Yanmei Jiao

Plasma IP-10 is associated with rapid disease progression in early HIV-1 infection.

Cytokines play key roles in modulating disease progression in simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) infection. There are a few studies on the relationship between early cytokines and HIV disease prognosis. In this study, we first report the relationship based on two groups with clearly different disease progression. We found that IP-10 was the only cytokine among the 26 cytokines tested that was always positively correlated with disease progression, and was associated with the time for CD4 counts to fall below 200 cells/μL during Fiebig stages III-V in HIV-1 infection. This suggests that high IP-10 levels in the blood are associated with rapid disease progression during Fiebig stages III-V in HIV-1 infection.

Rapid Turnover of 2-LTR HIV-1 DNA during Early Stage of Highly Active Antiretroviral Therapy

Background Despite prolonged treatment with highly active antiretroviral therapy (HAART), the infectious HIV-1 continues to replicate and resides latently in the resting memory CD4+ T lymphocytes, which blocks the eradication of HIV-1. The viral persistence of HIV-1 is mainly caused by its proviral DNA being either linear nonintegrated, circular nonintegrated, or integrated. Previous reports have largely focused on the dynamics of HIV-1 DNA from the samples collected with relatively long time intervals during the process of disease and HAART treatment, which may have missed the intricate changes during the intervals in early treatment. Methodology/Principal Findings In this study, we investigated the dynamics of HIV-1 DNA in patients during the early phase of HARRT treatment. Using optimized real time PCR, we observed significant changes in 2-LTR during the first 12-week of treatment, while total and integrated HIV-1 DNA remained stable. The doubling time and half-life of 2-LTR were not correlated with the baseline and the rate of changes in plasma viral load and various CD4+ T-cell populations. Longitudinal analyses on 2-LTR sequences and plasma lipopolysaccharide (LPS) levels did not reveal any significant changes in the same treatment period. Conclusions/Significance Our study revealed the rapid changes in 2-LTR concentration in a relatively large number of patients during the early HAART treatment. The rapid changes indicate the rapid infusion and clearance of cells bearing 2-LTR in the peripheral blood. Those changes are not expected to be caused by the blocking of viral integration, as our study did not include the integrase inhibitor raltegravir. Our study helps better understand the dynamics of HIV-DNA and its potential role as a biomarker for the diseases and for the treatment efficacy of HAART.

High CCR5 density on central memory CD4+ T cells in acute HIV-1 infection is mostly associated with rapid disease progression.

CD4+ central memory T cells play a critical role in the pathogenesis of simian immunodeficiency virus disease, and the CCR5 density on the surface of CD4 T cells is an important factor in human immunodeficiency virus (HIV)-1 disease progression. We hypothesized that quantifying central memory cells and CCR5 expression in the early stages of HIV-infection could provide useful prognostic information. We enrolled two different groups of acute HIV-infected subjects. One group progressed to CD4 T cell numbers below 250 cells/µl within 2 years (CD4 Low group), while the other group maintained CD4 cell counts above 450 cells/µl over 2 years (CD4 High group). We compared the CCR5 levels and percentage of CD4 subsets between the two groups during the 1st year of HIV infection. We found no differences between the two groups regarding the percentage of naïve, central memory and effector memory subsets of CD4 cells during the 1st year of HIV-1 infection. CCR5 levels on CD4+ CM subset was higher in the CD4 Low group compared with the CD4 High group during the 1st year of HIV-1 infection. High CCR5 levels on CD4 central memory cells in acute HIV infection are mostly associated with rapid disease progression. Our data suggest that low CCR5 expression on CD4 central memory cells protects CD4 cells from direct virus infection and favors the preservation of CD4+ T cell homeostasis.

