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1.
BMC Vet Res ; 18(1): 364, 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36192746

RESUMO

BACKGROUND: Selecting American mink (Neovison vison) for tolerance to Aleutian mink disease virus (AMDV) has gained popularity in recent years, but data on the outcomes of this activity are scant. The objectives of this study were to determine the long-term changes in viremia, seroconversion and survival in infected mink. Mink were inoculated intranasally with a local isolate of Aleutian mink disease virus (AMDV) over 4 years (n = 1742). The animals had been selected for tolerance to AMDV for more than 20 years (TG100) or were from herds free of AMDV (TG0). The progenies of TG100 and TG0, and their crosses with 25, 50 and 75% tolerance ancestry were also used. Blood samples were collected from each mink up to 14 times until 1211 days post-inoculation (dpi) and were tested for viremia by PCR and for anti-AMDV antibodies by counter-immunoelectrophoresis (CIEP). Viremia and CIEP status were not considered when selecting replacements. Low-performing animals were pelted and the presence of antibodies in their blood and antibody titer were measured by CIEP, and viremia and viral DNA in seven organs (n = 936) were tested by PCR. RESULTS: The peak incidences of viremia (66.7%) and seropositivity (93.5%) were at 35 dpi. The incidence of viremia decreased over time while the incidence of seroconversion increased. The least-squares means of the incidence of PCR positive of lymph node (0.743) and spleen (0.656) were significantly greater than those of bone marrow, liver, kidneys, lungs and small intestine (0.194 to 0.342). Differences in tolerant ancestry were significant for every trait measured. Incidences of viremia over time, terminal viremia, seropositivity over time, AMDV DNA in organs and antibody titer were highest in the susceptible groups (TG0 or TG25) and lowest in the tolerant groups (TG100 or TG75). CONCLUSION: Previous history of selection for tolerance resulted in mink with reduced viral replication and antibody titer. Viremia had a negative effect and antibody production had a positive effect on survival and productivity.


Assuntos
Vírus da Doença Aleutiana do Vison , Doença Aleutiana do Vison , Anticorpos Antivirais , Formação de Anticorpos , Vison , Viremia , Doença Aleutiana do Vison/sangue , Doença Aleutiana do Vison/imunologia , Doença Aleutiana do Vison/mortalidade , Doença Aleutiana do Vison/virologia , Vírus da Doença Aleutiana do Vison/genética , Vírus da Doença Aleutiana do Vison/imunologia , Vírus da Doença Aleutiana do Vison/isolamento & purificação , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , DNA Viral/análise , Feminino , Masculino , Vison/sangue , Vison/imunologia , Vison/virologia , Taxa de Sobrevida , Viremia/sangue , Viremia/imunologia , Viremia/veterinária , Viremia/virologia , Replicação Viral
2.
J Virol ; 96(16): e0058822, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35916523

RESUMO

Co-infection with hepatitis B (HBV) and human immunodeficiency virus (HIV) increases overall and liver-related mortality. In order to identify interactions between these two viruses in vivo, full-length HIV proviruses were sequenced from a cohort of HIV-HBV co-infected participants and from a cohort of HIV mono-infected participants recruited from Bangkok, Thailand, both before the initiation of antiretroviral therapy (ART) and after at least 2 years of ART. The co-infected individuals were found to have higher levels of genetically-intact HIV proviruses than did mono-infected individuals pre-therapy. In these co-infected individuals, higher levels of genetically-intact HIV proviruses or proviral genetic-diversity were also associated with higher levels of sCD14 and CXCL10, suggesting that immune activation is linked to more genetically-intact HIV proviruses. Three years of ART decreased the overall level of HIV proviruses, with fewer genetically-intact proviruses being identified in co-infected versus mono-infected individuals. However, ART increased the frequency of certain genetic defects within proviruses and the expansion of identical HIV sequences. IMPORTANCE With the increased availability and efficacy of ART, co-morbidities are now one of the leading causes of death in HIV-positive individuals. One of these co-morbidities is co-infection with HBV. However, co-infections are still relatively understudied, especially in countries where such co-infections are endemic. Furthermore, these countries have different subtypes of HIV circulating than the commonly studied HIV subtype B. We believe that our study serves this understudied niche and provides a novel approach to investigating the impact of HBV co-infection on HIV infection. We examine co-infection at the molecular level in order to investigate indirect associations between the two viruses through their interactions with the immune system. We demonstrate that increased immune inflammation and activation in HBV co-infected individuals is associated with higher HIV viremia and an increased number of genetically-intact HIV proviruses in peripheral blood cells. This leads us to hypothesize that inflammation could be a driver in the increased mortality rate of HIV-HBV co-infected individuals.


Assuntos
Coinfecção , Infecções por HIV , Hepatite B , Inflamação/virologia , Coinfecção/patologia , Coinfecção/virologia , DNA Viral/genética , Infecções por HIV/complicações , Infecções por HIV/patologia , Infecções por HIV/virologia , Hepatite B/complicações , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/fisiologia , Humanos , Provírus/genética , Tailândia/epidemiologia , Viremia/virologia
3.
Nature ; 606(7913): 375-381, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35650437

RESUMO

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.


