Identification of the HIV Reservoir in Lymph Nodes Using Single Cell RNA-Seq

使用单细胞 RNA-Seq 鉴定淋巴结中的 HIV 储库

• 批准号: 10333216
• 负责人: Alexander Sigal
• 金额: $ 14.19万
• 依托单位: KWAZULU-NATAL RESEARCH INSTITUTE TB-HIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333216
• 关键词: AIDS/HIV problem; Adherence; Africa South of the Sahara; Anatomy; Anti-Retroviral Agents; Antiretroviral resistance; Atlases; BLR1 gene; Biological Assay; Biology; CD3 Antigens; CD4 Positive T Lymphocytes; Cell Separation; Cell Therapy; Cell surface; Cells; Characteristics; Clinical; Collaborations; Collection; Complement; Computer Analysis; DNA; Dependence; Development; Elements; Epidemic; Frequencies; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; Goals; HIV; HIV Genome; HIV Infections; Helper-Inducer T-Lymphocyte; Heterogeneity; High Prevalence; Hospitals; Human; ImmunoPET; Individual; Infection; Institutional Review Boards; Joints; Lead; Lymphocyte; Macaca; Maintenance; Messenger RNA; Operative Surgical Procedures; Participant; Patients; Penetration; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Play; Prevalence; Production; Protocols documentation; Recording of previous events; Regimen; Reporting; Role; SIV; Seeds; Shock; Site; Source; South Africa; South African; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Technology; Testing; Tissues; Transcript; Viral; Viral reservoir; Virus; Virus Replication; antiretroviral therapy; base; cell type; cohort; density; experimental study; gene therapy; lymph nodes; mRNA Expression; macrophage; novel strategies; patient population; peripheral blood; programmed cell death protein 1; replication therapy; response; single-cell RNA sequencing; therapy design; transcriptome sequencing

MODIFIED PROJECT SUMMARY HIV persistence in the face of antiretroviral therapy (ART) necessitates lifelong treatment of infected individuals because of a reservoir of HIV infected cells. The Covid-19 pandemic has resulted in the critical need to better understand the interaction between HIV and SARS-CoV-2. Our preliminary data indicates that poorly controlled HIV infection leads to prolonged SARS-CoV-2 infection which evolves variant-like mutations. It also interferes with the neutralizing antibody response elicited by Covid-19 vaccines. As there is no sign that SARS-CoV-2 will be eliminated anytime soon, these questions are critical for both the health of people living with HIV and possibly to prevent continued emergence of SARS-CoV-2 variants. MODIFIED ABSTRACT HIV infection is currently lifelong due to the persistence of the infection in the face of ART because of a reservoir of HIV infected cells which is insensitive to antiretroviral drugs [1]. South Africa has a high proportion of people living with HIV (PLWH), with about one-third of the population in the Durban area being PLWH [2, 3]. Due Covid-19 and other factors, many individuals are not fully suppressed with ART and about 10% of PLWH in our Durban based cohort of confirmed SARS-CoV-2 infected cases have long-term unsuppressed HIV infection culminating in advanced HIV disease [2]. Incomplete suppression of HIV replication would lead to HIV reservoirs being replenished and maintained by ongoing HIV replication [1]. Furthermore, it may compromise immune responses to SARS-CoV-2 [4, 5]. This leads to long-term SARS-CoV-2 infection which we and others have found to evolve neutralizing antibody escape mutations in the SARS-CoV-2 spike protein [6]. Such evolution may form variants. In addition to causing prolonged SARS-CoV-2 infection, we have preliminary data showing that mRNA vaccines do not elicit an effective neutralizing immune response in PLWH with poorly suppressed HIV infection. There may also be unknown consequences to HIV reservoirs and the ability of ART to suppress the HIV reservoir in different anatomical compartments if SARS-CoV-2 infection is long and causes extensive immune activation. Given these unexpected developments which are the consequence of the Covid-19 pandemic, we propose to modify the current study Aims to understand the impact of HIV status and level of suppression on the immune response to SARS-CoV-2 infection and vaccines, as well as determine the effect of long-term SARS-CoV-2 infection on HIV reservoir suppression.

