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1.
Proc Natl Acad Sci U S A ; 118(13)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33771926

RESUMO

Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of N-linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons (Cercopithecus spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.

2.
PLoS Negl Trop Dis ; 14(12): e0008932, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33332357

RESUMO

BACKGROUND: Chagas disease is a neglected zoonosis of growing concern in the southern US, caused by the parasite Trypanosoma cruzi. We genotyped parasites in a large cohort of PCR positive dogs to shed light on parasite transmission cycles and assess potential relationships between parasite diversity and serological test performance. METHODOLOGY/PRINCIPAL FINDINGS: We used a metabarcoding approach based on deep sequencing of T. cruzi mini-exon marker to assess parasite diversity. Phylogenetic analysis of 178 sequences from 40 dogs confirmed the presence of T. cruzi discrete typing unit (DTU) TcI and TcIV, as well as TcII, TcV and TcVI for the first time in US dogs. Infections with multiple DTUs occurred in 38% of the dogs. These data indicate a greater genetic diversity of T. cruzi than previously detected in the US. Comparison of T. cruzi sequence diversity indicated that highly similar T. cruzi strains from these DTUs circulate in hosts and vectors in Louisiana, indicating that they are involved in a shared T. cruzi parasite transmission cycle. However, TcIV and TcV were sampled more frequently in vectors, while TcII and TcVI were sampled more frequently in dogs. CONCLUSIONS/SIGNIFICANCE: These observations point to ecological host-fitting being a dominant mechanism involved in the diversification of T. cruzi-host associations. Dogs with negative, discordant or confirmed positive T. cruzi serology harbored TcI parasites with different mini-exon sequences, which strongly supports the hypothesis that parasite genetic diversity is a key factor affecting serological test performance. Thus, the identification of conserved parasite antigens should be a high priority for the improvement of current serological tests.


Assuntos
Doença de Chagas/veterinária , Éxons/genética , Variação Genética , Trypanosoma cruzi/genética , Animais , Doença de Chagas/epidemiologia , Doença de Chagas/parasitologia , Doença de Chagas/transmissão , Estudos de Coortes , Cães , Genótipo , Humanos , Louisiana/epidemiologia , Filogenia , Testes Sorológicos/veterinária , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/fisiologia , Zoonoses
3.
J Med Primatol ; 49(5): 280-283, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32777101

RESUMO

Through the accumulation of adaptive mutations, HIV-2 originated from SIVsm. To identify these evolutionary changes, a humanized mouse model recapitulated the process that likely enabled this cross-species transmission event. Various adaptive mutations arose, as well as increased virulence and CD4+ T-cell decline as the virus was passaged in humanized mice.

4.
Front Microbiol ; 11: 1889, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849468

RESUMO

The genetic evolution of HIV-1 from its progenitor virus SIV following cross-species transmission is not well understood. Here we simulated the SIVcpz initial transmission to humans using humanized mice and followed the viral evolution during serial passages lasting more than a year. All three SIVcpz progenitor viruses used, namely LB715 and MB897 (group M) as well as EK505 (group N) readily infected hu-mice resulting in chronic viremia. Viral loads increased progressively to higher set-points and the CD4+ T cell decline became more pronounced by the end of the second serial passage indicating viral adaptation and increased pathogenicity. Viral genomes sequenced at different time points revealed many non-synonymous variants not previously reported that occurred throughout the viral genome, including the gag, pol, env, and nef genes. These results shed light on the potential changes that the SIVcpz genome had undergone during the initial stages of human infection and subsequent spread.

5.
Acta Trop ; 212: 105557, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32479838

RESUMO

BACKGROUND: The World Health Organization (WHO) attributes the entirety of malaria infection and transmission in the Democratic Republic of the Congo (DRC) to Plasmodium falciparum, one of the several species of malaria known to infect humans. Recent studies have put forth some evidence that transmission of Plasmodium vivax may also be occurring in the DRC. As interventions and treatments differ between malaria species, it is crucial to maintain the most accurate understanding of malaria species diversity in each region. METHODS: Blood samples were taken from aymptomatic children 0-5 years old living in three regions of the DRC in 2014. For this study, samples were taken from a larger pool of samples, collected as part of a population-based survey in three regions. Plasmodium infection was screened for using nested polymerase chain reaction (PCR) assays and species were confirmed by cloning and DNA sequencing. RESULTS: Of 336 samples screened by PCR, 62.2% (n=209) initially tested positive for P. falciparum and 14.6% (n=49) initially tested positive for P. vivax. Sanger sequencing was performed on PCR-positive Plasmodium samples to confirm identity of Plasmodium species. Sequencing showed Plasmodium malariae in one blood sample and Plasmodium ovale in another sample. Plasmodium vivax was detected in 12/65 cases (18.5%). Overall, 14/65 sequenced cases (21.5%) were infected with a non-falciparum malaria. 330bp 18s P. vivax DNA sequences were obtained. CONCLUSIONS: This study reveals Plasmodium vivax and other non-falciparum malaria across several regions of the DRC, and enforces the importance of further testing and more precise diagnostics when testing for and treating malaria in the DRC. Here, we find a higher proportion of cases of P. vivax malaria than found in previous studies. This is the most robust DNA sequencing of Plasmodium vivax in the DRC to date.