Assuntos
Fármacos Anti-HIV , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/imunologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Amplamente Neutralizantes/efeitos adversos , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Amplamente Neutralizantes/uso terapêutico , Método Duplo-Cego , Anticorpos Anti-HIV/administração & dosagem , Anticorpos Anti-HIV/efeitos adversos , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/isolamento & purificação , Humanos , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Viremia/imunologia , Viremia/virologia
4.
Ren Fail ; 44(1): 434-449, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35260039

RESUMO

Kidney transplantation is the treatment of choice in end-stage renal disease. The main issue which does not allow to utilize it fully is the number of organs available for transplant. Introduction of highly effective oral direct-acting antivirals (DAAs) to the treatment of chronic hepatitis C virus infection (HCV) enabled transplantation of HCV viremic organs to naive recipients. Despite an increasing number of reports on the satisfying effects of using HCV viremic organs, including kidneys, they are more often rejected than those from HCV negative donors. The main reason is the presence of HCV viremia and not the quality of the organ. The current state of knowledge points to the fact that a kidney transplant from an HCV nucleic acid testing positive (NAT+) donor to naive recipients is an effective and safe solution to the problem of the insufficient number of organs available for transplantation. It does not, however, allow to draw conclusions as to the long-term consequence of such an approach. This review analyzes the possibilities and limitations of the usage of HCV NAT + donor organs. Abbreviations: DAA: direct-acting antivirals; HCV: hepatitis C virus; NAT: nucleic acid testing; OPTN: Organ Procurement and Transplantation Network; KDIGO: Kidney Disease: Improving Global Outcomes; Ab: antigen; eGFR: estimated glomerular filtration rate; D: donor; R: recipient; CMV: cytomegalovirus; HBV: hepatitis B virus; UNOS: United Network for Organ Sharing; PHS: Public Health Service; EBR/GZR: elbasvir/grazoprevir; SVR: sustained virologic response; RAS: resistance-associated substitutions; SOF: soforbuvir; GLE/PIB: glecaprevir/pibrentasvir; ACR: acute cellular rejection; AR: acute rejection; DSA: donor-specific antibodies; KTR: kidney transplant recipients; AASLD: American Association for the Study of Liver Disease; IDSA: Infectious Diseases Society of America; PPI: proton pump inhibitors; CKD: chronic kidney disease; GN: glomerulonephritis; KAS: The Kidney Allocation system.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/transmissão , Transplante de Rim , Rim/virologia , Rejeição de Enxerto/virologia , Humanos , Obtenção de Tecidos e Órgãos , Viremia/virologia
5.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35181606

RESUMO

Cytomegalovirus (CMV) infection is associated with graft rejection in renal transplantation. Memory-like natural killer (NK) cells expressing NKG2C and lacking FcεRIγ are established during CMV infection. Additionally, CD8+ T cells expressing NKG2C have been observed in some CMV-seropositive patients. However, in vivo kinetics detailing the development and differentiation of these lymphocyte subsets during CMV infection remain limited. Here, we interrogated the in vivo kinetics of lymphocytes in CMV-infected renal transplant patients using longitudinal samples compared with those of nonviremic (NV) patients. Recipient CMV-seropositive (R+) patients had preexisting memory-like NK cells (NKG2C+CD57+FcεRIγ-) at baseline, which decreased in the periphery immediately after transplantation in both viremic and NV patients. We identified a subset of prememory-like NK cells (NKG2C+CD57+FcεRIγlow-dim) that increased during viremia in R+ viremic patients. These cells showed a higher cytotoxic profile than preexisting memory-like NK cells with transient up-regulation of FcεRIγ and Ki67 expression at the acute phase, with the subsequent accumulation of new memory-like NK cells at later phases of viremia. Furthermore, cytotoxic NKG2C+CD8+ T cells and γδ T cells significantly increased in viremic patients but not in NV patients. These three different cytotoxic cells combinatorially responded to viremia, showing a relatively early response in R+ viremic patients compared with recipient CMV-seronegative viremic patients. All viremic patients, except one, overcame viremia and did not experience graft rejection. These data provide insights into the in vivo dynamics and interplay of cytotoxic lymphocytes responding to CMV viremia, which are potentially linked with control of CMV viremia to prevent graft rejection.


Assuntos
Infecções por Citomegalovirus/imunologia , Citometria de Fluxo/métodos , Células Matadoras Naturais/metabolismo , Adulto , Linfócitos T CD8-Positivos/metabolismo , Separação Celular/métodos , Citomegalovirus/metabolismo , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/virologia , Feminino , Rejeição de Enxerto/imunologia , Humanos , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Células Matadoras Naturais/imunologia , Cinética , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Análise de Célula Única/métodos , Viremia/imunologia , Viremia/virologia
6.
Microbiol Spectr ; 10(1): e0085321, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35019681

