Haibo Ding

Genetic and epidemiologic characterization of HIV-1 infection in Liaoning Province, China.

Background:Although many studies of HIV-1 in China have focused on high-risk injecting drug users and former blood donors in high prevalence regions, little is known about HIV-1 in relatively low prevalence provinces. Here, we compare the epidemiologic and genetic profile of HIV-1 in Liaoning-a low prevalence province-with those identified in Chinas most severely affected provinces. Materials and Methods:Two hundred eight HIV-1-positive subjects from all major cities in Liaoning province were recruited between 2000 and 2008. 2.6 kilobase gag-pol sequences were amplified from plasma viral RNA and sequenced directly. The HIV-1 sequences obtained were analyzed using phylogenetic and recombinant approaches. Results:We have shown that in recent years, although HIV-1 prevalence in Liaoning has remained low, the rate of new infection has increased rapidly, particularly among men who have sex with men and heterosexual risk individuals (together comprising >54% of infected individuals in 2007). Furthermore, phylogenetic analysis has identified all major subtypes/circulating recombinant forms of HIV-1 in Liaoning previously identified in high prevalence provinces. Our study also shows close relationships between HIV-1 subtype/circulating recombinant form and certain risk behaviors. Notably, men who have sex with men and heterosexual risk individuals harbor most divergent strains of HIV-1 from multiple high-risk groups. Conclusions:Our study suggested that HIV-1 continues to spread to the general population through sexual contact; Liaoning, therefore, serves as the critical base for the introduction and spread of HIV-1 in northeast China. We believe the transmission patterns suggested herein will help guide public health workers in reducing further spread of HIV-1 within China.

Elevated interferon-γ–induced protein 10 and its receptor CXCR3 impair NK cell function during HIV infection

As the first line of defense in the human immune system, NK cells play essential roles in prevention of tumorigenesis and viral infection. It is known that NK cells have impaired function in HIV infection; however, it remains unclear why this occurs. IP‐10 is a chemokine and inflammatory factor that is associated with such diseases as tuberculosis, hepatitis B virus, and pancreatic cancer. The aim of this study was to evaluate IP‐10 levels and CXCR3 expression in NK cells that were affected by HIV and to elucidate whether NK cell function could be affected by IP‐10. Our results demonstrate that IP‐10 levels and expression of CXCR3 in NK cells was significantly higher in HIV‐infected participants compared with noninfected participants. Moreover, the ability of NK cells to secrete IFN‐γ and, specifically, to lyse K562, was suppressed with exposure to high levels of IP‐10. This study also showed that CXCR3+ NK cell function decreased dramatically when treated with IP‐10, which indicates that CXCR3+ NK cells were the main targets of IP‐10. Furthermore, IP‐10 or CXCR3 blocking could restore NK cell function. These data suggest that elevated IP‐10 levels may impair NK cell function during HIV infection and that IP‐10/CXCR3 blocking may be a novel therapeutic strategy in the control and functional cure of HIV.

NKG2C+NKG2A− Natural Killer Cells are Associated with a Lower Viral Set Point and may Predict Disease Progression in Individuals with Primary HIV Infection

Natural killer (NK) cells are the first line of defense against pathogens of the immune system and also play an important role in resistance against HIV. The activating receptor NKG2C and the inhibitory receptor NKG2A co-modulate the function of NK cells by recognizing the same ligand, HLA-E. However, the role of NKG2A and NKG2C on viral set point and the prediction of HIV disease progression have been rarely reported. In this study, we determined the expression of NKG2C or NKG2A on the surface of NK cells from 22 individuals with primary HIV infection (PHI) stage and 23 HIV-negative normal control (NC) subjects. The CD4+ T cell count and plasma level of HIV RNA in the infected individuals were longitudinally followed-up for about 720 days. The proportion of NKG2C+NKG2A− NK cells was higher in subjects from the low set point group and was negatively correlated with the viral load. In addition, strong anti-HIV activities were observed in NKG2C+ NK cells from the HIV-positive donors. Furthermore, a proportion of NKG2C+NKG2A− NK cells >35.45%, and a ratio of NKG2C/NKG2A >1.7 were predictive for higher CD4+ T cell counts 720 days after infection. Collectively, the experimental results allow us to draw the conclusion that NKG2C+ NK cells might exert an antiviral effect and that the proportion of NKG2C+NKG2A− NK cells, and the ratio of NKG2C/NKG2A, are potential biomarkers for predicting HIV disease progression.

Association of Hippocampal Magnetic Resonance Imaging With Learning and Memory Deficits in HIV-1-Seropositive Patients.