6.
Cell Rep ; 31(6): 107624, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32402293

RESUMO

We compare immunogenicity and protective efficacy of an HIV vaccine comprised of env and gag DNA and Env (Envelope) proteins by co-administration of the vaccine components in the same muscles or by separate administration of DNA + protein in contralateral sites in female rhesus macaques. The 6-valent vaccine includes gp145 Env DNAs, representing six sequentially isolated Envs from the HIV-infected individual CH505, and matching GLA-SE-adjuvanted gp120 Env proteins. Interestingly, only macaques in the co-administration vaccine group are protected against SHIV CH505 acquisition after repeated low-dose intravaginal challenge and show 67% risk reduction per exposure. Macaques in the co-administration group develop higher Env-specific humoral and cellular immune responses. Non-neutralizing Env antibodies, ADCC, and antibodies binding to FcγRIIIa are associated with decreased transmission risk. These data suggest that simultaneous recognition, processing, and presentation of DNA + Env protein in the same draining lymph nodes play a critical role in the development of protective immunity.

7.
Vaccine ; 38(29): 4584-4591, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32417142

RESUMO

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi is one of the most important neglected parasitic diseases in the Americas. Vaccines represent an attractive complementary strategy for the control of T. cruzi infection and pre-clinical studies in mice demonstrated that trypomastigote surface antigen (TSA-1) and the flagellar calcium-binding (Tc24) parasite antigens are promising candidates for vaccine development. We performed here the first evaluation of the safety and immunogenicity of two recombinant vaccine antigens (named TSA1-C4 and Tc24-C4) in naïve non-human primates. Three rhesus macaques received 3 doses of each recombinant protein, formulated with E6020 (Eisai Co., Ltd.), a novel Toll-like receptor-4 agonist, in a stable emulsion. All parameters from blood chemistry and blood cell counts were stable over the course of the study and unaffected by the vaccine. A specific IgG response against both antigens was detectable after the first vaccine dose, and increased with the second dose. After three vaccine doses, stimulation of PBMCs with a peptide pool derived from TSA1-C4 resulted in the induction of TSA1-C4-specific TNFα-, IL-2- and IFNγ-producing CD4+ in one or two animals while stimulation with a peptide pool derived from Tc24-C4 only activated IFNγ-producing CD4+T cells in one animal. In two animals there was also activation of TSA1-C4-specific IL2-producing CD8+ T cells. This is the first report of the immunogenicity of T. cruzi-derived recombinant antigens formulated as an emulsion with a TLR4 agonist in a non-human primate model. Our results strongly support the need for further evaluation of the preventive efficacy of this type of vaccine in non-human primates and explore the effect of the vaccine in a therapeutic model of naturally-infected Chagasic non-human primates, which would strengthen the rationale for the clinical development as a human vaccine against Chagas disease.

8.
J Med Primatol ; 49(1): 40-43, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31576587

RESUMO

HIV-1 evolved from its progenitor SIV strains, but details are lacking on its adaptation to the human host. We followed the evolution of SIVcpz in humanized mice to mimic cross-species transmission. Increasing viral loads, CD4+ T-cell decline, and non-synonymous mutations were seen in the entire genome reflecting viral adaptation.

9.
J Med Primatol ; 49(5): 221, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33460144
10.
J Med Primatol ; 49(5): 284-287, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33460210

RESUMO

HIV-1 evolved from SIV during cross-species transmission events, though viral genetic changes are not well understood. Here, we studied the evolution of SIVcpzLB715 into HIV-1 Group M using humanized mice. High viral loads, rapid CD4+ T-cell decline, and non-synonymous substitutions were identified throughout the viral genome suggesting viral adaptation.

12.
Nat Commun ; 10(1): 3753, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434895

RESUMO

Semen is the vehicle for virion dissemination in the female reproductive tract (FRT) in male-to-female HIV transmission. Recent data suggests that higher frequency semen exposure is associated with activation of anti-HIV mechanisms in HIV negative sex workers. Here, we use a non-human primate (NHP) model to show that repeated vaginal exposure to semen significantly reduces subsequent infection by repeated low-dose vaginal SIVmac251 challenge. Repeated semen exposures result in lower CCR5 expression in circulating CD4+ T-cells, as well as higher expression of Mx1 (in correlation with IFNε expression) and FoxP3 in the cervicovaginal mucosa, and increased infiltration of CD4+ T-cells. Establishing in vivo evidence of competing effects of semen on transmission impacts our basic understanding of what factors may determine HIV infectivity in humans. Our results clearly indicate that repeated semen exposure can profoundly modulate the FRT microenvironment, paradoxically promoting host resistance against HIV acquisition.