RESUMO

Although combination antiretroviral therapy (cART) can suppress the replication of HIV, the virus persists and rebounds when treatment is stopped. To find a cure that can eradicate latent reservoir, a method should be able to quantify the lingering HIV. Unlike other digital PCR technologies, droplet digital PCR (ddPCR), provides absolute quantification of target DNA molecules using fluorescent dually labeled probes by massively partitioning the sample into droplets. ddPCR enables exquisitely sensitive detection and quantification of viral DNA from very limiting clinical samples, including brain tissues. We developed and optimized duplex ddPCR assays for the detection and quantification of HIV proviral DNA and integrated DNA in the brain of HIV-1-infected patients. We have applied these approaches to successfully analyze 77 human brain tissues obtained from 27 HIV-1-infected individuals, either fully virally suppressed or with encephalitis, and were able to quantify low levels of viral DNA. Further developments and advancement of digital PCR technology is promising to aid in accurate quantification and characterization of the persistent HIV reservoir. IMPORTANCE We developed ddPCR assays to quantitatively measure HIV DNA and used this ddPCR assays to detect and quantitatively measure HIV DNA in the archived brain tissues from HIV patients. The tissue viral loads assessed by ddPCR was highly correlative with those assessed by qPCR. HIV DNA in the brain was detected more frequently by ddPCR than by qPCR. ddPCR also showed higher sensitivity than qPCR since ddPCR detected HIV DNA signals in some tissues from virally suppressed individuals while qPCR could not.


Assuntos
Encéfalo/virologia , Encefalite/virologia , Infecções por HIV/virologia , HIV-1/genética , Reação em Cadeia da Polimerase/métodos , Provírus/genética , Viremia/virologia , DNA Viral/genética , Encefalite/imunologia , Infecções por HIV/imunologia , HIV-1/isolamento & purificação , HIV-1/fisiologia , Humanos , Provírus/isolamento & purificação , Provírus/fisiologia , Carga Viral , Viremia/imunologia , Integração Viral
7.
Nat Commun ; 13(1): 121, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013215

RESUMO

HIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1. Utilizing genetically barcoded virus technology, we show these natural killer cells efficiently reduced viral clones rebounding from latency. Moreover, a kick and kill strategy comprised of the protein kinase C modulator and latency reversing agent SUW133 and allogeneic human peripheral blood natural killer cells during anti-retroviral therapy eliminated the viral reservoir in a subset of mice. Therefore, combinations utilizing latency reversal agents with targeted cellular killing agents may be an effective approach to eradicating the viral reservoir.


Assuntos
Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/terapia , HIV-1/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Inibidores de Proteínas Quinases/farmacologia , Viremia/terapia , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/virologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Técnicas de Cocultura , Feminino , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Células Matadoras Naturais/transplante , Masculino , Camundongos , Camundongos Transgênicos , Proteína Quinase C/genética , Proteína Quinase C/imunologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/virologia , Carga Viral/efeitos dos fármacos , Viremia/genética , Viremia/imunologia , Viremia/virologia , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
8.
Am J Gastroenterol ; 117(2): 288-294, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506308

RESUMO

INTRODUCTION: The necessity of antiviral therapy (AVT) for hepatitis B virus (HBV)-infected compensated cirrhosis with low-level viremia (LLV) is controversial. Herein, we evaluated its natural history. METHODS: From 3 tertiary hospitals, we enrolled untreated patients with compensated cirrhosis with persistent serum HBV-DNA levels <2,000 IU/mL; LLV was defined as having at least 1 detectable serum HBV-DNA (20-2,000 IU/mL) episode, whereas maintained virological response (MVR) was defined as having persistently undetectable serum HBV-DNA (<20 IU/mL). When serum HBV-DNA was ≥2,000 IU/mL during follow-up, AVT was administered according to guidelines. Study end points were development of cirrhotic complication event (CCE) or hepatocellular carcinoma (HCC). RESULTS: Among 567 patients analyzed, cumulative HCC risk at 3, 5, and 7 years was comparable between LLV (n = 391) vs MVR (n = 176) groups (5.7%, 10.7%, and 17.3% vs 7.2%, 15.5%, and 19.4%, respectively [P = 0.390]). CCE risk was also comparable between 2 groups (7.5%, 12.8%, and 13.7% vs 7.8%, 12.3%, and 14.6%, respectively [P = 0.880]). By multivariate analysis, LLV (vs MVR) was not associated with HCC or CCE risks, with adjusted hazard ratios of 1.422 (95% confidence interval [CI] 0.694-2.913; P = 0.336) and 1.816 (95% CI: 0.843-3.911; P = 0.128), respectively. Inverse probability of treatment weighting analysis yielded comparable outcomes between 2 groups, regarding HCC and CCE risks with hazard ratios of 0.903 (95% CI: 0.528-1.546; P = 0.711) and 1.192 (95% CI: 0.675-2.105; P = 0.545), respectively. DISCUSSION: Episodic LLV among untreated patients with compensated cirrhosis does not increase the risk of disease progression compared with MVR status. Thus, the benefits of AVT for episodic LLV should be re-evaluated.


