Beulah P. Sabundayo

Biphasic Decay of Latently Infected CD4+ T Cells in Acute Human Immunodeficiency Virus Type 1 Infection

Latent infection of resting CD4(+) T cells represents a major barrier to eradication of human immunodeficiency virus type 1 (HIV-1). The establishment and rate of decay of latent HIV-1 in resting CD(+) T cells from 9 acute seroconverters, 7 of whom began to receive highly active antiretroviral therapy (HAART) shortly after presentation, were studied. Before the initiation of therapy, these patients had very high frequencies of latently infected CD4(+) T cells, with a median frequency of 205 infectious units per million resting CD4(+) T cells. These values are > or =1 log higher than those seen in chronically infected patients who are not undergoing HAART. The number of latently infected cells declined dramatically after initiation of HAART but then tended to level off at a low but stable level. The biphasic decay of latent HIV in resting CD4(+) T cells in acute seroconverters supports current models of pre- and postintegration latency.

A Single Dose of Any of Four Different Live Attenuated Tetravalent Dengue Vaccines Is Safe and Immunogenic in Flavivirus-naive Adults: A Randomized, Double-blind Clinical Trial

BACKGROUND Dengue virus (DENV) causes hundreds of millions of infections annually. Four dengue serotypes exist, and previous infection with one serotype increases the likelihood of severe disease with a second, heterotypic DENV infection. METHODS In a randomized, placebo-controlled study, the safety and immunogenicity of 4 different admixtures of a live attenuated tetravalent (LATV) dengue vaccine were evaluated in 113 flavivirus-naive adults. Serum neutralizing antibody levels to all 4 dengue viruses were measured on days 0, 28, 42, and 180. RESULTS A single dose of each LATV admixture induced a trivalent or better neutralizing antibody response in 75%-90% of vaccinees. There was no significant difference in the incidence of adverse events between vaccinees and placebo-recipients other than rash. A trivalent or better response correlated with rash and with non-black race (P < .0001). Black race was significantly associated with a reduced incidence of vaccine viremia. CONCLUSIONS TV003 induced a trivalent or greater antibody response in 90% of flavivirus-naive vaccinees and is a promising candidate for the prevention of dengue. Race was identified as a factor influencing the infectivity of the LATV viruses, reflecting observations of the effect of race on disease severity in natural dengue infection.

Robust and Balanced Immune Responses to All 4 Dengue Virus Serotypes Following Administration of a Single Dose of a Live Attenuated Tetravalent Dengue Vaccine to Healthy, Flavivirus-Naive Adults

BACKGROUND The 4 serotypes of dengue virus, DENV-1-4, are the leading cause of arboviral disease globally. The ideal dengue vaccine would provide protection against all serotypes after a single dose. METHODS Two randomized, placebo-controlled trials were performed with 168 flavivirus-naive adults to demonstrate the safety and immunogenicity of a live attenuated tetravalent dengue vaccine (TV003), compared with those of a second tetravalent vaccine with an enhanced DENV-2 component (TV005), and to evaluate the benefit of a booster dose at 6 months. Safety data, viremia, and neutralizing antibody titers were evaluated. RESULTS A single dose of TV005 elicited a tetravalent response in 90% of vaccinees by 3 months after vaccination and a trivalent response in 98%. Compared with TV003, the higher-dose DENV-2 component increased the observed frequency of immunogenicity to DENV-2 in the TV005 trial. Both the first and second doses were well tolerated. Neither vaccine viremia, rash, nor a significant antibody boost were observed following a second dose. CONCLUSIONS A single subcutaneous dose of TV005 dengue vaccine is safe and induces a tetravalent antibody response at an unprecedented frequency among vaccinees. A second dose has limited benefit and appears to be unnecessary. Studies to confirm these findings and assess vaccine efficacy will now move to populations in regions where DENV transmission is endemic. CLINICAL TRIALS REGISTRATION NCT01072786 and NCT01436422.

