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.

修改后的项目摘要 由于 HIV 感染细胞的储存，在抗逆转录病毒治疗 (ART) 的情况下，HIV 的持续存在需要对感染者进行终生治疗。 Covid-19 大流行导致迫切需要更好地了解 HIV 和 SARS-CoV-2 之间的相互作用。我们的初步数据表明，HIV 感染控制不善会导致 SARS-CoV-2 感染时间延长，从而产生变异样突变。它还会干扰 Covid-19 疫苗引发的中和抗体反应。由于没有迹象表明 SARS-CoV-2 会很快被消灭，因此这些问题对于 HIV 感染者的健康至关重要，并且可能对于防止 SARS-CoV-2 变种的持续出现至关重要。修改后的摘要 由于 HIV 感染细胞库对抗逆转录病毒药物不敏感，因此在 ART 面前感染持续存在，目前 HIV 感染是终生的[1]。南非的艾滋病毒感染者 (PLWH) 比例很高，德班地区约三分之一的人口是艾滋病毒感染者 [2, 3]。由于 Covid-19 和其他因素，许多人并未通过 ART 得到完全抑制，在我们位于德班的确诊 SARS-CoV-2 感染病例队列中，约 10% 的 PLWH 患有长期未抑制的 HIV 感染，最终导致晚期 HIV 疾病 [2 ]。 HIV 复制的不完全抑制将导致 HIV 病毒库通过持续的 HIV 复制得到补充和维持 [1]。此外，它可能会损害对 SARS-CoV-2 的免疫反应 [4, 5]。这会导致长期的 SARS-CoV-2 感染，我们和其他人发现这种感染会在 SARS-CoV-2 刺突蛋白中进化出中和抗体逃逸突变 [6]。这种进化可能会形成变体。除了导致 SARS-CoV-2 感染时间延长外，我们的初步数据显示，mRNA 疫苗不会在 HIV 感染抑制不佳的感染者中引发有效的中和免疫反应。如果 SARS-CoV-2 感染时间较长并导致广泛的免疫激活，则 HIV 储存库以及 ART 抑制不同解剖区室中的 HIV 储存库的能力也可能会产生未知的后果。鉴于 Covid-19 大流行造成的这些意外发展，我们建议修改当前的研究，旨在了解 HIV 状态和抑制水平对 SARS-CoV-2 感染和疫苗免疫反应的影响以确定长期 SARS-CoV-2 感染对 HIV 储存抑制的影响。

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

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

SARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization and requires ACE2 for infection.

• DOI: 10.1101/2021.12.08.21267417
• 发表时间: 2021-12-17
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Cele, Sandile;Jackson, Laurelle;Sigal, Alex
• 通讯作者: Sigal, Alex

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