Assuntos
DNA Viral/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Cirrose Hepática/etiologia , Carga Viral , Viremia/diagnóstico , Biomarcadores/sangue , Estudos Transversais , Progressão da Doença , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Viremia/complicações , Viremia/virologia
9.
J Virol ; 96(1): e0134021, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-34643433

RESUMO

The limited knowledge on the role of many of the approximately 170 proteins encoded by African swine fever virus restricts progress toward vaccine development. Previously, the DP148R gene was deleted from the genome of genotype I virulent Benin 97/1 isolate. This virus, BeninΔDP148R, induced transient moderate clinical signs after immunization and high levels of protection against challenge. However, the BeninΔDP148R virus and genome persisted in blood over a prolonged period. In the current study, deletion of either EP402R or EP153R genes individually or in combination from BeninΔDP148R genome was shown not to reduce virus replication in macrophages in vitro. However, deletion of EP402R dramatically reduced the period of infectious virus persistence in blood in immunized pigs from 28 to 14 days and virus genome from 59 to 14 days while maintaining high levels of protection against challenge. The additional deletion of EP153R (BeninΔDP148RΔEP153RΔEP402R) further attenuated the virus, and no viremia or clinical signs were observed postimmunization. This was associated with decreased protection and detection of moderate levels of challenge virus in blood. Interestingly, the deletion of EP153R alone from BeninΔDP148R did not result in further virus attenuation and did not reduce the period of virus persistence in blood. These results show that EP402R and EP153R have a synergistic role in reducing clinical signs and levels of virus in blood. IMPORTANCE African swine fever virus (ASFV) causes a disease of domestic pigs and wild boar which results in death of almost all infected animals. The disease has a high economic impact, and no vaccine is available. We investigated the role of two ASFV proteins, called EP402R and EP153R, in determining the levels and length of time virus persists in blood from infected pigs. EP402R causes ASFV particles and infected cells to bind to red blood cells. Deletion of the EP402R gene dramatically reduced virus persistence in blood but did not reduce the level of virus. Deletion of the EP153R gene alone did not reduce the period or level of virus persistence in blood. However, deleting both EP153R and EP402R resulted in undetectable levels of virus in blood and no clinical signs showing that the proteins act synergistically. Importantly, the infected pigs were protected following infection with the wild-type virus that kills pigs.


Assuntos
Vírus da Febre Suína Africana/fisiologia , Febre Suína Africana/virologia , Proteínas Virais/metabolismo , Viremia/virologia , Febre Suína Africana/imunologia , Febre Suína Africana/metabolismo , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , Antígenos Virais/metabolismo , Biomarcadores , Células Cultivadas , Engenharia Genética , Genótipo , Interações Hospedeiro-Patógeno , Imunização , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/virologia , Deleção de Sequência , Suínos , Proteínas Virais/genética , Proteínas Virais/imunologia , Vacinas Virais/imunologia , Virulência , Replicação Viral
10.
J Virol ; 96(1): e0149921, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-34668779

RESUMO

Human immunodeficiency virus type 1 (HIV-1) viremic nonprogressors (VNPs) represent a very rare HIV-1 extreme phenotype. VNPs are characterized by persistent high plasma viremia and maintenance of CD4+ T-cell counts in the absence of treatment. However, the causes of nonpathogenic HIV-1 infection in VNPs remain elusive. Here, we identified for the first time two VNPs who experienced the loss of CD4+ homeostasis (LoH) after more than 13 years. We characterized in deep detail viral and host factors associated with the LoH and compared with standard VNPs and healthy controls. The viral factors determined included HIV-1 coreceptor usage and replicative capacity. Changes in CD4+ and CD8+ T-cell activation, maturational phenotype, and expression of CCR5 and CXCR6 in CD4+ T-cells were also evaluated as host-related factors. Consistently, we determined a switch in HIV-1 coreceptor use to CXCR4 concomitant with an increase in replicative capacity at the LoH for the two VNPs. Moreover, we delineated an increase in the frequency of HLA-DR+CD38+ CD4+ and CD8+ T cells and traced the augment of naive T-cells upon polyclonal activation with LoH. Remarkably, very low and stable levels of CCR5 and CXCR6 expression in CD4+ T-cells were measured over time. Overall, our results demonstrated HIV-1 evolution toward highly pathogenic CXCR4 strains in the context of very limited and stable expression of CCR5 and CXCR6 in CD4+ T cells as potential drivers of LoH in VNPs. These data bring novel insights into the correlates of nonpathogenic HIV-1 infection. IMPORTANCE The mechanism behind nonpathogenic human immunodeficiency virus type 1 (HIV-1) infection remains poorly understood, mainly because of the very low frequency of viremic nonprogressors (VNPs). Here, we report two cases of VNPs who experienced the loss of CD4+ T-cell homeostasis (LoH) after more than 13 years of HIV-1 infection. The deep characterization of viral and host factors supports the contribution of viral and host factors to the LoH in VNPs. Thus, HIV-1 evolution toward highly replicative CXCR4 strains together with changes in T-cell activation and maturational phenotypes were found. Moreover, we measured very low and stable levels of CCR5 and CXCR6 in CD4+ T-cells over time. These findings support viral evolution toward X4 strains limited by coreceptor expression to control HIV-1 pathogenesis and demonstrate the potential of host-dependent factors, yet to be fully elucidated in VNPs, to control HIV-1 pathogenesis.