Objective:To investigate the relationship between cognitive impairment and hippocampal morphological and functional changes in HIV-seropositive patients. Methods:Thirty HIV+ patients who complain of memory decrease and 15 healthy volunteers were recruited. Performances of learning and memory were assessed using Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R). Bilateral hippocampal volume, apparent diffusion coefficient (ADC) value, fractional anisotropy value, and magnetic resonance spectroscopy variables of bilateral hippocampus and parahippocampal gyrus were detected by 3.0 T magnetic resonance scanner. Results:We found significant differences in all cognitive outcomes but one between HIV+ and HIV− patients. There was a difference in the ADC value of left parahippocampal gyrus between mild-impairment group and severe-impairment group (P = 0.018). We found differences in the choline (Cho), Cho/creatinine (Cr), and N-acetylaspartate/Cr of left hippocampus (P = 0.002, P = 0.008, P = 0.002) and the Cho/Cr of right parahippocampal gyrus (P = 0.023) between HIV+ and HIV− patients and in the myoinositol of left hippocampus (P = 0.003) and the glutamate and glutamine of right hippocampus (P < 0.001) between mild-impairment group and severe-impairment group. We found significant positive correlations between N-acetylaspartate/Cr of left hippocampus and outcomes of HVLT-R and BVMT-R. There were significant negative correlations between ADC values of hippocampus and parahippocampal gyrus and outcomes of HVLT-R and BVMT-R and between Cho and Cho/Cr of hippocampus and parahippocampal gyrus and outcomes of HVLT-R and BVMT-R. Conclusions:The performance of verbal learning and visual memory was significantly decreased in HIV-1–seropositive patients. The cognitive impairment of HIV infection was associated with conductive function and metabolic changes of hippocampus and parahippocampal gyrus in this study.

The biological characteristics of predominant strains of HIV‐1 genotype: Modeling of HIV‐1 infection among men who have sex with men

To investigate the molecular subtypes of prevalent HIV‐1 strains and characterize the genetics of dominant strains among men who have sex with men. Molecular epidemiology surveys in this study concentrated on the prevalent HIV‐1 strains in Liaoning province by year. 229 adult patients infected with HIV‐1 and part of a high‐risk group of men who have sex with men were recruited. Reverse transcription and nested PCR amplification were performed. Sequencing reactions were conducted and edited, followed by codon‐based alignment. NJ phylogenetic tree analyses detected two distinct CRF01_AE phylogenetic clusters, designated clusters 1 and 2. Clusters 1 and 2 accounted for 12.8% and 84.2% of sequences in the pol gene and 17.6% and 73.1% of sequences in the env gene, respectively. Another six samples were distributed on other phylogenetic clusters. Cluster 1 increased significantly from 5.6% to 20.0%, but cluster 2 decreased from 87.5% to 80.0%. Genetic distance analysis indicated that CRF01_AE cluster 1 in Liaoning was homologous to epidemic CRF01_AE strains, but CRF01_AE cluster 2 was different from other scattered strains. Additionally, significant differences were found in tetra‐peptide motifs at the tip of V3 loop between cluster 1 and 2; however, differences in coreceptor usage were not detected. This study shows that subtype CRF01_AE strain may be the most prevalent epidemic strain in the men who have sex with men. Genetic characteristics of the subtype CRF01_AE cluster strain in Liaoning showed homology to the prevalent strains of men who have sex with men in other parts of China. J. Med. Virol. 87:557–568, 2015.

The investigation of CD4+T-cell functions in primary HIV infection with antiretroviral therapy

Abstract Human immunodeficiency virus (HIV) infection leads to reduced CD4+T-cell counts and immune dysfunction. Initiation of antiretroviral therapy (ART) in HIV primary infection has been recommended to achieve an optimal clinical outcome, but a comprehensive study on restoration of CD4+T-cell function in primary HIV-infected individuals with ART still needs to be eluciated. We investigated longitudinal changes in the CD4+T-cell counts, phenotypes, and functions in HIV-infected individuals with early ART (initiated within 6 months after HIV infection) or later ART (initiated more than 12 months after HIV infection). Patients from early ART and later ART groups had received ART for at least 1 year. Individuals with early ART had more CD4+T cells, a faster rate of CD4+T-cell recovery than those receiving later ART; the levels of CD4+T-cell activation and senescence were lower in early ART compared to those with later ART (P = .031; P = .016), but the activation was higher than normal controls (NC) (P = .001); thymic emigrant function was more upregulated in early ART than in later ART (P = .015), but still lower than NC (P = .027); proliferative capacity and interferon-&ggr; secretion of CD4+T cells were significantly decreased in primary infection (P < .001; P = .029), and early ART restored these CD4+T-cell functions, there is no difference with NC, later ART could partially restore the functions of CD4+T cells, but it remained lower than that of NC (P = .005; P = .019). Early ART could better improve CD4+T-cell function.

The Role of HIV-1 in Affecting the Proliferation Ability of HPCs Derived From BM.

