Multiple V1/V2 env Variants Are Frequently Present during Primary Infection with Human Immunodeficiency Virus Type 1

Human immunodeficiency virus type 1 (HIV-1) exists as a complex population of multiple genotypic variants in persons with chronic infection. However, acute HIV-1 infection via sexual transmission is a low-probability event in which there is thought to be low genetic complexity in the initial inoculum. In order to assess the viral complexity present during primary HIV-1 infection, the V1/V2 and V3 variable regions of the env gene were examined by using a heteroduplex tracking assay (HTA) capable of resolving these genotypic variants. Blood plasma samples from 26 primary HIV-1-infected subjects were analyzed for their level of diversity. Half of the subjects had more than one V1/V2 viral variant during primary infection, indicating the frequent transmission of multiple variants. This observation is inconsistent with the idea of infrequent transmission based on a small transmitting inoculum of cell-free virus. In chronically infected subjects, the complexity of the viral populations was even greater in both the V1/V2 and the V3 regions than in acutely infected subjects, indicating that in spite of the presence of multiple variants in acute infection, the virus does pass through a genetic bottleneck during transmission. We also examined how well the infecting virus penetrated different anatomical compartments by using the HTA. Viral variants detected in blood plasma were compared to those detected in seminal plasma and/or cerebral spinal fluid of six individuals. The virus in each of these compartments was to a large extent identical to virus in blood plasma, a finding consistent with rapid penetration of the infecting variant(s). The low-probability transmission of multiple variants could be the result of transient periods of hyperinfectiousness or hypersusceptibility. Alternatively, the inefficient transfer of a multiply infected cell could account for both the low probability of transmission and the transfer of multiple variants

Viral Resistance in Hepatitis B: Prevalence and Management

Hepatitis B is a DNA virus affecting hundreds of millions of individuals worldwide. As the clinical sequelae of cirrhosis and hepatocellular cancer are increasingly recognized to be related to viral levels, the impetus increases to offer treatment to those previously not treated. With the development of more robust antivirals with reasonable safety profiles, long-term treatment is becoming more common. The oral nucleos(t)ide analogs have become the preferred first-line therapies for most genotypes of hepatitis B. Five are now available, all with different potencies and resistance profiles. Long-term data spanning several years are now available for most compounds in this arena. This article focuses on the common natural variants and those secondary to nucleos(t)ide therapy, as well as diagnostic methods to detect resistance

HIV-1 Envelope Subregion Length Variation during Disease Progression

The V3 loop of the HIV-1 Env protein is the primary determinant of viral coreceptor usage, whereas the V1V2 loop region is thought to influence coreceptor binding and participate in shielding of neutralization-sensitive regions of the Env glycoprotein gp120 from antibody responses. The functional properties and antigenicity of V1V2 are influenced by changes in amino acid sequence, sequence length and patterns of N-linked glycosylation. However, how these polymorphisms relate to HIV pathogenesis is not fully understood. We examined 5185 HIV-1 gp120 nucleotide sequence fragments and clinical data from 154 individuals (152 were infected with HIV-1 Subtype B). Sequences were aligned, translated, manually edited and separated into V1V2, C2, V3, C3, V4, C4 and V5 subregions. V1-V5 and subregion lengths were calculated, and potential N-linked glycosylation sites (PNLGS) counted. Loop lengths and PNLGS were examined as a function of time since infection, CD4 count, viral load, and calendar year in cross-sectional and longitudinal analyses. V1V2 length and PNLGS increased significantly through chronic infection before declining in late-stage infection. In cross-sectional analyses, V1V2 length also increased by calendar year between 1984 and 2004 in subjects with early and mid-stage illness. Our observations suggest that there is little selection for loop length at the time of transmission; following infection, HIV-1 adapts to host immune responses through increased V1V2 length and/or addition of carbohydrate moieties at N-linked glycosylation sites. V1V2 shortening during early and late-stage infection may reflect ineffective host immunity. Transmission from donors with chronic illness may have caused the modest increase in V1V2 length observed during the course of the pandemic

Chemistry and Materials Science Directorate 2005 Annual Report

In 1952, we began laboratory operations in the barracks building of the Naval Air Station with approximately 50 employees. Today, the Chemistry and Materials Science (CMS) Directorate is a major organization at the Lawrence Livermore National Laboratory with more than 500 employees who continue to contribute to our evolving national security mission. For more than half a century, the mission of the Laboratory revolved primarily around nuclear deterrence and associated defense technologies. Today, Livermore supports a broad-based national security mission, and our specialized capabilities increasingly support emerging missions in human health and energy security. In the future, CMS will play a significantly expanded role in science and technology at the intersection of national security, energy and environment, and health. Our world-class workforce will provide the science and technology base for radically innovative materials to our programs and sponsors. Our 2005 Annual Report describes how our successes and breakthroughs follow a path set forward by our strategic plan and four organizing research themes, each with key scientific accomplishments by our staff and collaborators. Organized into two major sections-research themes and dynamic teams, this report focuses on achievements arising from earlier investments that address future challenges. The research presented in this annual report gives substantive examples of how we are proceeding in each of these four theme areas and how they are aligned with our national security mission. Research Themes: (1) Materials Properties and Performance under Extreme Conditions--We are developing ultrahard nanocrystalline metals, exploring the properties of nanotubes when exposed to very high temperatures, and engineering stronger materials to meet future needs for materials that can withstand extreme conditions. (2) Chemistry under Extreme Conditions and Chemical Engineering to Support National-Security Programs--Our recent discovery of a new source of coherent light adds a new tool to an array of methods we use to more fully understand the properties of materials. Insights into the early stages of polymer crystallization may lead to new materials for our national-security mission and private industry. (3) Science Supporting National Objectives at the Intersection of Chemistry, Materials Science, and Biology--We are improving drug binding for cancer treatment through the use of new tools that are helping us characterize protein-antibody interactions. By probing proteins and nucleic acids, we may gain an understanding of Alzheimer's, Mad Cow, and other neurodegenerative diseases. (4) Applied Nuclear Science for Human Health and National Security--Our work with cyanobacteria is leading to a fuller understanding of how these microorganisms affect the global carbon cycle. We are also developing new ways to reduce nuclear threats with better radiation detectors. Dynamic Teams: The dynamic teams section illustrates the directorate's organizational structure that supports a team environment across disciplinary and institutional boundaries. Our three divisions maintain a close relationship with Laboratory programs, working with directorate and program leaders to ensure an effective response to programmatic needs. CMS's divisions are responsible for line management and leadership, and together, provide us with the flexibility and agility to respond to change and meet program milestones. The three divisions are: Materials Science and Technology Division; Chemistry and Chemical Engineering Division; and Chemical Biology and Nuclear Science Division. By maintaining an organizational structure that offers an environment of collaborative problem-solving opportunities, we are able to nurture the discoveries and breakthroughs required for future successes. The dynamic teams section also presents the work of CMS's postdoctoral fellows, who bring to the Laboratory many of the most recent advances taking place in academic departments and provide a research stimulus to established research teams. Postdoctoral fellows are selected for their scientific expertise, capability, and enthusiasm for working in a highly productive environment that places a premium on scientific innovation