Assuntos
Contagem de Linfócito CD4 , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Carga Viral , Viremia/virologia , Feminino , Infecções por HIV/imunologia , HIV-1/classificação , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ativação Linfocitária , Masculino , Filogenia , Receptores CCR5/metabolismo , Receptores CCR6/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
11.
Ann Intern Med ; 175(1): 95-100, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34781719

RESUMO

BACKGROUND: A sterilizing cure of HIV-1 infection has been reported in 2 persons living with HIV-1 who underwent allogeneic hematopoietic stem cell transplantations from donors who were homozygous for the CCR5Δ32 gene polymorphism. However, this has been considered elusive during natural infection. OBJECTIVE: To evaluate persistent HIV-1 reservoir cells in an elite controller with undetectable HIV-1 viremia for more than 8 years in the absence of antiretroviral therapy. DESIGN: Detailed investigation of virologic and immunologic characteristics. SETTING: Tertiary care centers in Buenos Aires, Argentina, and Boston, Massachusetts. PATIENT: A patient with HIV-1 infection and durable drug-free suppression of HIV-1 replication. MEASUREMENTS: Analysis of genome-intact and replication-competent HIV-1 using near-full-length individual proviral sequencing and viral outgrowth assays, respectively; analysis of HIV-1 plasma RNA by ultrasensitive HIV-1 viral load testing. RESULTS: No genome-intact HIV-1 proviruses were detected in analysis of a total of 1.188 billion peripheral blood mononuclear cells and 503 million mononuclear cells from placental tissues. Seven defective proviruses, some of them derived from clonally expanded cells, were detected. A viral outgrowth assay failed to retrieve replication-competent HIV-1 from 150 million resting CD4+ T cells. No HIV-1 RNA was detected in 4.5 mL of plasma. LIMITATIONS: Absence of evidence for intact HIV-1 proviruses in large numbers of cells is not evidence of absence of intact HIV-1 proviruses. A sterilizing cure of HIV-1 can never be empirically proved. CONCLUSION: Genome-intact and replication-competent HIV-1 were not detected in an elite controller despite analysis of massive numbers of cells from blood and tissues, suggesting that this patient may have naturally achieved a sterilizing cure of HIV-1 infection. These observations raise the possibility that a sterilizing cure may be an extremely rare but possible outcome of HIV-1 infection. PRIMARY FUNDING SOURCE: National Institutes of Health and Bill & Melinda Gates Foundation.


Assuntos
Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1/genética , Receptores CCR5/genética , Adulto , Argentina , Linfócitos T CD4-Positivos/imunologia , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno , Humanos , Massachusetts , Gravidez , Resultado da Gravidez , Provírus/genética , Provírus/imunologia , Carga Viral , Viremia/virologia , Replicação Viral/imunologia
12.
J Virol ; 96(2): e0153521, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34757843

RESUMO

HIV-specific CD8+ T cells play a central role in immune control of adult HIV, but their contribution in pediatric infection is less well characterized. Previously, we identified a group of ART-naive children with persistently undetectable plasma viremia, termed "elite controllers," and a second group who achieved aviremia only transiently. To investigate the mechanisms of failure to maintain aviremia, we characterized in three transient aviremic individuals (TAs), each of whom expressed the disease-protective HLA-B*81:01, longitudinal HIV-specific T-cell activity, and viral sequences. In two TAs, a CD8+ T-cell response targeting the immunodominant epitope TPQDLNTML (Gag-TL9) was associated with viral control, followed by viral rebound and the emergence of escape variants with lower replicative capacity. Both TAs mounted variant-specific responses, but only at low functional avidity, resulting in immunological progression. In contrast, in TA-3, intermittent viremic episodes followed aviremia without virus escape or a diminished CD4+ T-cell count. High quality and magnitude of the CD8+ T-cell response were associated with aviremia. We therefore identify two distinct mechanisms of loss of viral control. In one scenario, CD8+ T-cell responses initially cornered low-replicative-capacity escape variants, but with insufficient avidity to prevent viremia and disease progression. In the other, loss of viral control was associated with neither virus escape nor progression but with a decrease in the quality of the CD8+ T-cell response, followed by recovery of viral control in association with improved antiviral response. These data suggest the potential for a consistently strong and polyfunctional antiviral response to achieve long-term viral control without escape. IMPORTANCE Very early initiation of antiretroviral therapy (ART) in pediatric HIV infection offers a unique opportunity to limit the size and diversity of the viral reservoir. However, only rarely is ART alone sufficient to achieve remission. Additional interventions that likely include contributions from host immunity are therefore required. The HIV-specific T-cell response plays a central role in immune control of adult HIV, often mediated through protective alleles such as HLA-B*57/58:01/81:01. However, due to the tolerogenic and type 2 biased immune response in early life, HLA-I-mediated immune suppression of viremia is seldom observed in children. We assessed a rare group of HLA-B*81:01-positive, ART-naive children who achieved aviremia, albeit only transiently, and investigated the role of the CD8+ T-cell response in the establishment and loss of viral control. We identified a mechanism by which the HIV-specific response can achieve viremic control without viral escape that can be explored in strategies to achieve remission.