The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model

A controlled dengue human challenge model may determine whether to evaluate candidate dengue vaccines in large efficacy trials. Dengue model rises to the challenge Human efficacy testing remains a major hurdle in bringing new vaccine candidates to the clinic. In the absence of accepted correlates of protection, rounds of safety trials must be performed before efficacy can be tested in a large population in an endemic area. Kirkpatrick et al. have developed a controlled dengue human challenge model to assess the protective efficacy of the most clinically advanced dengue vaccine candidate. They found that TV003, a live attenuated dengue vaccine that induces antibodies to all four dengue virus serotypes, protected against infection of an attenuated virus in 21 recipients when compared with 20 nonvaccinated controls. This model may serve as an early check for dengue vaccine candidates, limiting the risk of conducting large unsuccessful trials. A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for about 390 million infections annually. Protective efficacy results for the most advanced dengue vaccine candidate (CYD) were disappointing despite its ability to induce neutralizing antibodies against all four dengue virus (DENV) serotypes. TV003 is a live attenuated tetravalent DENV vaccine currently in phase 2 evaluation. To better assess the protective efficacy of TV003, a randomized double-blind, placebo-controlled trial in which recipients of TV003 or placebo were challenged 6 months later with a DENV-2 strain, rDEN2Δ30, was conducted. The primary endpoint of the trial was protection against dengue infection, defined as rDEN2Δ30 viremia. Secondary endpoints were protection against rash and neutropenia. All 21 recipients of TV003 who were challenged with rDEN2Δ30 were protected from infection with rDEN2Δ30. None developed viremia, rash, or neutropenia after challenge. In contrast, 100% of the 20 placebo recipients who were challenged with rDEN2Δ30 developed viremia, 80% developed rash, and 20% developed neutropenia. TV003 induced complete protection against challenge with rDEN2Δ30 administered 6 months after vaccination. TV003 will be further evaluated in dengue-endemic areas. The controlled dengue human challenge model can accelerate vaccine development by evaluating the protection afforded by the vaccine, thereby eliminating poor candidates from further consideration before the initiation of large efficacy trials.

Anatomical loci of HIV-associated immune activation and association with viraemia

BACKGROUND Lymphocyte activation, associated with vaccination or infection, can be measured by positron emission tomography (PET). We investigated the ability of PET to detect and measure magnitude of lymph-node activation among asymptomatic HIV-1-infected individuals. METHODS Initially we assessed PET response in eight HIV-1-uninfected individuals who had received licensed killed influenza vaccine. In an urban teaching hospital, we recruited 12 patients recently infected with HIV-1 (<18 months since seroconversion) and 11 chronic long-term HIV-1 patients who had stable viraemia by RT-PCR (non-progressors). After injection with fluorine-18-labelled fluorodeoxyglucose, patients underwent PET. We correlated summed PET signal from nodes with viral load by linear regression on log-transformed values. FINDINGS Node activation was more localised after vaccination than after HIV-1 infection. In early and chronic HIV-1 disease, node activation was greater in cervical and axillary than in inguinal and iliac chains (p<0.0001), and summed PET signal correlated with viraemia across a 4 log range (r2=0.98, p<0.0001). Non-progressors had small numbers of persistently active nodes, most of which were surgically accessible. INTERPRETATION The anatomical restriction we noted may reflect microenvironmental niche selection, and tight correlation of PET signal with viraemia suggests target-cell activation determines steady-state viral replication.

Association of Gag-Specific T Lymphocyte Responses during the Early Phase of Human Immunodeficiency Virus Type 1 Infection and Lower Virus Load Set Point

T lymphocyte responses to human immunodeficiency virus (HIV) type 1 Gag were measured in 9 patients by interferon-gamma enzyme-linked immunospot assay at 3 time points within 12 months of infection. Patients with early recognition of HIV-1 Gag had lower subsequent HIV-1 load set points, as measured during the first 2 years of infection, compared with those of patients with undetectable Gag-specific responses (median, 4.27 vs. 5.05 log(10) HIV-1 RNA copies/mL, respectively; P=.028). An inverse correlation existed between the magnitude of the Gag-specific responses and the HIV-1 load set point (r=-0.733; P=.025). Early sustained T lymphocyte responses to HIV-1 Gag may be important for the establishment of virus load set point.

