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The effects of antiretroviral therapy initiation time on HIV reservoir size in Chinese chronically HIV infected patients: a prospective, multi-site cohort study.

ABSTRACT: BACKGROUND:The effect of ART initiation time on HIV-1 DNA reservoir in chronically infected individuals is not well understood. Determining the potential influencing factors associated with a low HIV-1 DNA level in chronic infection is an important step toward drug-free control. METHODS:A prospective study included 444 chronically HIV-infected adults was performed. Participants were divided into two groups: early initiation group (EIG) or delayed initiation group (DIG) based on their baseline CD4 count; 350 to 500 and?

SUBMITTER: Luo L

PROVIDER: S-EPMC6419375 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The effects of antiretroviral therapy initiation time on HIV reservoir size in Chinese chronically HIV infected patients: a prospective, multi-site cohort study.

Luo Ling L Wang Nidan N Yue Yongsong Y Han Yang Y Lv Wei W Liu Zhengyin Z Qiu Zhifeng Z Lu Hongzhou H Tang Xiaoping X Zhang Tong T Zhao Min M He Yun Y Shenghua He H Wang Min M Li Yongzhen Y Huang Shaobiao S Li Yong Y Liu Jing J Tuofu Zhu Z Routy Jean-Pierre JP Li Taisheng T

BMC infectious diseases 20190314 1

<h4>Background</h4>The effect of ART initiation time on HIV-1 DNA reservoir in chronically infected individuals is not well understood. Determining the potential influencing factors associated with a low HIV-1 DNA level in chronic infection is an important step toward drug-free control.<h4>Methods</h4>A prospective study included 444 chronically HIV-infected adults was performed. Participants were divided into two groups: early initiation group (EIG) or delayed initiation group (DIG) based on th ...[more]

PMID: 30871484

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Project description:BackgroundA major challenge to HIV eradication strategies is the lack of an accurate measurement of the total burden of replication-competent HIV (the "reservoir"). We assessed the association of anti-HIV antibody responses and the estimated size of the reservoir during antiretroviral therapy (ART).MethodsWe evaluated anti-HIV antibody profiles using luciferase immunoprecipitation systems (LIPS) assay in relation to several blood-based HIV reservoir measures: total and 2-LTR DNA (rtPCR or droplet digital PCR); integrated DNA (Alu PCR); unspliced RNA (rtPCR), multiply-spliced RNA (TILDA), residual plasma HIV RNA (single copy PCR), and replication-competent virus (outgrowth assay). We also assessed total HIV DNA and RNA in gut-associated lymphoid tissue (rtPCR). Spearman correlations and linear regressions were performed using log-transformed blood- or tissue-based reservoir measurements as predictors and log-transformed antibody levels as outcome variables.ResultsAmong 51 chronically HIV-infected ART-suppressed participants (median age = 57, nadir CD4+ count = 196 cells/mm3, ART duration = 9 years), the most statistically significant associations were between antibody responses to integrase and HIV RNA in gut-associated lymphoid tissue (1.17 fold-increase per two-fold RNA increase, P = 0.004) and between antibody responses to matrix and integrated HIV DNA in resting CD4+ T cells (0.35 fold-decrease per two-fold DNA increase, P = 0.003). However, these associations were not statistically significant after a stringent Bonferroni-adjustment of P<0.00045. Multivariate models including age and duration of ART did not markedly alter results.ConclusionsOur findings suggest that anti-HIV antibody responses may reflect the size of the HIV reservoir during chronic treated HIV disease, possibly via antigen recognition in reservoir sites. Larger, prospective studies are needed to validate the utility of antibody levels as a measure of the total body burden of HIV during treatment.

Project description:In this study, we examined the peripheral blood (PB) central memory (TCM) CD4(+) T cell subsets designated peripheral T follicular helper cells (pTfh cells) and non-pTfh cells to assess HIV permissiveness and persistence. Purified pTfh and non-pTfh cells from healthy HIV-negative donors were tested for HIV permissiveness using green fluorescent protein (GFP)-expressing HIV-1NL4-3/Ba-L, followed by viral reactivation using beads coated with anti-CD3/anti-CD28 monoclonal antibodies. The role of pTfh cells in HIV persistence was analyzed in 12 chronically HIV-1 infected patients before and 48 weeks after initiation of raltegravir-containing combination antiretroviral therapy (cART). Total cellular HIV-1 DNA and episomes containing two copies of the viral long terminal repeat (2LTR circles) were analyzed in using droplet digital PCR in the purified pTfh and non-pTfh cells. Activation-inducible HIV p24 expression was determined by flow cytometry. Results indicate that pTfh cells, in particular PD1(+) pTfh cells, showed greater permissiveness for HIV infection than non-pTfh cells. At week 48 on cART, HIV DNA levels were unchanged from pre-cART levels, although a significant decrease in 2LTR circles was observed in both cell subsets. Inducible HIV p24 expression was higher in pTfh cells than in non-pTfh cells, with the highest frequencies in the PD1(+) CXCR3(-) pTfh cell subset. Frequencies of HLADR(+) CD38(+) activated CD4 T cells correlated with 2LTR circles in pTfh and non-pTfh cells at both time points and with p24(+) cells at entry. In conclusion, among CD4 TCM cells in PB of aviremic patients on cART, pTfh cells, in particular the PD1(+) CXCR3(-) subset, constitute a major HIV reservoir that is sustained by ongoing residual immune activation. The inducible HIV p24 assay is useful for monitoring HIV reservoirs in defined CD4 T cell subsets.Identification of the type and nature of the cellular compartments of circulating HIV reservoirs is important for targeting of HIV cure strategies. In lymph nodes (LN), a subset of CD4 T cells called T follicular helper (Tfh) cells are preferentially infected by HIV. Central memory (TCM) CD4 T cells are the major cellular reservoir for HIV in peripheral blood and contain a subset of CD4 TCM cells expressing chemokine receptor CXCR5 similar in function to LN Tfh cells termed peripheral Tfh (pTfh) cells. We found that the circulating pTfh cells are highly susceptible to HIV infection and that in HIV-infected patients, HIV persists in these cells following plasma virus suppression with potent cART. These pTfh cells, which constitute a subset of TCM CD4 T cells, can be readily monitored in peripheral blood to assess HIV persistence.

Dataset Information

The effects of antiretroviral therapy initiation time on HIV reservoir size in Chinese chronically HIV infected patients: a prospective, multi-site cohort study.

Publications

The effects of antiretroviral therapy initiation time on HIV reservoir size in Chinese chronically HIV infected patients: a prospective, multi-site cohort study.

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