Assuntos
Infecções por HIV/imunologia , Sobreviventes de Longo Prazo ao HIV , Viremia/imunologia , Adolescente , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Criança , Pré-Escolar , Feminino , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , Antígenos HLA-B/imunologia , Humanos , Evasão da Resposta Imune , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/imunologia , Lactente , Masculino , Carga Viral , Viremia/virologia , Replicação Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
13.
J Med Virol ; 94(4): 1734-1737, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34897741

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load dynamics in respiratory samples have been studied, but knowledge about changes in serial serum samples of infected patients in relation to their immunological response is lacking. We investigated the dynamics of SARS-CoV-2 viral load and antibody response in sequential serum of coronavirus disease 2019 (COVID-19) patients and attempted to culture the virus in the serum. A total of 81 sequential serum samples from 10 confirmed COVID-19 patients (5 with mild and 5 with moderate symptoms) were analyzed. Samples were collected during hospitalization and after discharge (median follow-up of 35 days). SARS-CoV-2 ribonucleic acid in the serum was detected by real-time polymerase chain reaction. Total antibody and IgG to SARS-CoV-2 Spike protein were analyzed by Chemiluminescent Immunoassays, and neutralizing antibodies were detected using a Surrogate Virus Neutralization Test. Viremia was observed in all cases at admission, and viral copy gradually dropped to undetectable levels in patients with mild symptoms but fluctuated and remained persistent in moderate cases. The viral culture of samples with the highest viral load for each patient did not show any cytopathic change. The antibody response was faster and higher in moderate cases. This study provides a basic clue for infectious severity-dependent immune response, viremia, and antibody acquisition pattern.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Viremia/imunologia , Viremia/virologia , Adulto , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Feminino , Seguimentos , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/genética , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Carga Viral
14.
J Virol ; 96(4): e0186721, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-34878888

RESUMO

Common to all cytomegalovirus (CMV) genomes analyzed to date is the presence of G protein-coupled receptors (GPCR). Animal models of CMV provide insights into their role in viral fitness. The mouse cytomegalovirus (MCMV) GPCR, M33, facilitates dendritic cell (DC)-dependent viremia, the extravasation of blood-borne infected DCs to the salivary gland, and the frequency of reactivation events from latently infected tissue explants. Constitutive G protein-coupled M33 signaling is required for these phenotypes, although the contribution of distinct biochemical pathways activated by M33 is unknown. M33 engages Gq/11 to constitutively activate phospholipase C ß (PLCß) and downstream cyclic AMP response-element binding protein (CREB) in vitro. Identification of a MCMV M33 mutant (M33ΔC38) for which CREB signaling was disabled but PLCß activation was preserved provided the opportunity to investigate their relevance in vivo. Following intranasal infection with MCMV M33ΔC38, the absence of M33 CREB Gq/11-dependent signaling correlated with reduced mobilization of lytically-infected DCs to the draining lymph node high endothelial venules (HEVs) and reduced viremia compared with wild type MCMV. In contrast, M33ΔC38-infected DCs within the vascular compartment extravasated to the salivary glands via a pertussis toxin-sensitive, Gi/o-dependent, and CREB-independent mechanism. In the context of MCMV latency, spleen explants from M33ΔC38-infected mice were markedly attenuated for reactivation. Taken together, these data demonstrate that key features of the MCMV life cycle are coordinated in diverse tissues by distinct pathways of the M33 signaling repertoire. IMPORTANCE G protein-coupled receptors (GPCRs) act as cell surface molecular "switches" that regulate the cellular response to environmental stimuli. All cytomegalovirus (CMV) genomes analyzed to date possess GPCR homologs with phylogenetic evidence for independent gene capture events, signifying important in vivo roles. The mouse CMV (MCMV) GPCR homolog, designated M33, is important for cell-associated virus spread and the establishment and/or reactivation of latent MCMV infection. The signaling repertoire of M33 is distinct from cellular GPCRs and little is known of the relevance of component signaling pathways for in vivo M33 function. In this report, we showed that temporal and tissue-specific M33 signaling was required to facilitate in vivo infection. Understanding the relevance of the viral GPCR signaling profiles for in vivo function will provide opportunities for future targeted interventions.


Assuntos
Infecções por Herpesviridae/virologia , Muromegalovirus/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Virais/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Células Dendríticas/virologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Infecções por Herpesviridae/metabolismo , Linfonodos/virologia , Camundongos , Camundongos Endogâmicos BALB C , Muromegalovirus/genética , Muromegalovirus/metabolismo , Mutação , Fosfolipase C beta/metabolismo , Receptores Acoplados a Proteínas G/genética , Glândulas Salivares/virologia , Transdução de Sinais , Proteínas Virais/genética , Viremia/metabolismo , Viremia/virologia , Ativação Viral/genética
15.
Dev Comp Immunol ; 127: 104291, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34710469

RESUMO

Spring viremia of carp virus (SVCV) causes severe morbidity and mortality in grass carp (Ctenopharyngodon idellus) in Europe, America and several Asian countries. We found that FKBP5 (FK506-binding protein 5) is an SVCV infection response factor; however, its role in the innate immune mechanism caused by SVCV infection remains unknown. This study cloned gcFKBP5 (grass carp FKBP5) and made its mimic protein structure for function discussion. We found that gcFKBP5 expression in the primary innate immune organs of grass carp, including intestine, liver and spleen, was highly upregulated by SVCV in 24 h, with a similar result in fish cells by poly(I:C) treatment. gcFKBP overexpression aggravates viral damage to cells and increases viral replication. Furthermore, SVCV engages gcFKBP5 interacting with TRAF2 (tumour necrosis factor receptor-associated factor 2) to promote host cell apoptosis for supporting viral replication. The enhanced viral replication seems not to be due to the repression of IFN and other antiviral factors as expected. For the first time, these data show the pivotal role of gcFKBP5 in the innate immune response of grass carp to SVCV infection.