Abstract:HIV-1 causes chronic infection characterized by the depletion of CD4+ T lymphocytes and the development of AIDS. Current antiretroviral drugs inhibit viral spread, but they do not lead to a full immune recovery. Hematopoietic stem cells (HSCs) and multipotent hematopoietic progenitor cells (HPCs) give rise to all blood and immune cells, and in HIV infection, hematological abnormalities frequently occur in patients. Here, we used bone marrow samples from HIV-1–infected people to study the relationship between the proliferation ability of HSCs/HPCs and peripheral CD4+ T lymphocytes. Three indexes were used to reflect the proliferation ability of HSCs and HPCs: (1) colony-forming units of bone marrow mononuclear cells (BMMCs), (2) amplification of CD34+ cells purified from bone marrow mononuclear cells, (3) expression of HOXB4 and HOXA9 in CD34+ cells. We observed a direct correlation between peripheral number of CD4+ T lymphocytes and the HSCs/HPCs proliferation ability in our study. We also compared HIV-infected patients with or without antiretroviral therapy (ART). Our results demonstrated that after antiretroviral therapy, CD4+ T-cell recovery and HPCs proliferation ability are correlated. Our findings have implications in understanding whether bone marrow-derived HPCs can supplement for the loss of CD4+ T lymphocytes during HIV-1 infection.

Expression of the Inhibitory Receptor TIGIT Is Up-Regulated Specifically on NK Cells With CD226 Activating Receptor From HIV-Infected Individuals

Natural killer (NK) cells are important for maintenance of innate immune system stability and serve as a first line of defense against tumors and virus infections; they can act either directly or indirectly and are regulated via co-operation between inhibitory and stimulatory surface receptors. The recently reported inhibitory receptor, TIGIT, can be expressed on the NK cell surface; however, the expression level and function of TIGIT on NK cells during HIV infection is unknown. In this study, for the first time, we investigated the expression and function of TIGIT in NK cells from HIV-infected individuals. Our data demonstrate that the level of TIGIT is higher on NK cells from patients infected with human immunodeficiency virus (HIV) compared with HIV-negative healthy controls. TIGIT expression is inversely correlated with CD4+ T cell counts and positively correlated with plasma viral loads. Additionally, levels of the TIGIT ligand, CD155, were higher on CD4+ T cells from HIV-infected individuals compared with those from healthy controls; however, there was no difference in the level of the activating receptor, CD226, which recognizes the same ligands as TIGIT. Furthermore, TIGIT was found to specifically up-regulated on CD226+ NK cells in HIV-infected individuals, and either rIL-10, or rIL-12 + rIL-15, could induce TIGIT expression on these cells. In addition, high TIGIT expression inhibited the production of interferon-gamma (IFN-γ) by NK cells, while TIGIT inhibition restored IFN-γ production. Overall, these results highlight the important role of TIGIT in NK cell function and suggest a potential new avenue for the development of therapeutic strategies toward a functional cure for HIV.

The Early Antibody-Dependent Cell-Mediated Cytotoxicity Response Is Associated With Lower Viral Set Point in Individuals With Primary HIV Infection

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune response largely mediated by natural killer (NK) cells that can lyse target cells and combat tumors and viral infections. However, the role of ADCC in response to primary HIV infection is poorly understood. In the present study, we explored the ADCC response and evaluated its characteristics in 85 HIV-infected individuals, including 42 with primary infections. Our results showed that ADCC occurs during acute infection, and the earliest ADCC response to a single peptide was detected at 52 days. Primary HIV-infected individuals exhibiting ADCC responses had lower viral set points than those with no ADCC response, and functional analyses demonstrated that the ADCC response could significantly inhibit viral infection during primary HIV infection. HIV epitopes that provoked the ADCC response were determined and three relatively conserved epitopes (HNVWATYACVPTDPNPQE, TSVIKQACPKISFDPIPI, and VVSTQLLLNGSLAEEEII) from the surface of the three-dimensional structure of the HIV Env protein were identified. Overall, our data indicate that ADCC responses may be significant for the control of HIV from an early stage during infection. These findings merit further investigation and will facilitate improvements in vaccines or therapeutic interventions against HIV infection.

AID recruits the RNA exosome to degrade HIV‐1 nascent transcripts through interaction with the Tat‐P‐TEFb‐TAR RNP complex

Activation‐induced cytidine deaminase (AID), a member of the APOBEC family that induces antibody diversification, has been shown to inhibit the replication of hepatitis B virus, Kaposis sarcoma‐associated herpesvirus, and retro‐transposons. However, whether AID can inhibit human immunodeficiency virus 1 (HIV‐1) replication remains unclear. Here, we report that AID impairs the synthesis of HIV‐1 components by interacting with the complex of Tat. This interaction recruits the RNA exosome to degrade the nascent HIV‐1 transcript. AID also targets the HIV‐1‐integrated genome via the Tat‐P‐TEFb‐TAR complex. Thus, we propose a novel function for AID as an adaptor protein that represses viral transcription. Our findings provide insights into developing anti‐HIV therapeutics and understanding how host cells restrict integrated virus replication.