Central Memory CD4 Cells Are an Early Indicator of Immune Reconstitution in HIV/AIDS Patients with Anti-Retroviral Treatment

The number of central memory cells among the CD4+ T cells and the of activation of CD8+ T cells is believed to be a better indicator of immune restoration in patients on antiretroviral therapy (ART) than the absolute numbers of CD4+ and CD8+ T cells alone. In the current study, we investigated the changes in the CD4+ T cell subsets and their association with immune reconstitution and immune activation at early stages of ART. A prospective study was performed in 21 asymptomatic treatment-naive HIV-infected patients with CD4+ T cells less than 350 cells/μl. Blood samples were evaluated at base line, and at 2, 4, 8 and 12 weeks’ post antiretroviral therapy (ART). A biphasic increase of CD4+ T cells, central memory CD4 cells (CD4 CM) and CD4 naïve cells were observed after ART, with a rapid increase before week 4. Change in CD4 CM at week 4 positively correlated with the change in CD4+ T cells at weeks 12 post ART, and negatively correlated with the change in CD8+CD38+ T cells at weeks 12 post ART. We conclude that CD4 CM cells are a major contributor to early immune reconstitution in treatment-naive HIV-infected patients with delayed ART, and might be an early indicator for immune reconstitution.

HIV burden in men who have sex with men: a prospective cohort study 2007–2012

We conducted a prospective cohort study among HIV-negative MSM aged 18 years or older between 2007 and 2012 in Beijing, China to measure the rates of incident HIV and identify risk factors for infection. Among 5,800 participants evaluated at enrollment, we identified 486 prevalent cases of HIV (8.4%). Among the 3,625 enrollees who were HIV-negative at enrollment and completed at least one follow-up interview, we identified 440 incident cases of HIV in the follow up period: this constituted an HIV incidence rate of 7.1 per 100 person-years (95% CI: 6.4–7.7). Early treatment of syphilis may have significantly reduced risk of HIV infection (RR: 1.45, 95% CI: 1.11–1.93), while MSM presenting perfect compliance in the cohort did not show reduction in HIV infection. Our study suggested that HIV incidence has been remained high in this sample of Chinese MSM during the intensive preventive intervention, suggesting that we need to find new strategies to prevent HIV infection in this population.

Longitudinal Changes in Plasma Caspase-1 and Caspase-3 during the First 2 Years of HIV-1 Infection in CD4Low and CD4High Patient Groups

Over 95% of CD4 cell death occurs by Caspase-1-mediated pyroptosis during HIV infection. Caspase-3-mediated apoptosis accounts for the death in a small proportion of infected CD4 cells. To date, there have been no reports on the dynamics of Caspase-1 and Caspase-3 and their relationship with disease progression in acute HIV-1 infection. In this study, two distinct HIV-1 patient groups were enrolled. The CD4High group maintained a CD4 level above450 cells/μl while CD4 levels in the CD4Low group dropped below 250 cells/μl within 2 years after infection. Blood samples were collected at 1, 2, 3, 4, 6, 12 and 24 months after HIV infection. Plasma Caspase-1 and Caspase-3 levels in the two patients groups were determined by a single-step ELISA using commercially available monoclonal antibodies. The results showed that Caspase-1 and Caspase-3 levels in the CD4High group increased rapidly and then decreased within a short time during early HIV-1 infection. In contrast, Caspase-1 and Caspase-3 levels in the CD4Low group were obviously increased after 1 year of HIV-1 infection.

Hepatitis C therapy with interferon-α and ribavirin reduces the CD4 cell count and the total, 2LTR circular and integrated HIV-1 DNA in HIV/HCV co-infected patients

This study investigated whether treatment with IFN-α and ribavirin (RBV) reduces 2LTR circular HIV DNA in addition to the total and integrated HIV DNA. Two groups of patients were enrolled. Group 1 comprised HIV/HCV co-infected patients who were treated with highly active antiretroviral therapy (HAART), IFN-α and RBV for 48 weeks. After the 48 weeks of treatment, IFN-α and RBV treatment was discontinued and HAART was continued. Group 2 comprised HIV-infected patients who were treated with HAART. Real-time polymerase chain reaction (RT-PCR) was used to quantify the levels of HIV-1 DNA. We found that compared with Group 2 patients, Group 1 patients exhibited an obvious decrease in the CD4 cell count and the total DNA, 2LTR circular DNA, and integrated HIV DNA after 48 weeks of treatment. After the discontinuation of IFN-α and RBV treatment in Group 1 patients, the levels of HIV DNA recovered. Therefore, we concluded that treatment with IFN-α and ribavirin (RBV) reduces 2LTR circular HIV DNA.