Assuntos
Carpas , Doenças dos Peixes , Infecções por Rhabdoviridae , Rhabdoviridae , Proteínas de Ligação a Tacrolimo , Replicação Viral , Animais , Apoptose , Doenças dos Peixes/metabolismo , Doenças dos Peixes/virologia , Proteínas de Peixes/metabolismo , Rhabdoviridae/fisiologia , Fator 2 Associado a Receptor de TNF/genética , Proteínas de Ligação a Tacrolimo/metabolismo , Viremia/metabolismo , Viremia/virologia
16.
PLoS Pathog ; 17(12): e1010165, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34929000

RESUMO

The HIV latent reservoir exhibits slow decay on antiretroviral therapy (ART), impacted by homeostatic proliferation and activation. How these processes contribute to the total dynamic while also producing the observed profile of sampled latent clone sizes is unclear. An agent-based model was developed that tracks individual latent clones, incorporating homeostatic proliferation of cells and activation of clones. The model was calibrated to produce observed latent reservoir dynamics as well as observed clonal size profiles. Simulations were compared to previously published latent HIV integration data from 5 adults and 3 children. The model simulations reproduced reservoir dynamics as well as generating residual plasma viremia levels (pVL) consistent with observations on ART. Over 382 Latin Hypercube Sample simulations, the median latent reservoir grew by only 0.3 log10 over the 10 years prior to ART initiation, after which time it decreased with a half-life of 15 years, despite number of clones decreasing at a faster rate. Activation produced a maximum size of genetically intact clones of around one million cells. The individual simulation that best reproduced the sampled clone profile, produced a reservoir that decayed with a 13.9 year half-life and where pVL, produced mainly from proliferation, decayed with a half-life of 10.8 years. These slow decay rates were achieved with mean cell life-spans of only 14.2 months, due to expansion of the reservoir through proliferation and activation. Although the reservoir decayed on ART, a number of clones increased in size more than 4,000-fold. While small sampled clones may have expanded through proliferation, the large sizes exclusively arose from activation. Simulations where homeostatic proliferation contributed more to pVL than activation, produced pVL that was less variable over time and exhibited fewer viral blips. While homeostatic proliferation adds to the latent reservoir, activation can both add and remove latent cells. Latent activation can produce large clones, where these may have been seeded much earlier than when first sampled. Elimination of the reservoir is complicated by expanding clones whose dynamic differ considerably to that of the entire reservoir.


Assuntos
Infecções por HIV/virologia , Infecção Latente/virologia , Modelos Teóricos , Latência Viral/fisiologia , Proliferação de Células/fisiologia , Células Clonais/virologia , Humanos , Viremia/virologia , Replicação Viral/fisiologia
17.
PLoS One ; 16(12): e0260010, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34855793

RESUMO

Little is known about how specific individual viral lineages replicating systemically during acute Human Immunodeficiency Virus or Simian Immunodeficiency Virus (HIV/SIV) infection persist into chronic infection. In this study, we use molecularly barcoded SIV (SIVmac239M) to track distinct viral lineages for 12 weeks after intravenous (IV) or intrarectal (IR) challenge in macaques. Two Mafa-A1*063+ cynomolgus macaques (Macaca fascicularis, CM) were challenged IV, and two Mamu-A1*001+ rhesus macaques (Macaca mulatta, RM) were challenged IR with 200,000 Infectious Units (IU) of SIVmac239M. We sequenced the molecular barcode of SIVmac239M from all animals over the 12 weeks of the study to characterize the diversity and persistence of virus lineages. During the first three weeks post-infection, we found ~70-560 times more unique viral lineages circulating in the animals challenged IV compared to those challenged IR, which is consistent with the hypothesis that the challenge route is the primary driver restricting the transmission of individual viral lineages. We also characterized the sequences of T cell epitopes targeted during acute SIV infection, and found that the emergence of escape variants in acutely targeted epitopes can occur on multiple virus templates simultaneously, but that elimination of some of these templates is likely a consequence of additional host factors. These data imply that virus lineages present during acute infection can still be eliminated from the systemic virus population even after initial selection.


Assuntos
Membrana Mucosa/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Animais , Epitopos/imunologia , Feminino , Produtos do Gene tat/genética , Injeções Intravenosas , Macaca fascicularis/imunologia , Macaca fascicularis/virologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Membrana Mucosa/imunologia , Mutação , RNA Viral/sangue , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/patogenicidade , Linfócitos T/imunologia , Linfócitos T/virologia , Carga Viral , Viremia/imunologia , Viremia/virologia
18.
PLoS One ; 16(12): e0260892, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34855890