经修订的项目摘要艾滋病毒在抗逆转录病毒疗法(ART)面前的持久性需要对感染者进行终身治疗，因为艾滋病毒感染细胞的储存库。新冠肺炎大流行导致迫切需要更好地了解艾滋病毒和SARS-CoV-2之间的相互作用。我们的初步数据表明，控制不佳的艾滋病毒感染会导致SARS-CoV-2感染时间延长，从而进化出变种样突变。它还会干扰新冠肺炎疫苗引发的中和抗体反应。由于没有迹象表明SARS-CoV-2将在短期内被消灭，这些问题对艾滋病毒携带者的健康至关重要，也可能对防止SARS-CoV-2变种的继续出现至关重要。目前艾滋病毒感染是终生的，因为面对抗逆转录病毒药物不敏感的HIV感染细胞的贮存库[1]，这种感染是持续的。南非的艾滋病毒携带者比例很高，德班地区约有三分之一的人口是艾滋病毒携带者[2，3]。由于新冠肺炎和其他因素，许多人没有完全接受抗逆转录病毒治疗，在我们德班确诊的SARS-CoV-2感染病例队列中，约有10%的PLWH患者长期未被抑制的艾滋病毒感染，最终发展为晚期艾滋病毒疾病[2]。对艾滋病毒复制的不完全抑制将导致正在进行的艾滋病毒复制来补充和维持艾滋病毒储存库[1]。此外，它可能会损害对SARS-CoV-2的免疫反应[4，5]。这会导致SARS-CoV-2的长期感染，我们和其他人已经发现，这种感染会在SARS-CoV-2刺突蛋白中进化出中和抗体逃逸突变[6]。这样的进化可能会形成变异。除了导致SARS-CoV-2的长期感染外，我们有初步数据表明，在HIV感染抑制较差的PLWH中，mRNA疫苗不能诱导有效的中和免疫反应。如果SARS-CoV-2长期感染并引起广泛的免疫激活，也可能对艾滋病毒宿主和ART在不同解剖区段抑制艾滋病毒宿主的能力产生未知的后果。鉴于这些意外的事态发展是新冠肺炎大流行的后果，我们建议修改目前的研究，旨在了解艾滋病毒状态和抑制水平对SARS-CoV-2感染和疫苗的免疫反应的影响，以及确定长期感染SARS-CoV-2对艾滋病毒宿主抑制的影响。

项目成果

Association Between Human Immunodeficiency Virus Viremia and Compromised Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 Beta Variant.

• DOI: 10.1093/infdis/jiac343
• 发表时间: 2023-01-11
• 期刊: The Journal of infectious diseases

SARS-CoV-2 prolonged infection during advanced HIV disease evolves extensive immune escape.

• DOI: 10.1016/j.chom.2022.01.005
• 发表时间: 2022-02-09
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Cele S;Karim F;Lustig G;San JE;Hermanus T;Tegally H;Snyman J;Moyo-Gwete T;Wilkinson E;Bernstein M;Khan K;Hwa SH;Tilles SW;Singh L;Giandhari J;Mthabela N;Mazibuko M;Ganga Y;Gosnell BI;Karim SSA;Hanekom W;Van Voorhis WC;Ndung'u T;COMMIT-KZN Team;Lessells RJ;Moore PL;Moosa MS;de Oliveira T;Sigal A
• 通讯作者: Sigal A

Emergence and phenotypic characterization of the global SARS-CoV-2 C.1.2 lineage.

• DOI: 10.1038/s41467-022-29579-9
• 发表时间: 2022-04-08
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Scheepers C;Everatt J;Amoako DG;Tegally H;Wibmer CK;Mnguni A;Ismail A;Mahlangu B;Lambson BE;Martin DP;Wilkinson E;San JE;Giandhari J;Manamela N;Ntuli N;Kgagudi P;Cele S;Richardson SI;Pillay S;Mohale T;Ramphal U;Naidoo Y;Khumalo ZT;Kwatra G;Gray G;Bekker LG;Madhi SA;Baillie V;Van Voorhis WC;Treurnicht FK;Venter M;Mlisana K;Wolter N;Sigal A;Williamson C;Hsiao NY;Msomi N;Maponga T;Preiser W;Makatini Z;Lessells R;Moore PL;de Oliveira T;von Gottberg A;Bhiman JN
• 通讯作者: Bhiman JN

Omicron infection enhances Delta antibody immunity in vaccinated persons.

• DOI: 10.1038/s41586-022-04830-x
• 发表时间: 2022-07
• 期刊: Nature
• 影响因子: 64.8

T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy.

• DOI: 10.1371/journal.ppat.1009871
• 发表时间: 2021-09
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Lustig G;Cele S;Karim F;Derache A;Ngoepe A;Khan K;Gosnell BI;Moosa MS;Ntshuba N;Marais S;Jeena PM;Govender K;Adamson J;Kløverpris H;Gupta RK;Harrichandparsad R;Patel VB;Sigal A
• 通讯作者: Sigal A