More than 1.1 million Americans and 36 million people worldwide are currently living with HIV. For these individuals, and for those who will become infected with HIV in the next few years, any future vaccine will come too late, and effective antiviral therapies must be used to combat their HIV infections.
The application of therapies using combinations of antiviral drugs has shown that HIV replication in infected people can be suppressed, which provides considerable and long-lasting clinical improvement. These therapies have helped large numbers of infected patients live relatively normal lives. Most importantly, they validate the concept that antiviral drugs can offer long-term relief to patients with HIV infections. However, current therapies do not eliminate the virus from infected patients; thus, lifelong treatment is required. This long-term therapy is associated with a number of problems, including toxicity, poor patient compliance, and, in some cases, the appearance of drug-resistance mutations. There remains, therefore, an urgent need to understand how the virus develops resistance to drugs; this understanding can be used to develop more effective strategies and drugs for the treatment of HIV infections.
The HIV Dynamics and Replication Program (HIV DRP) was formed in 1997 as the HIV Drug Resistance Program, with the mission of conducting and fostering multidisciplinary basic, translational, and clinical research focused on problems related to drug-resistant HIV. The HIV DRP has built on the existing strengths of the NCI’s basic and clinical research programs in retrovirology, drug discovery, and AIDS, exploiting studies in structural biology, biochemistry, virology, virus-host interaction, evolution, and in vivo virus biology to better understand mechanisms of retroviral replication. These are areas of critical importance to the AIDS epidemic, and they raise both basic and clinical research challenges whose solution will enhance our understanding of fundamental aspects of virology and cell biology, and guide the development of more effective therapeutics and therapies. Although the Program focuses primarily on HIV, drug resistance is a major concern for other infectious agents as well as cancer, and it is likely that our research will be beneficial in these and other areas.
Because antiviral therapies are now relatively effective, some of the focus in the field, and within the HIV DRP, has shifted toward questions that include, but are not limited to, the interactions of HIV with the host. These include basic and molecular questions involving the host cell factors that HIV exploits during its replication and factors that the host cell uses to help control the replication of HIV and other viruses. There is also an interest in how the virus is able to persist in infected patients who have been successfully treated with antiviral drugs for many years. It now appears that some HIV-infected cells in patients can grow and divide. This clonal expansion helps the cells, and the viruses they carry, to persist, and may contribute to the reservoir that has made developing a cure for HIV infections a challenging goal.
The scope of research conducted by HIV DRP scientists has expanded over the years to encompass a broader range of important problems in retrovirus biology. Thus, in 2015, the name of the Program was changed to HIV Dynamics and Replication to better capture the breadth of the research carried out by the Program.
The HIV DRP comprises a basic research component (Retroviral Replication Laboratory) and a clinical component (Host-Virus Interaction Branch).
The Retroviral Replication Laboratory (RRL) focuses on obtaining a detailed understanding of important events in the life cycle of human retroviruses, with a primary focus on HIV-1, from the initial interactions between the virion and the host cell through reverse transcription and integration to mechanisms of virus assembly and release. There is extensive work on the biochemistry and biology of viral replication, drug resistance, recombination, and the generation of mutations. Studies also include discovery, development, and mechanistic analysis of novel replication inhibitors, as well as whole-organism studies, including development of important animal models, and the development and use of retroviral vectors. The RRL is composed of six Sections: The Vector Design and Replication Section, directed by Dr. Stephen H. Hughes, has two principal areas of research interest: 1) HIV-1 reverse transcriptase (RT); and 2) HIV-1 integrase. The Retrovirus Assembly Section, led by Dr. Alan Rein, has been focusing primarily on the roles of elements of the Gag protein, nucleic acid, and host factors in virus assembly. The Virus-Cell Interaction Section, under the direction of Dr. Eric O. Freed, is well known for its work on the assembly and release of HIV-1 from infected cells and the host factors essential for efficient assembly and release. The Viral Recombination Section, directed by Dr. Wei-Shau Hu, focuses on mechanisms of recombination, RNA packaging, and virus assembly. The Viral Mutation Section, headed by Dr. Vinay K. Pathak, focuses on in vivo mechanisms of reverse transcription, APOBEC, RT template switching, and how mutations in the C-terminal portion of RT contribute to resistance to both nucleoside RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). The Antiviral Immunity and Resistance Section, led by Dr. Alex Compton, focuses on mechanisms of protection mediated by the cell-intrinsic innate immune response, as well as the strategies employed by HIV and emerging viruses to evade or overcome these immune barriers.
As the clinical arm of the HIV DRP, the Host-Virus Interaction Branch (HVIB) conducts fundamental studies on the nature of HIV drug resistance in vivo. The HVIB has developed sensitive and specific tools that are being used to address questions of HIV-1 population genetics, replication dynamics, and emergence of resistance in infected individuals. Ongoing studies are focused on the following objectives: characterizing the replicating population size and genetics of HIV in infected individuals before, during, and after antiretroviral therapy (ART); defining the genetic mechanisms, kinetics of emergence and decay, and clinical consequences of HIV drug resistance; identifying the tissue and cellular sources of persistent viremia despite suppressive ART; and testing novel therapeutics to reduce persistent viremia and deplete HIV reservoirs.
The HVIB comprises several elements.
The Clinical Retrovirology Section, headed by Dr. Frank Maldarelli, directs the protocol development, regulatory affairs, patient recruitment, and sample collection effort for the HVIB at the NIH Clinical Center, in collaboration with the AIDS clinical research programs of the National Cancer Institute (HAMB, Dr. Robert Yarchoan), the National Institute of Allergy and Infectious Diseases (Dr. H. Clifford Lane), and the Critical Care Medicine Department (Dr. Henry Masur). The Clinical Retrovirology Section also conducts fundamental studies of HIV pathogenesis in vivo, including studies of HIV genetic variation and the emergence of antiretroviral drug resistance.
The Translational Research Unit, led by Dr. Mary Kearney, works in concert with the Clinical Retrovirology Section by developing and applying new technologies to characterize and identify sources of persistent HIV-1 viremia despite ART and to evaluate the impact of HIV-1 genetic diversity and low-frequency drug resistance mutations on response to ART. Dr. John Mellors (Chief, Division of Infectious Diseases, and Director, HIV/AIDS Program, University of Pittsburgh) provides critical consultation on all aspects of HIV clinical research, including protocol design and implementation. Dr. Mellors provides an invaluable interface with the extramural academic HIV/AIDS, including the AIDS Clinical Trials Group and international collaborative trials, making possible the Program's participation in major multicenter trials. The Mellors laboratory also collaborates closely with the HVIB on development of novel laboratory techniques for analysis of clinical material, and in basic studies of the mechanism of resistance to reverse transcriptase inhibitors. Dr. John Coffin (American Cancer Society Research Professor of Molecular Biology and Microbiology at Tufts University and founding Director of the HIV DRP) now serves as advisor to the Director of the Center for Cancer Research and consultant to the clinical program, providing critical advice on all aspects of the HVIB's research, particularly in the areas of assay design, development, and evaluation; data analysis and interpretation; and basic and clinical research approaches.
modified: 10 January 2018