γδ T cells are involved in acute HIV infection and associated with AIDS progression.

Background Early diagnosis is vital to HIV control. γδ T cells play critical roles in viral infections, but their activation in acute HIV infected patients and follow up to 18 months has not been described. Methods Changes in γδ T cells, including subsets, function and activation, in treated and untreated acutely HIV-infected patients (n = 79) were compared by cytotoxicity assay and flow cytometry with healthy controls (n = 21) at month 0, 6, 12 and 18. Results In acutely HIV-infected patients, Vδ1 cell proportion was elevated (P = 0.027) with Vδ2 population reduced (P = 0.002). Effector and central memory γδ T cell factions were decreased (P = 0.006 and P = 0.001, respectively), while proportion of terminal γδ T cells increased (P = 0.002). γδ T cell cytotoxicity was compromised over time. Fraction of IL-17-producing cells increased (P = 0.008), and IFN-γ-producing cells were unaffected (P = 0.115). Elevation of a microbial translocation marker, sCD14, was associated with γδ T cell activation (P = 0.001), which increased in a time-dependent manner, correlating with CD4/CD8 T cell activation set-points and CD4 counts. Antiretroviral therapy did not affect these changes. Conclusions γδ T cell subpopulation and functions change significantly in acute HIV infection and over time. Early γδ T cell activation was associated with CD4/CD8 T cell activation set-points, which predict AIDS progression. Therefore, γδ T cell activation represents a potential surrogate marker of AIDS progression.

Primary CXCR4 Co-receptor Use in Acute HIV Infection Leads to Rapid Disease Progression in the AE Subtype

This is a comparative study of HIV co-receptor usage in the early stages of HIV infection between two distinct patient groups, one with a low CD4 count (group 1), and the other with a high CD4 count (group 2). Group 1 progressed to a CD4 count below 200 cells/μL within 2 y, while group 2 had a CD4 count above 500 cells/μL within 2 y. Viral RNA was extracted from the plasma of these patients, and the C2-V5 region of the HIV-1 env genes were cloned and sequenced. The co-receptor usage was predicated based on V3 loop amino acid sequences using Geno2pheno and PSSM programs. Our results indicate that in acute HIV infection of rapid progressors (low CD4 count; group 1), the primary co-receptor usage is CXCR4, while in the high CD4 count group (group 2), the co-receptor usage is predominantly CCR5. One-year follow-up data from these patients showed no obvious change in HIV co-receptor usage in either group. Sequence analysis of patients from both study groups showed prevalence of the AE subtype, and therefore we can speculate that the CXCR4 co-receptor may be the primary HIV-1 co-receptor used in the HIV-1 AE subtype, and may be responsible for rapid HIV-1 disease progression in the MSM cohort.

Longitudinal Changes of Peripheral Blood DC Subsets and Regulatory T Cells in Chinese Chronic HIV-1-Infected Patients during Antiretroviral Therapy

It has been emphasized that chronic generalized immune dysfunction is the leading event in the pathogenesis of HIV infection, in which the contribution of dendritic cells (DCs) and regulatory T cells (Tregs) should not be underestimated. In current study, we assessed the longitudinal changes of peripheral blood DC subsets and Tregs in chronically asymptomatic treatment-naive HIV-1-infected patients during 60 weeks of antiretroviral therapy (ART), and compared with those in healthy controls and long term non-progressors (LTNPs). Blood samples were collected at week 0, 4, 12, 24, 48 and 60 of treatment to measure the counts of DC subsets and Tregs by flow cytometry and IFN-a plasma levels by ELISA. The counts of myeloid dendritic cells (mDCs) increased during ART, reaching similar levels to healthy controls at week 60 post ART but still lower than those of LTNPs. In HIV-1-infected patients, the mDCs counts were directly correlated with CD4 counts during ART. Changes in mDCs at week 8 were positively correlated with the changes in CD4 counts at week 60 post ART. However, the counts and function of plasmacytoid dendritic cells (pDCs) remained relatively stable during ART, and similar to those in healthy controls and LTNPs. The percentage of Tregs increased before ART and normalized after ART. Importantly, we found pDCs counts were associated with percentage of Tregs during ART, which may help in understanding of the role of these cells in HIV infection.