Assuntos
Colo do Útero/imunologia , Membrana Mucosa/imunologia , Sêmen/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/imunologia , Vagina/imunologia , Animais , Linfócitos T CD4-Positivos , Colo do Útero/virologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/transmissão , Humanos , Macaca mulatta , Membrana Mucosa/metabolismo , Proteínas de Resistência a Myxovirus/metabolismo , Receptores CCR5/metabolismo , Vagina/virologia
13.
Parasit Vectors ; 12(1): 322, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238941

RESUMO

BACKGROUND: Chagas disease is a zoonotic disease caused by the protozoan parasite Trypanosoma cruzi. The role of dogs as sentinels has been proposed in multiple regions, as they are a domestic reservoir for T. cruzi. Our objective was to determine the prevalence of T. cruzi infection in shelter dogs from southern Louisiana, and assess its magnitude and distribution. RESULTS: A total of 540 dogs were enrolled, from 20 animal shelters, and tested for T. cruzi infection by serological tests (rapid test, ELISA and western blot) and PCR. We documented a high prevalence of T. cruzi infection with at least 6.9% (95% CI: 5.0-9.3%) seropositive and 15.7% (95% CI: 12.9-19.1%) PCR-positive dogs. Serological tests showed limited agreement, and concordance between serology and PCR was higher when considering reactivity to single serological tests. Trypanosoma cruzi infection was distributed evenly among shelters. Infection was significantly correlated with age (R2 = 0.99), indicating an incidence of new cases of 2.27 ± 0.25% per year. CONCLUSION: Trypanosoma cruzi infection is a significant and widespread veterinary problem in shelter dogs in the region, although it is mostly unnoticed by health professionals. This highlights the need for greater awareness of T. cruzi infection among the veterinary community and dog owners.


Assuntos
Doença de Chagas/veterinária , Doenças do Cão/epidemiologia , Cães/parasitologia , Animais , Anticorpos Antiprotozoários/sangue , Doença de Chagas/epidemiologia , Doenças do Cão/parasitologia , Ensaio de Imunoadsorção Enzimática , Feminino , Louisiana/epidemiologia , Masculino , Prevalência , Testes Sorológicos , Trypanosoma cruzi/genética , Trypanosoma cruzi/isolamento & purificação
14.
J Med Primatol ; 47(5): 298-301, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30255956

RESUMO

How SIV progenitors evolved into deadly HIV-1 and HIV-2 following initial cross-species transmission still remains a mystery. Here, we used humanized mice as a human surrogate system to evaluate SIVsm evolution into HIV-2. Increased viral virulence to human CD4+ T cells and adaptive genetic changes were observed during serial passages.


Assuntos
Cercocebus atys/virologia , Modelos Animais de Doenças , HIV-2/crescimento & desenvolvimento , HIV-2/genética , Animais , Humanos , Camundongos , Inoculações Seriadas , Vírus da Imunodeficiência Símia , Carga Viral
16.
J Virol ; 92(18)2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29976668

RESUMO

The host restriction factor tetherin inhibits virion release from infected cells and poses a significant barrier to successful zoonotic transmission of primate lentiviruses to humans. While most simian immunodeficiency viruses (SIV), including the direct precursors of human immunodeficiency virus type 1 (HIV-1) and HIV-2, use their Nef protein to counteract tetherin in their natural hosts, they fail to antagonize the human tetherin ortholog. Pandemic HIV-1 group M and epidemic group O strains overcame this hurdle by adapting their Vpu and Nef proteins, respectively, whereas HIV-2 group A uses its envelope (Env) glycoprotein to counteract human tetherin. Whether or how the remaining eight groups of HIV-2 antagonize this antiviral factor has remained unclear. Here, we show that Nef proteins from diverse groups of HIV-2 do not or only modestly antagonize human tetherin, while their ability to downmodulate CD3 and CD4 is highly conserved. Experiments in transfected cell lines and infected primary cells revealed that not only Env proteins of epidemic HIV-2 group A but also those of a circulating recombinant form (CRF01_AB) and rare groups F and I decrease surface expression of human tetherin and significantly enhance progeny virus release. Intriguingly, we found that many SIVsmm Envs also counteract human as well as smm tetherin. Thus, Env-mediated tetherin antagonism in different groups of HIV-2 presumably stems from a preadaptation of their SIVsmm precursors to humans. In summary, we identified a phenotypic trait of SIVsmm that may have facilitated its successful zoonotic transmission to humans and the emergence of HIV-2.IMPORTANCE HIV-2 groups A to I resulted from nine independent cross-species transmission events of SIVsmm to humans and differ considerably in their prevalence and geographic spread. Thus, detailed characterization of these viruses offers a valuable means to elucidate immune evasion mechanisms and human-specific adaptations determining viral spread. In a systematic comparison of rare and epidemic HIV-2 groups and their simian SIVsmm counterparts, we found that the ability of Nef to downmodulate the primary viral entry receptor CD4 and the T cell receptor CD3 is conserved, while effects on CD28, CD74, and major histocompatibility complex class I surface expression vary considerably. Furthermore, we show that not only the Env proteins of HIV-2 groups A, AB, F, and I but also those of some SIVsmm isolates antagonize human tetherin. This finding helps to explain why SIVsmm has been able to cross the species barrier to humans on at least nine independent occasions.