RESUMO

With the highest HIV incidence and prevalence globally, the government of Eswatini started a substantial scale-up of HIV treatment and prevention services in 2011. Two sequential large population-based surveys were conducted before and after service expansion to assess the impact of the national response. Cross-sectional, household-based, nationally representative samples of adults, ages 18 to 49 years, were sampled in 2011 and 2016. We measured HIV prevalence, incidence (recent infection based on limiting antigen ≤1.5 optical density units and HIV RNA ≥1000 copies/mL), viral load suppression (HIV RNA <1000 copies/mL among all seropositive adults) and unsuppressed viremia (HIV RNA ≥1000 copies/mL among all, regardless of HIV status) and assessed for temporal changes by conducting a trend analysis of the log ratio of proportions, using a Z statistic distribution. HIV prevalence remained stable from 2011 to 2016 [32% versus 30%, p = 0.10]. HIV incidence significantly declined 48% [2.48% versus 1.30%, p = 0.01]. Incidence remained higher among women than men [2011: 3.16% versus 1.83%; 2016: 1.76% versus 0.86%], with a smaller but significant relative reduction among women [44%; p = 0.04] than men [53%; p = 0.09]. The proportion of seropositive adults with viral load suppression significantly increased from 35% to 71% [p < .001]. The proportion of the total adult population with unsuppressed viremia decreased from 21% to 9% [p < .001]. National HIV incidence in Eswatini decreased by nearly half and viral load suppression doubled over a five-year period. Unsuppressed viremia in the total population decreased 58%. These population-based findings demonstrate the national impact of expanded HIV services in a hyperendemic country.


Assuntos
Infecções por HIV/epidemiologia , HIV-1/isolamento & purificação , Carga Viral , Viremia/epidemiologia , Adolescente , Adulto , Estudos Transversais , Essuatíni/epidemiologia , Feminino , Infecções por HIV/virologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Viremia/virologia , Adulto Jovem
19.
Front Immunol ; 12: 758368, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858411

RESUMO

The porcine respiratory disease complex (PRDC) is responsible for significant economic losses in the pig industry worldwide. Porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza virus are major viral contributors to PRDC. Vaccines are cost-effective measures for controlling PRRS, however, their efficacy in the context of co-infections has been poorly investigated. In this study, we aimed to determine the effect of PRRSV-2 and swine influenza H3N2 virus co-infection on the efficacy of PRRSV modified live virus (MLV) vaccination, which is widely used in the field. Following simultaneous challenge with contemporary PRRSV-2 and H3N2 field isolates, we found that the protective effect of PRRS MLV vaccination on clinical disease and pathology was abrogated, although viral load was unaffected and antibody responses were enhanced. In contrast, co-infection in non-immunized animals reduced PRRSV-2 viremia and H3N2 virus load in the upper respiratory tract and potentiated T cell responses against both PRRSV-2 and H3N2 in the lung. Further analysis suggested that an upregulation of inhibitory cytokines gene expression in the lungs of vaccinated pigs may have influenced responses to H3N2 and PRRSV-2. These findings provide important insights into the effect of viral co-infections on PRRS vaccine efficacy that may help identify more effective vaccination strategies against PRDC in the field.


Assuntos
Coinfecção/veterinária , Vírus da Influenza A Subtipo H3N2/imunologia , Infecções por Orthomyxoviridae/imunologia , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/biossíntese , Coinfecção/imunologia , Coinfecção/virologia , Citocinas/biossíntese , Citocinas/genética , Conjuntos de Dados como Assunto , Cães , Feminino , Células Madin Darby de Rim Canino , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/virologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Suínos , Vacinação/veterinária , Eficácia de Vacinas , Vacinas Atenuadas/imunologia , Carga Viral , Viremia/prevenção & controle , Viremia/virologia
20.
PLoS Pathog ; 17(11): e1010034, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34762717

RESUMO

Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. Using in vivo phenotypic analyses, we found that Siglec-9+ CD56dim NK cells, during HIV infection, exhibit an activated phenotype with higher expression of activating receptors and markers (NKp30, CD38, CD16, DNAM-1, perforin) and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9- CD56dim NK cells. We also found that levels of Siglec-9+ CD56dim NK cells inversely correlate with viral load during viremic infection and CD4+ T cell-associated HIV DNA during suppressed infection. Using in vitro cytotoxicity assays, we confirmed that Siglec-9+ NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9- NK cells. These data are consistent with the notion that Siglec-9+ NK cells are highly cytotoxic against HIV-infected cells. However, blocking Siglec-9 enhanced NK cells' ability to lyse HIV-infected cells, consistent with the known inhibitory function of the Siglec-9 molecule. Together, these data support a model in which the Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells even whilst being restrained by the inhibitory effects of Siglec-9. To harness the cytotoxic capacity of the Siglec-9+ NK subpopulation, which is dampened by Siglec-9, we developed a proof-of-concept approach to selectively disrupt Siglec/sialoglycan interactions between NK and HIV-infected cells. We achieved this goal by conjugating Sialidase to several HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK cells' capacity to kill them. In summary, we identified a novel, glycan-based interaction that may contribute to HIV-infected cells' ability to evade NK immunosurveillance and developed an approach to break this interaction.


Assuntos
Antígenos CD/metabolismo , Antígeno CD56/imunologia , Infecções por HIV/patologia , HIV/fisiologia , Células Matadoras Naturais/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Carga Viral , Viremia/patologia , Antígenos CD/genética , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Células Matadoras Naturais/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Viremia/imunologia , Viremia/metabolismo , Viremia/virologia
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