Immune activation and IL-12 production during acute/early HIV infection in the absence and presence of highly active, antiretroviral therapy

Suppressed IL‐12 production and maladaptive immune activation, both of which are ameliorated by successful highly active antiretroviral therapy (HAART), are thought to play important roles in the immunopathogenesis of chronic HIV infection. Despite the important effects of the immunological and virological events of early HIV infection on subsequent disease progression, IL‐12 production and immune activation in early infection remain under‐defined. To quantify IL‐12 production and immune activation during acute/early HIV infection, in the presence and absence of HAART, we performed a prospective, longitudinal study of participants in the Baltimore site of the Acute Infection and Early Disease Research Program, with cross‐sectional comparison to healthy control subjects. PBMC cytokine productive capacity and plasma immune activation markers [soluble CD8 (sCD8), sCD4, granzyme B, neopterin, β2‐microglobulin, sIL‐2R, sTNFRI, sTNFRII, and IL‐12p70] were quantified by ELISA. Notably, PBMC from patients with acute/early HIV infection exhibited in vivo IL‐12p70 production along with increased, maximal in vitro IL‐12 production. Further, despite evidence from plasma markers of generalized immune activation, no elevation in plasma levels of sCD4 was observed, suggesting relative blunting of in vivo CD4+ T cell activation from the beginning of HIV infection. Finally, despite successful virological responses to HAART, heightened in vivo CD8+ T cell activation, IL‐12 production, and IFN activity were sustained for at least 6 months during primary HIV infection. These data underscore the need for comparative mechanistic analysis of the immunobiology of early and chronic HIV infection.

A 12-Month–Interval Dosing Study in Adults Indicates That a Single Dose of the National Institute of Allergy and Infectious Diseases Tetravalent Dengue Vaccine Induces a Robust Neutralizing Antibody Response

UNLABELLED The ideal dengue vaccine will provide protection against all serotypes of dengue virus and will be economical and uncomplicated in its administration. To determine the ability of a single dose of the live attenuated tetravalent dengue vaccine TV003 to induce a suitable neutralizing antibody response, a placebo-controlled clinical trial was performed in 48 healthy adults who received 2 doses of vaccine or placebo administered 12 months apart. Evaluation of safety, vaccine viremia, and neutralizing antibody response after each dose indicated that the first dose of vaccine was capable of preventing infection with the second dose, thus indicating that multiple doses are unnecessary. CLINICAL TRIALS REGISTRATION NCT01782300.

High Frequency of Highly Active Antiretroviral Therapy Modifications in Patients with Acute or Early Human Immunodeficiency Virus Infection

Study Objectives. To examine the frequency of highly active antiretroviral therapy (HAART) modifications, the reasons for these modifications, and toxicities of these drugs in patients receiving their first HAART regimen after a diagnosis of acute (< 2 mo from infection) or early (2–12 mo) human immunodeficiency virus (HIV) infection.

Standardized Uptake Values in 2-Deoxy-2-[18F]Fluoro-D-Glucose with Positron Emission Tomography. Clinical Significance of Iterative Reconstruction and Segmented Attenuation Compared with Conventional Filtered Back Projection and Measured Attenuation Correction.

PURPOSE To evaluate the clinical significance of differences in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) lymph node standardized uptake values (SUV) in human immunodeficiency virus (HIV) infection using iterative reconstruction with segmented attenuation correction (IR SAC) compared to filtered back-projection with measured attenuation correction (FBP MAC). PROCEDURES Seven patients with HIV infection and multiple focal lymph node abnormalities were investigated with whole-body FDG-PET. Mean and maximum SUVs from lymph node regions of interest (n = 961) were compared for quantitative differences between reconstruction techniques. RESULTS IR MAC resulted in significantly lower mean SUV [0.06; 95% (confidence interval (CI)) = 0.04-0.07] and maximum SUV (0.82; 95% CI = 0.77-0.88) values compared to FBP MAC. With IR, segmentation of attenuation correction (AC) resulted in significantly higher mean SUV (0.12; 95% CI = 0.11-0.13) and maximum SUV (0.21; 95% CI = 0.18-0.23) values compared to IR MAC. The overall effect of both IR and SAC was a slight but significant increase in mean SUV (0.06; 95% CI = 0.06-0.08; bias = 2.1%) and a significant decrease in maximum SUV (0.62; 95% CI = 0.56-0.67) compared to FBP MAC. CONCLUSIONS With our reconstruction parameters, significant differences in mean and maximum SUV values were observed. The magnitude of the mean SUV difference, however, was small. IR SAC is a promising method to accurately quantify standardized uptake values for clinical use.