Assuntos
Antígenos CD/genética , Produtos do Gene nef/genética , HIV-2/genética , Vírus da Imunodeficiência Símia/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Antígenos CD/metabolismo , Complexo CD3/genética , Antígenos CD4/genética , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , HIV-2/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Vírus da Imunodeficiência Símia/metabolismo
17.
Hum Vaccin Immunother ; 14(9): 2163-2177, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29939820

RESUMO

HIV sequence diversity and the propensity of eliciting immunodominant responses targeting inessential variable regions are hurdles in the development of an effective AIDS vaccine. We developed a DNA vaccine comprising conserved elements (CE) of SIV p27Gag and HIV-1 Env and found that priming vaccination with CE DNA is critical to efficiently overcome the dominance imposed by Gag and Env variable regions. Here, we show that DNA vaccinated macaques receiving the CE prime/CE+full-length DNA co-delivery booster vaccine regimens developed broad, potent and durable cytotoxic T cell responses targeting conserved protein segments of SIV Gag and HIV Env. Gag CE-specific T cells showed robust anamnestic responses upon infection with SIVmac239 which led to the identification of CE-specific cytotoxic lymphocytes able to recognize epitopes covering distinct CE on the surface of SIV infected cells in vivo. Though not controlling infection overall, we found an inverse correlation between Gag CE-specific CD8+ T cell responses and peak viremia. The T cell responses induced by the HIV Env CE immunogen were recalled in some animals upon SIV infection, leading to the identification of two cross-reactive epitopes between HIV and SIV Env based in sequence homology. These data demonstrate that a vaccine combining Gag and Env CE DNA subverted the normal immunodominance patterns, eliciting immune responses that included subdominant, highly conserved epitopes. These vaccine regimens augment cytotoxic T cell responses to highly conserved epitopes in the viral proteome and maximize response breadth. The vaccine-induced CE-specific T cells were expanded upon SIV infection, indicating that the predicted CE epitopes incorporated in the DNA vaccine are processed and exposed by infected cells in their natural context within the viral proteome.


Assuntos
Vacinas contra a AIDS/imunologia , Epitopos de Linfócito T/imunologia , Produtos do Gene env/imunologia , Produtos do Gene gag/imunologia , Vacinas contra a SAIDS/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas de DNA/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Animais , Sequência Conservada , Produtos do Gene env/genética , Produtos do Gene gag/genética , Esquemas de Imunização , Macaca , Masculino , Vacinas contra a SAIDS/administração & dosagem , Vacinas contra a SAIDS/genética , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética , Viremia/prevenção & controle
18.
Virology ; 510: 175-184, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28750321

RESUMO

HIV-2 is thought to have originated from an SIV progenitor native to sooty mangabeys. To model the initial human transmission and understand the sequential viral evolution, humanized mice were infected with SIVsm and serially passaged for five generations. Productive infection was seen by week 3 during the initial challenge followed by chronic viremia and gradual CD4+ T cell decline. Viral loads increased by the 5th generation resulting in more rapid CD4+ T cell decline. Genetic analysis revealed several amino acid substitutions that were nonsynonymous and fixed in multiple hu-mice across each of the 5 generations in the nef, env and rev regions. The highest rate of substitution occurred in the nef and env regions and most were observed within the first two generations. These data demonstrated the utility of hu-mice in modeling the SIVsm transmission to the human and to evaluate its potential sequential evolution into a human pathogen of HIV-2 lineage.


Assuntos
Cercocebus atys/virologia , Evolução Molecular , HIV-2/crescimento & desenvolvimento , HIV-2/genética , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Vírus da Imunodeficiência Símia/genética , Substituição de Aminoácidos , Animais , Contagem de Linfócito CD4 , Humanos , Camundongos , Camundongos SCID , Modelos Biológicos , Inoculações Seriadas , Carga Viral , Proteínas Virais/genética
19.
J Med Primatol ; 46(4): 120, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28748660
20.
J Med Primatol ; 46(4): 119, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28748663
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