interruption may A394. CROI Foundation/IAS–USA reveal whether remission is achieved or 5. Salgado, M. et al. (2018) Mechanisms that contribute to a profound reduction of the HIV-1 reservoir after allogeneic not. Because only 19 months have passed stem cell transplant. Ann. Intern. Med. 169, 674–683 after cART interruption in the London pa- 6. Henrich, T.J. et al. (2014) Antiretroviral-free HIV-1 remission and viral rebound following allogeneic stem cell tient, it is premature to conclude that this transplantation: a report of two cases. Ann. Intern. patient has been cured. Moreover, will the Med. 161, 319–327 duration of the off-treatment period be suf- 7. Cummins, N.W. et al. (2017) Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic ficient to cross the gap between remission stem cell transplant and analytic cessation of antiretroviral therapy: a case study. PLoS Med. 14, e1002461 and cure? Some individuals – natural con8. Kordelas, L. et al. (2014) Shift of HIV tropism in stem-cell trollers and post-treatment controllers – transplantation with CCR5 delta32 mutation. N. Engl. J. Med. 371, 880–882 are able to maintain undetectable viremia 9. Rothenberger, M. et al. (2018) Transplantation of CCR5Δ32 for decades [10]. Although in most of homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired HIV these controllers viral DNA is still readily deinfection. Open Forum Infect. Dis. 5, ofy090 tectable in the blood, in some cases the 10. Saez-Cirion, A. et al. (2013) Post-treatment HIV-1 controllers with a long-term virological remission after the interrupcontrol is very stringent (with undetectable tion of early initiated antiretroviral therapy ANRS VISCONTI viremia at the single-copy level); they can study. PLoS Pathog. 9, e1003211 display weakly reactive or negative western 11. Mendoza, D. et al. (2012) Comprehensive analysis of unique cases with extraordinary control over HIV replication. Blood blots for anti-HIV antibodies, and some 119, 4645–4655
Spotlight
Dengue and Zika: The Complexities of Being Related Florian Krammer1,@ and Jean K. Lim1,*,@ Following the recent Zika virus (ZIKV) outbreak in the Americas, a major question that has arisen is how dengue virus (DENV) immunity impacts Zika virus infection and disease. A recent study (Rodriguez-Barraquer, I. et al. Science 2019;363:607–610) shows that DENV immunity is, for the most part, protective against ZIKV, but exceptions may exist. Zika virus (ZIKV) is a mosquito-transmitted flavivirus that is closely related to dengue virus (DENV). Since its discovery in 1947, ZIKV remained relatively unnoticed, causing small, local outbreaks primarily in parts of Africa and Asia, and was associated with minor symptoms, such as mild fever. However, in the past decade, ZIKV started to spread geographically across the Pacific Islands, eventually reaching South America, where it caused an explosive outbreak that started in Brazil in 2015 and rapidly spread to other South and Central American countries. This has been accompanied by a startling link between ZIKV infection during pregnancy and the development of birth defects among fetuses and babies, including microcephaly [1]. It is unclear what factors may have led to the massive ZIKV outbreak or the severe disease manifestations in the Americas, but one potential variable is that much of the at-risk population in the Americas have pre-existing immunity to DENV. It is well documented that preexisting immunity to one serotype of DENV can alter the disease pathogenesis of a subsequent infection with a different DENV
Trends in Immunology, June 2019, Vol. 40, No. 6
467